69 results on '"Koichi Obata"'
Search Results
2. FLIPPIN': Exploring a Paper-based Book UI Design in a Public Space.
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Koichi Yoshino, Koichi Obata, and Satoru Tokuhisa
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- 2017
- Full Text
- View/download PDF
3. MeLight: Embodied Appreciation of 'Inouzu'.
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Mina Shibasaki, Karin Iwazaki, Minato Takeda, Youichi Kamiyama, Koichi Obata, Koichi Yoshino, Shimizu Endo, Satoru Tokuhisa, and Kouta Minamizawa
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- 2017
- Full Text
- View/download PDF
4. Interest Arousal by Haptic Feedback During a Storytelling for Kindergarten Children
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Shinkuro Tsuchiya, Elaine Czech, Soichiro Matsuda, Kouta Minamizawa, Mina Shibasaki, Koichi Obata, Takayuki Hasegawa, Keisuke Kishi, Yusuke Wakamoto, and Youichi Kamiyama
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Focus (computing) ,Picture books ,05 social sciences ,ComputingMilieux_PERSONALCOMPUTING ,020207 software engineering ,02 engineering and technology ,Field tests ,Space (commercial competition) ,Arousal ,User studies ,0202 electrical engineering, electronic engineering, information engineering ,Mathematics education ,0501 psychology and cognitive sciences ,Psychology ,050107 human factors ,Storytelling ,Haptic technology - Abstract
In this paper, we introduce “Kinder BURU BURU cushion” a vibrotactile cushion that is used during storytelling time to grab the attention of children to help them to focus on the story. We conducted field tests using our system, which confirmed that children were more interested in a story when using our system compared to normal storytelling. For this research, we collaborated with a printing company and a picture book company, designed our system based on user studies at a kid’s space, and conducted empirical field experiments.
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- 2020
5. FLIPPIN'
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Koichi Obata, Koichi Yoshino, and Satoru Tokuhisa
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business.industry ,Computer science ,05 social sciences ,020207 software engineering ,Usability ,02 engineering and technology ,Paper based ,Field (computer science) ,World Wide Web ,Public space ,Human–computer interaction ,0202 electrical engineering, electronic engineering, information engineering ,Information system ,0501 psychology and cognitive sciences ,User interface ,business ,050107 human factors - Abstract
Digital information systems are increasingly being used in public spaces such as museums. Such systems should be easily accessible, arouse interest and offer useful information, and be easy to use. We present FLIPPIN' user interface (UI) system, which mimics the look, feel, and usability of traditional books. We explored how the paper-based book UI is designed to improve the usability problems in a public space while creating the prototypes with the aim of introducing Japanese cultural assets and conducting a field evaluation to compare the proposed system to a touch panel UI. The results of evaluation indicated the positive effects of the system, especially in terms of the usability and user's active appreciation derived from a physical book interaction. In addition, we present design guidelines derived from our findings. The suggested design guidelines are expected to facilitate the future development of effective interactive digital information systems in public spaces.
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- 2017
6. MeLight
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Youich Kamiyama, Shimizu Endo, Mina Shibasaki, Karin Iwazaki, Satoru Tokuhisa, Kouta Minamizawa, Koichi Obata, Koichi Yoshino, and Minato Takeda
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Embodied cognition ,National museum ,Computer science ,05 social sciences ,0202 electrical engineering, electronic engineering, information engineering ,020201 artificial intelligence & image processing ,0501 psychology and cognitive sciences ,02 engineering and technology ,Physical interaction ,Cultural artifact ,050107 human factors ,Visual arts - Abstract
The purpose of this study was to make the appreciation in the museum that visitors understood precious cultural artifacts more deeply. We designed an embodied appreciation system called MeLight that allows various visitors including children to actively appreciate exhibits they are interested in. MeLight was installed in the Tokyo National Museum. We observed users during use of MeLight, and it seemed that they often traced the contour of coastlines with the flashlight device. As a result, it was effective to design, implement and introduce a system in which visitors used physical interaction to trigger active appreciation of and interest in the museum's cultural assets.
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- 2017
7. Comparative study of the distribution of the α-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons
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Koichi Obata, Koichi Noguchi, Tetsuo Fukuoka, Yi Dai, Kimiko Kobayashi, and Hiroki Yamanaka
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Glial Cell Line-Derived Neurotrophic Factor Receptors ,Molecular Sequence Data ,Tropomyosin receptor kinase A ,Tropomyosin receptor kinase C ,Sodium Channels ,Dorsal root ganglion ,Neurofilament Proteins ,Neurotrophic factors ,Ganglia, Spinal ,Glial cell line-derived neurotrophic factor ,medicine ,Animals ,Protein Isoforms ,Receptor, trkC ,RNA, Messenger ,Receptor, trkA ,Horseradish Peroxidase ,In Situ Hybridization ,Cell Size ,Neurons ,biology ,General Neuroscience ,Sodium channel ,Immunohistochemistry ,Rats ,Cell biology ,Electrophysiology ,medicine.anatomical_structure ,Nerve growth factor ,nervous system ,biology.protein ,Neuroscience - Abstract
We compared the distribution of the alpha-subunit mRNAs of voltage-gated sodium channels Nav1.1-1.3 and Nav1.6-1.9 and a related channel, Nax, in histochemically identified neuronal subpopulations of the rat dorsal root ganglia (DRG). In the naïve DRG, the expression of Nav1.1 and Nav1.6 was restricted to A-fiber neurons, and they were preferentially expressed by TrkC neurons, suggesting that proprioceptive neurons possess these channels. Nav1.7, -1.8, and -1.9 mRNAs were more abundant in C-fiber neurons compared with A-fiber ones. Nax was evenly expressed in both populations. Although Nav1.8 and -1.9 were preferentially expressed by TrkA neurons, other alpha-subunits were expressed independently of TrkA expression. Actually, all IB4(+) neurons expressed both Nav1.8 and -1.9, and relatively limited subpopulations of IB4(+) neurons (3% and 12%, respectively) expressed Nav1.1 and/or Nav1.6. These findings provide useful information in interpreting the electrophysiological characteristics of some neuronal subpopulations of naïve DRG. After L5 spinal nerve ligation, Nav1.3 mRNA was up-regulated mainly in A-fiber neurons in the ipsilateral L5 DRG. Although previous studies demonstrated that nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) reversed this up-regulation, the Nav1.3 induction was independent of either TrkA or GFRalpha1 expression, suggesting that the induction of Nav1.3 may be one of the common responses of axotomized DRG neurons without a direct relationship to NGF/GDNF supply.
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- 2008
8. Activation of Extracellular Signal-Regulated Protein Kinase in Sensory Neurons After Noxious Gastric Distention and Its Involvement in Acute Visceral Pain in Rats
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Jun Sakurai, Kan Miyoshi, Kimiko Kobayashi, Yasuo Sugiura, Takayuki Matsumoto, Yi Dai, Takashi Kondo, Hiroki Yamanaka, Atsushi Tokunaga, Koichi Noguchi, Koichi Obata, Noriyuki Ozaki, and Hiroto Miwa
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,TRPV Cation Channels ,Nerve Tissue Proteins ,Stimulation ,Mitogen-activated protein kinase kinase ,Splanchnic nerves ,Sodium Channels ,Catheterization ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Neurofilament Proteins ,Ganglia, Spinal ,Physical Stimulation ,Internal medicine ,Nitriles ,Butadienes ,medicine ,Animals ,Neurons, Afferent ,Enzyme Inhibitors ,Acid-sensing ion channel ,Mitogen-Activated Protein Kinase 3 ,Hepatology ,Electromyography ,business.industry ,Stomach ,Gastroenterology ,Membrane Proteins ,Nodose Ganglion ,Visceral pain ,Vagotomy ,Immunohistochemistry ,Abdominal Pain ,Rats ,Acid Sensing Ion Channels ,Enzyme Activation ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Gastric Emptying ,nervous system ,Acute Disease ,medicine.symptom ,business - Abstract
Background & Aims: Changes in the properties of visceral sensory neurons contribute to the development of gastrointestinal pain. However, little is known about the molecules involved in mechanosensation from the gastrointestinal tract. We investigated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase cascade, in dorsal root ganglion (DRG) and nodose ganglion (NG) neurons by noxious gastric distention (GD) and its involvement in acute visceral pain in rats. Methods: Electromyographic responses to gastric balloon distention through gastrostomy were recorded from the acromiotrapezius muscle in rats after splanchnic nerve resection or vagotomy and in control rats. We then examined the phosphorylated-ERK1/2 (p-ERK1/2) labeling in the DRG and NG after GD using immunohistochemistry. Results: Gastric distention induced p-ERK1/2 in DRG and NG neurons with a peak at 2 minutes after stimulation. We found a stimulus intensity-dependent increase in the number of activated neurons, and this activation corresponded well with the incidence of the visceromotor response. Most of these p-ERK1/2–labeled neurons were small- and medium-sized neurons that coexpressed transient receptor potential vanilloid 1 ion channel and acid-sensing ion channel 3. Splanchnic nerve resection, but not vagotomy, affected the visceromotor response, and attenuated the ERK1/2 activation in DRG neurons produced by GD. Furthermore, intrathecal administration of the mitogen-activated protein kinase kinase 1/2 inhibitor, U0126, altered the response to noxious GD. Conclusions: The activation of ERK1/2 pathways in DRG neurons by noxious GD may be correlated with functional activity, and may be involved in acute visceral pain.
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- 2008
9. Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain
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Makoto Tominaga, Tetsuo Fukuoka, Xiuyu Cui, Shenglan Wang, Koichi Obata, Yi Dai, Koichi Noguchi, Hiroki Yamanaka, and Kimiko Kobayashi
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Ankyrins ,Male ,medicine.medical_specialty ,Patch-Clamp Techniques ,Pain ,Bradykinin ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Isothiocyanates ,Ganglia, Spinal ,Internal medicine ,medicine ,Animals ,Humans ,Bradykinin receptor ,Protein kinase A ,TRPA1 Cation Channel ,Cells, Cultured ,Protein kinase C ,TRPC Cation Channels ,Inflammation ,Dose-Response Relationship, Drug ,Phospholipase C ,Drug Synergism ,Long-term potentiation ,Cyclic AMP-Dependent Protein Kinases ,Rats ,Cell biology ,Endocrinology ,chemistry ,Type C Phospholipases ,Hyperalgesia ,Nociceptor ,Calcium Channels ,Neurology (clinical) ,medicine.symptom ,Signal Transduction - Abstract
Bradykinin is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia in inflamed tissues by exciting and/or sensitizing nociceptors. TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain. Here, using electrophysiological, immunocytochemical and behavioural analyses, we showed a functional interaction of these two inflammation-related molecules in both heterologous expressing systems and primary sensory neurons. We found that bradykinin increased the TRPA1 currents evoked by allyl isothiocyanate (AITC) or cinnamaldehyde in HEK293 cells expressing TRPA1 and bradykinin receptor 2 (B2R). This potentiation was inhibited by phospholipase C (PLC) inhibitor or protein kinase A (PKA) inhibitor, and mimicked by PLC or PKA activator. The functional interaction between B2R and TRPA1, as well as the modulation mechanism, was also observed in rat dorsal root ganglia neurons. In an occlusion experiment, the PLC activator could enhance AITC-induced TRPA1 current further even in saturated PKA-mediated potentiation, indicating the additive potentiating effects of the PLC and PKA pathways. These data for the first time indicate that a cAMP-PKA signalling is involved in the downstream from B2R in dorsal root ganglia neurons in addition to PLC. Finally, subcutaneous pre-injection of a sub-inflammatory dose of bradykinin into rat hind paw enhanced AITC-induced pain behaviours, which was consistent with the observations in vitro. Collectively, these results represent a novel mechanism through which bradykinin released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.
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- 2008
10. THIS ARTICLE HAS BEEN RETRACTED: Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury
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Koichi Noguchi, Hiroki Yamanaka, Tetsuo Fukuoka, Koichi Obata, Hirokazu Katsura, Kan Miyoshi, Kimiko Kobayashi, Takashi Kondo, Yi Dai, and Shizuo Akira
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Toll-like receptor ,Microglia ,business.industry ,Central nervous system ,Hyperesthesia ,chemical and pharmacologic phenomena ,Nerve injury ,Spinal cord ,Biochemistry ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Peripheral nerve injury ,medicine ,Neuroglia ,medicine.symptom ,business ,Neuroscience - Abstract
Toll-like receptors (TLRs) play an essential role in innate immune responses and in the initiation of adaptive immune responses. Microglia, the resident innate immune cells in the CNS, express TLRs. In this study, we show that TLR3 is crucial for spinal cord glial activation and tactile allodynia after peripheral nerve injury. Intrathecal administration of TLR3 antisense oligodeoxynucleotide suppressed nerve injury-induced tactile allodynia, and decreased the phosphorylation of p38 mitogen-activated protein kinase, but not extracellular signal-regulated protein kinases 1/2, in spinal glial cells. Antisense knockdown of TLR3 also attenuated the activation of spinal microglia, but not astrocytes, caused by nerve injury. Furthermore, down-regulation of TLR3 inhibited nerve injury-induced up-regulation of spinal pro-inflammatory cytokines, such as interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha. Conversely, intrathecal injection of the TLR3 agonist polyinosine-polycytidylic acid induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Indeed, TLR3-deficient mice did not develop tactile allodynia after nerve injury or polyinosine-polycytidylic acid injection. Our results indicate that TLR3 has a substantial role in the activation of spinal glial cells and the development of tactile allodynia after nerve injury. Thus, blocking TLR3 in the spinal glial cells might provide a fruitful strategy for treating neuropathic pain.
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- 2008
11. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury
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Takashi Kondo, Hiroki Yamanaka, Masafumi Sakagami, Yi Dai, Koichi Obata, Koichi Noguchi, Hirokazu Katsura, Tetsuo Fukuoka, Kan Miyoshi, and Kimiko Kobayashi
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Male ,MAPK/ERK pathway ,Time Factors ,p38 mitogen-activated protein kinases ,TRPV1 ,Down-Regulation ,Biology ,p38 Mitogen-Activated Protein Kinases ,Gene Expression Regulation, Enzymologic ,Oligodeoxyribonucleotides, Antisense ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Mitogen-Activated Protein Kinase 8 ,Protein kinase A ,Spinal Cord Injuries ,Microglia ,Kinase ,Nerve injury ,MAP Kinase Kinase Kinases ,Hindlimb ,Rats ,Kinetics ,Spinal Nerves ,medicine.anatomical_structure ,Spinal Cord ,Neurology ,Sensory Thresholds ,Peripheral nerve injury ,medicine.symptom ,Neuroscience - Abstract
Mitogen-activated protein kinase (MAPK) plays an important role in the induction and maintenance of neuropathic pain. Transforming growth factor-activated kinase 1 (TAK1), a member of the MAPK kinase kinase family, is indispensable for the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We now show that TAK1 induced in spinal cord astrocytes is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in the expression of TAK1 in the ipsilateral dorsal horn, and TAK1 was increased in hyperactive astrocytes, but not in neurons or microglia. Intrathecal administration of TAK1 antisense oligodeoxynucleotide (AS-ODN) prevented and reversed nerve injury-induced mechanical, but not heat hypersensitivity. Furthermore, TAK1 AS-ODN suppressed the activation of JNK1, but not p38 MAPK, in spinal astrocytes. In contrast, there was no change in TAK1 expression in primary sensory neurons, and TAK1 AS-ODN did not attenuate the induction of transient receptor potential ion channel TRPV1 in sensory neurons. Taken together, these results demonstrate that TAK1 upregulation in spinal astrocytes has a substantial role in the development and maintenance of mechanical hypersensitivity through the JNK1 pathway. Thus, preventing the TAK1/JNK1 signaling cascade in astrocytes might provide a fruitful strategy for treating intractable neuropathic pain. © 2008 Wiley-Liss, Inc.
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- 2008
12. Differential Activation of p38 and Extracellular Signal-Regulated Kinase in Spinal Cord in a Model of Bee Venom-Induced Inflammation and Hyperalgesia
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Hiroki Yamanaka, Kimiko Kobayashi, Xiuyu Cui, Koichi Noguchi, Koichi Obata, Yi Dai, Shenglan Wang, and Jun Chen
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Male ,Pain Threshold ,MAPK/ERK pathway ,Pyridines ,Mitogen-Activated Protein Kinase 3 ,p38 mitogen-activated protein kinases ,Inflammation ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Nitriles ,Threshold of pain ,Butadienes ,Hypersensitivity ,lcsh:Pathology ,medicine ,Animals ,Extracellular Signal-Regulated MAP Kinases ,Protein kinase A ,business.industry ,Research ,Imidazoles ,Immunohistochemistry ,Rats ,Enzyme Activation ,Bee Venoms ,Sting ,Anesthesiology and Pain Medicine ,Spinal Cord ,Hyperalgesia ,Immunology ,Molecular Medicine ,medicine.symptom ,business ,lcsh:RB1-214 - Abstract
Background: Honeybee's sting on human skin can induce ongoing pain, hyperalgesia and inflammation. Injection of bee venom (BV) into the intraplantar surface of the rat hindpaw induces an early onset of spontaneous pain followed by a lasting thermal and mechanical hypersensitivity in the affected paw. The underlying mechanisms of BV-induced thermal and mechanical hypersensitivity are, however, poorly understood. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK) in the generation of BV-induced pain hypersensitivity. Results: We found that BV injection resulted in a quick activation of p38, predominantly in the L4/L5 spinal dorsal horn ipsilateral to the inflammation from 1 hr to 7 d post-injection. Phosphorylated p38 (p-p38) was expressed in both neurons and microglia, but not in astrocytes. Intrathecal administration of the p38 inhibitor, SB203580, prevented BV-induced thermal hypersensitivity from 1 hr to 3 d, but had no effect on mechanical hypersensitivity. Activated ERK1/2 was observed exclusively in neurons in the L4/L5 dorsal horn from 2 min to 1 d, peaking at 2 min after BV injection. Intrathecal administration of the MEK inhibitor, U0126, prevented both mechanical and thermal hypersensitivity from 1 hr to 2 d. p-ERK1/2 and p-p38 were expressed in neurons in distinct regions of the L4/L5 dorsal horn; p-ERK1/2 was mainly in lamina I, while p-p38 was mainly in lamina II of the dorsal horn. Conclusion: The results indicate that differential activation of p38 and ERK1/2 in the dorsal horn may contribute to the generation and development of BV-induced pain hypersensitivity by different mechanisms.
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- 2008
13. Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation
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Toshiyuki Mizushima, Jun Sakurai, Koichi Noguchi, Tetsuo Fukuoka, Masafumi Sakagami, Yi Dai, Kimiko Kobayashi, Hirokazu Katsura, Koichi Obata, and Hiroki Yamanaka
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biology ,Chemistry ,TRPV1 ,Biochemistry ,Sensory neuron ,Cell biology ,Cellular and Molecular Neuroscience ,Transient receptor potential channel ,medicine.anatomical_structure ,nervous system ,Dorsal root ganglion ,Anesthesia ,Mitogen-activated protein kinase ,Hyperalgesia ,medicine ,biology.protein ,Phosphorylation ,medicine.symptom ,Protein kinase A - Abstract
Heat and cold hyperalgesia is a common feature of inflammatory pain. To investigate whether activation of extracellular signal-regulated protein kinase 5 (ERK5), also known as big mitogen-activated protein kinase 1, in primary sensory neurons participates in inflammatory pain, we examined the phosphorylation of ERK5 in the dorsal root ganglion (DRG) after peripheral inflammation. Inflammation induced by complete Freund's adjuvant produced heat and cold hyperalgesia on the ipsilateral hind paw and induced an increase in the phosphorylation of ERK5, mainly in tyrosine kinase A-expressing small- and medium-size neurons. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. ERK5 antisense, but not mismatch, oligodeoxynucleotide decreased the activation of ERK5 and suppressed inflammation-induced heat and cold hyperalgesia. Furthermore, the inhibition of ERK5 blocked the induction of transient receptor potential channel TRPV1 and TRPA1 expression in DRG neurons after peripheral inflammation. Our results show that ERK5 activated in DRG neurons contribute to the development of inflammatory pain. Thus, blocking ERK5 signaling in sensory neurons that has the potential for preventing pain after inflammation.
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- 2007
14. Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain
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Koichi Obata, Toshiyuki Mizushima, Hirokazu Katsura, Jun Sakurai, Tetsuo Fukuoka, Kimiko Kobayashi, Hiroki Yamanaka, Yi Dai, and Koichi Noguchi
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Brain-derived neurotrophic factor ,business.industry ,Central nervous system ,Nerve injury ,Biochemistry ,Sensory neuron ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,nervous system ,Dorsal root ganglion ,Neurotrophic factors ,Peripheral nerve injury ,Neuropathic pain ,medicine ,medicine.symptom ,business ,Neuroscience - Abstract
Neuropathic pain that occurs after peripheral nerve injury is poorly controlled by current therapies. Increasing evidence shows that mitogen-activated protein kinase (MAPK) play an important role in the induction and maintenance of neuropathic pain. Here we show that activation of extracellular signal-regulated protein kinases 5 (ERK5), also known as big MAPK1, participates in pain hypersensitivity caused by nerve injury. Nerve injury increased ERK5 phosphorylation in spinal microglia and in both damaged and undamaged dorsal root ganglion (DRG) neurons. Antisense knockdown of ERK5 suppressed nerve injury-induced neuropathic pain and decreased microglial activation. Furthermore, inhibition of ERK5 blocked the induction of transient receptor potential channels and brain-derived neurotrophic factor expression in DRG neurons. Our results show that ERK5 activated in spinal microglia and DRG neurons contributes to the development of neuropathic pain. Thus, blocking ERK5 signaling in the spinal cord and primary afferents has potential for preventing pain after nerve damage.
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- 2007
15. Alteration of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain
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Yi Dai, Koichi Noguchi, Koichi Obata, Kimiko Kobayashi, Hiroki Yamanaka, and Tetsuo Fukuoka
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animal structures ,medicine.diagnostic_test ,Chemistry ,General Neuroscience ,Spinal cord ,Cell biology ,Nociception ,medicine.anatomical_structure ,Western blot ,Dorsal root ganglion ,Neuropathic pain ,Peripheral nerve injury ,medicine ,Extracellular ,Sciatic nerve ,Neuroscience - Abstract
The cell adhesion molecule L1 (L1-CAM) plays important functional roles in the developing and adult nervous systems. Here we show that peripheral nerve injury induced dynamic post-transcriptional alteration of L1-CAM in the rat dorsal root ganglia (DRGs) and spinal cord. Sciatic nerve transection (SCNT) changed the expression of L1-CAM protein but not L1-CAM mRNA. In DRGs, SCNT induced accumulation of the L1-CAM into the surface of somata, which resulted in the formation of immunoreactive ring structures in a number of unmyelinated C-fiber neurons. These neurons with L1-CAM-immunoreactive ring structures were heavily colocalized with phosphorylated p38 MAPK. Western blot analysis revealed the increase of full-length L1-CAM and decrease of fragments of L1-CAM after SCNT in DRGs. Following SCNT, L1-CAM-immunoreactive profiles in the dorsal horn showed an increase mainly in pre-synaptic areas of laminae I–II with a delayed onset and colocalized with growth-associated protein 43. In contrast to DRGs, SCNT increased the proteolytic 80-kDa fragment of L1-CAM and decreased full-length L1-CAM in the spinal cord. The intrathecal injection of L1-CAM antibody for the extracellular domain of L1-CAM inhibited activation of p38 MAPK and emergence of ring structures of L1-CAM immunoreactivity in injured DRG neurons. Moreover, inhibition of extracellular L1-CAM binding by intrathecal administration of antibody suppressed the mechanical allodynia and thermal hyperalgesia induced by partial SCNT. Collectively, these data suggest that the modification of L1-CAM in nociceptive pathways might be an important pathomechanism of neuropathic pain.
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- 2007
16. Intensity-Dependent Activation of Extracellular Signal-Regulated Protein Kinase 5 in Sensory Neurons Contributes to Pain Hypersensitivity
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Hirokazu Katsura, Jun Sakurai, Toshiyuki Mizushima, Kimiko Kobayashi, Hiroki Yamanaka, Takashi Mashimo, Yi Dai, Koichi Noguchi, Koichi Obata, and Tetsuo Fukuoka
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Male ,Hot Temperature ,Blotting, Western ,TRPV1 ,TRPV Cation Channels ,Rats, Sprague-Dawley ,Transient receptor potential channel ,chemistry.chemical_compound ,Dorsal root ganglion ,medicine ,Noxious stimulus ,Animals ,RNA, Antisense ,Neurons, Afferent ,Phosphorylation ,Protein kinase A ,In Situ Hybridization ,Mitogen-Activated Protein Kinase 6 ,Pharmacology ,Behavior, Animal ,Chemistry ,Diffuse noxious inhibitory control ,Immunohistochemistry ,Rats ,Cell biology ,Cold Temperature ,Enzyme Activation ,Posterior Horn Cells ,medicine.anatomical_structure ,nervous system ,Hyperalgesia ,Capsaicin ,Molecular Medicine ,medicine.symptom ,Neuroscience ,Signal Transduction - Abstract
Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.
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- 2007
17. Suppression of the p75 Neurotrophin Receptor in Uninjured Sensory Neurons Reduces Neuropathic Pain after Nerve Injury
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Koichi Obata, Kimiko Kobayashi, Koichi Noguchi, Tetsuo Fukuoka, Hiroki Yamanaka, Jun Sakurai, Hirokazu Katsura, and Yi Dai
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Male ,Down-Regulation ,TRPV Cation Channels ,Tropomyosin receptor kinase A ,Axonal Transport ,Receptor, Nerve Growth Factor ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,Transient receptor potential channel ,Dorsal root ganglion ,Ganglia, Spinal ,Animals ,Medicine ,Low-affinity nerve growth factor receptor ,Neurons, Afferent ,Phosphorylation ,Receptor, trkA ,Ligation ,business.industry ,General Neuroscience ,Peripheral Nervous System Diseases ,Articles ,Nerve injury ,Denervation ,Rats ,Disease Models, Animal ,Spinal Nerves ,medicine.anatomical_structure ,Nerve growth factor ,nervous system ,Hyperalgesia ,Neuropathic pain ,Neuralgia ,sense organs ,medicine.symptom ,business ,Neuroscience - Abstract
The p75 neurotrophin receptor (p75NTR) has been implicated in diverse neuronal responses, including survival, cell death, myelination, and inhibition of regeneration. However, the role of p75NTR in neuropathic pain, for which there is currently no effective therapy, has not been explored. Here, we report that the pharmacological blockade of p75NTR in primary sensory neurons reversed neuropathic pain after nerve injury. Nerve injury increased the expression and axonal transport of p75NTR and phosphorylation of TrkA in the uninjured primary afferents. Functional inhibition of p75NTR suppressed injury-induced neuropathic pain and decreased the phosphorylation of TrkA and p38 mitogen-activated protein kinase, and the induction of transient receptor potential channels in dorsal root ganglion (DRG) neurons. Our results show that p75NTR induced in undamaged DRG neurons facilitates TrkA signaling and contributes to heat and cold hyperalgesia.
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- 2006
18. The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint
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Atsushi Tokunaga, Koichi Noguchi, Hiroki Yamanaka, Yi Dai, Shinichi Yoshiya, Daisuke Seino, Koichi Obata, Toshiya Tachibana, and Kimiko Kobayashi
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Male ,MAPK/ERK pathway ,Freund's Adjuvant ,Arthritis ,Osteoarthritis ,Knee Joint ,Axonal Transport ,Injections, Intra-Articular ,Rats, Sprague-Dawley ,Adenosine Triphosphate ,Dorsal root ganglion ,Ganglia, Spinal ,Purinergic P2 Receptor Antagonists ,Phosphorylation ,Range of Motion, Articular ,Extracellular Signal-Regulated MAP Kinases ,Injections, Spinal ,MEK inhibitor ,Osteoarthritis, Knee ,Stifle ,medicine.anatomical_structure ,Neurology ,Hyperalgesia ,Joint pain ,Anesthesia ,medicine.symptom ,Signal Transduction ,musculoskeletal diseases ,medicine.medical_specialty ,Pain ,Internal medicine ,Nitriles ,Butadienes ,medicine ,Animals ,Neurons, Afferent ,Receptors, Purinergic P2 ,business.industry ,medicine.disease ,Arthritis, Experimental ,Rats ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,Endocrinology ,Stress, Mechanical ,Neurology (clinical) ,Neuron ,business ,Protein Processing, Post-Translational ,Receptors, Purinergic P2X3 - Abstract
Pain during inflammatory joint diseases is enhanced by the generation of hypersensitivity in nociceptive neurons in the peripheral nervous system. To explore the signaling mechanisms of mechanical hypersensitivity during joint inflammation, experimental arthritis was induced by injection of complete Freund's adjuvant (CFA) into the synovial cavity of rat knee joints. As a pain index, the struggle threshold of the knee extension angle was measured. In rats with arthritis, the phosphorylation of extracellular signal-regulated kinase (ERK), induced by passive joint movement, increased significantly in dorsal root ganglion (DRG) neurons innervating the knee joint compared to the naïve rats that received the same movement. The intrathecal injection of a MEK inhibitor, U0126, reduced the phosphorylation of ERK in DRG neurons and alleviated the struggle behavior elicited by the passive movement of the joint. In addition, the injection of U0126 into the joint also reduced the struggle behavior. These findings indicate that the ERK signaling is activated in both cell bodies in DRG neurons and peripheral nerve fibers and may be involved in the mechanical sensitivity of the inflamed joint. Furthermore, the phosphorylated ERK-positive neurons co-expressed the P2X3 receptor, and the injection of TNP-ATP, which antagonizes P2X receptors, into the inflamed joint reduced the phosphorylated ERK and the struggle behavior. Thus, it is suggested that the activation of the P2X3 receptor is involved in the phosphorylation of ERK in DRG neurons and the mechanical hypersensitivity of the inflamed knee joint.
- Published
- 2006
19. Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats
- Author
-
Toshiyuki Mizushima, Atsushi Tokunaga, Koichi Obata, Masafumi Sakagami, Tetsuo Fukuoka, Hiroki Yamanaka, Hirokazu Katsura, Koichi Noguchi, Yi Dai, and Kimiko Kobayashi
- Subjects
Ankyrins ,Male ,medicine.medical_specialty ,Time Factors ,TRPV1 ,TRPM Cation Channels ,Rats, Sprague-Dawley ,Developmental Neuroscience ,Dorsal root ganglion ,Internal medicine ,medicine ,TRPM8 ,Animals ,Ligation ,TRPA1 Cation Channel ,Pain Measurement ,TRPC Cation Channels ,business.industry ,Oligonucleotides, Antisense ,Nerve injury ,Calcium Channel Blockers ,Hindlimb ,Rats ,Cold Temperature ,Spinal Nerves ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Neurology ,Hyperalgesia ,Anesthesia ,Spinal nerve ,Gene Targeting ,Neuropathic pain ,Calcium Channels ,Neuron ,medicine.symptom ,business - Abstract
Patients with neuropathic pain frequently experience hypersensitivity to cold stimulation. However, the underlying mechanisms of this enhanced sensitivity to cold are not well understood. After partial nerve injury, the transient receptor potential ion channel TRPV1 increases in the intact small dorsal root ganglion (DRG) neurons in several neuropathic pain models. In the present study, we precisely examined the incidence of cold hyperalgesia and the changes of TRPA1 and TRPM8 expression in the L4 and L5 DRG following L5 spinal nerve ligation (SNL), because it is likely that the activation of two distinct populations of TRPA1- and TRPM8-expressing small neurons underlie the sensation of cold. We first confirmed that L5 SNL rats developed cold hyperalgesia for more than 14 days after surgery. In the nearby uninjured L4 DRG, TRPA1 mRNA expression increased in trkA-expressing small-to-medium diameter neurons from the 1st to 14th day after the L5 SNL. This upregulation corresponded well with the development and maintenance of nerve injury-induced cold hyperalgesia of the hind paw. In contrast, there was no change in the expression of the TRPM8 mRNA/protein in the L4 DRG throughout the 2-week time course of the experiment. In the injured L5 DRG, on the other hand, both TRPA1 and TRPM8 expression decreased over 2 weeks after ligation. Furthermore, intrathecal administration of TRPA1, but not TRPM8, antisense oligodeoxynucleotide suppressed the L5 SNL-induced cold hyperalgesia. Our data suggest that increased TRPA1 in uninjured primary afferent neurons may contribute to the exaggerated response to cold observed in the neuropathic pain model.
- Published
- 2006
20. Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord
- Author
-
Kimiko, Kobayashi, Tetsuo, Fukuoka, Hiroki, Yamanaka, Hirok, Iyamanaka, Yi, Dai, Koichi, Obata, Atsushi, Tokunaga, and Koichi, Noguchi
- Subjects
Male ,Tropomyosin receptor kinase B ,In situ hybridization ,Tropomyosin receptor kinase A ,Biology ,Tropomyosin receptor kinase C ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Animals ,Tissue Distribution ,RNA, Messenger ,Receptor ,In Situ Hybridization ,Neurons ,Microglia ,Receptors, Purinergic P2 ,General Neuroscience ,Spinal cord ,Immunohistochemistry ,Rats ,Cell biology ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,Neuroglia ,Neuroscience - Abstract
We examined the precise distribution of mRNAs for six cloned rat P2Y receptor subtypes, P2Y1, P2Y2, P2Y4, P2Y6, P2Y12, and P2Y14, in the dorsal root ganglion (DRG) and spinal cord by in situ hybridization histochemistry (ISHH) with 35S-labeled riboprobes. In the DRG, P2Y1 and P2Y2 mRNAs were expressed by 15% and 24% of all neurons, respectively. Although each receptor was evenly distributed between neurofilament-positive and -negative neurons, P2Y2 was rather selectively expressed by TrkA-positive neurons. Schwann cells expressed P2Y2 mRNA, and the nonneuronal cells around the DRG neurons, perhaps the satellite cells, expressed P2Y12 and P2Y14 mRNAs. No ISHH signals for P2Y4 or P2Y6 were seen in any cellular components of the DRG. In the spinal cord, P2Y1 and P2Y4 mRNAs were expressed by some of the dorsal horn neurons, whereas the motor neurons in the ventral horn had P2Y4 and P2Y6 mRNAs. In addition, astrocytes in the gray matter had P2Y1 mRNA, and the microglia throughout the spinal cord expressed P2Y12 mRNA. P2Y14 mRNA was weakly expressed by putative microglia. These findings should provide useful information in interpreting pharmacological and electrophysiological studies in this field given the lack of highly selective antagonists for each P2Y receptor subtype.
- Published
- 2006
21. Cold Receptors in the DRG: Basic Science and Clinical Implications
- Author
-
Kimiko Kobayashi, Koichi Noguchi, Koichi Obata, and Tetsuo Fukuoka
- Subjects
Anesthesiology and Pain Medicine ,Basic science ,business.industry ,Medicine ,business ,Receptor ,Neuroscience - Published
- 2006
22. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury
- Author
-
Yi Dai, Kimiko Kobayashi, Koichi Noguchi, Hirokazu Katsura, Koichi Obata, Hiroki Yamanaka, Makoto Tominaga, Toshiyuki Mizushima, Tetsuo Fukuoka, and Atsushi Tokunaga
- Subjects
Ankyrins ,Male ,MAP Kinase Signaling System ,TRPM Cation Channels ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Neurotrophic factors ,Ganglia, Spinal ,Nerve Growth Factor ,Glial cell line-derived neurotrophic factor ,medicine ,TRPM8 ,Animals ,Glial Cell Line-Derived Neurotrophic Factor ,Neurons, Afferent ,TRPA1 Cation Channel ,In Situ Hybridization ,Pain Measurement ,TRPC Cation Channels ,Inflammation ,biology ,Chemistry ,food and beverages ,General Medicine ,Nerve injury ,Rats ,Cold Temperature ,Nerve growth factor ,medicine.anatomical_structure ,nervous system ,Hyperalgesia ,Anesthesia ,biology.protein ,Nociceptor ,Calcium Channels ,medicine.symptom ,psychological phenomena and processes ,Research Article - Abstract
Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Inflammation and nerve injury increased TRPA1, but not TRPM8, expression in tyrosine kinase A-expressing dorsal root ganglion (DRG) neurons. Intrathecal administration of anti-nerve growth factor (anti-NGF), p38 MAPK inhibitor, or TRPA1 antisense oligodeoxynucleotide decreased the induction of TRPA1 and suppressed inflammation- and nerve injury-induced cold hyperalgesia. Conversely, intrathecal injection of NGF, but not glial cell line-derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.
- Published
- 2005
23. Ca2+/calmodulin-dependent protein kinase II in the spinal cord contributes to neuropathic pain in a rat model of mononeuropathy
- Author
-
Hiroki Yamanaka, Hu Wang, Akiko Ogawa, Yi Dai, Atsushi Tokunaga, Koichi Noguchi, and Koichi Obata
- Subjects
Male ,medicine.drug_class ,Central nervous system ,Pharmacology ,Receptors, N-Methyl-D-Aspartate ,environment and public health ,Rats, Sprague-Dawley ,Mononeuropathy ,Ca2+/calmodulin-dependent protein kinase ,Animals ,Medicine ,Phosphorylation ,business.industry ,Nerve Compression Syndromes ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,Mononeuropathies ,Spinal cord ,Receptor antagonist ,Rats ,Posterior Horn Cells ,Disease Models, Animal ,enzymes and coenzymes (carbohydrates) ,medicine.anatomical_structure ,Nociception ,nervous system ,Calcium-Calmodulin-Dependent Protein Kinases ,Chronic Disease ,Peripheral nerve injury ,Neuropathic pain ,cardiovascular system ,Neuralgia ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,business ,Neuroscience - Abstract
Ca 2 + /calmodulin-dependent protein kinase II (CaMKII) is known to subserve activity-dependent neuronal plasticity in the central nervous system. To examine in vivo the implication of spinal CaMKII activity in the generation and development of neuropathic pain after peripheral nerve injury, we used an animal model of mononeuropathy, the chronic constriction injury (CCI) model, in the rat. We found that, 3 days after CCI, the total CaMKII (tCaMKII) immunoreactivity increased in the superficial laminae of the spinal cord and this increase continued for up to 14 days. The immunoreactivity of phosphorylated CaMKII showed an increase from 1 day after CCI, which preceded the up-regulation of tCaMKII. A non-selective N-methyl-D-aspartate receptor antagonist, MK801, significantly attenuated the increase of tCaMKII and phosphorylated CaMKII. Moreover, intrathecal administration of an inhibitor of CaMKII, KN93, before the CCI surgery attenuated the development of thermal hyperalgesia and mechanical allodynia. In addition, KN93 significantly reduced the nociceptive behavior in phase II of the formalin test. These findings demonstrate that the activity of CaMKII in spinal neurons is elevated after peripheral nerve injury and may be involved in central sensitization. The alteration of CaMKII is considered to be a neuroplastic change that occurs in spinal neurons that contributes to neuropathic pain, suggesting the potential for the development of novel therapeutics for neuropathic pain that target CaMKII.
- Published
- 2005
24. Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats
- Author
-
Koichi Noguchi, Koichi Obata, Toshiyuki Mizushima, Tetsuo Fukuoka, Yi Dai, Hiroki Yamanaka, and Atsushi Tokunaga
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,business.industry ,General Neuroscience ,Nerve injury ,Intracellular signal transduction ,Endocrinology ,Nerve growth factor ,medicine.anatomical_structure ,nervous system ,Dorsal root ganglion ,Neurotrophic factors ,Internal medicine ,medicine ,Nociceptor ,Sciatic nerve ,medicine.symptom ,business ,Neuroscience - Abstract
To investigate the intracellular signal transduction pathways involved in the pathophysiological mechanisms of neuropathic pain after partial nerve injury, we examined the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglion (DRG) in the chronic constriction injury (CCI) model. The CCI induced an increase in the phosphorylation of ERK in predominantly injured medium-sized and large-sized DRG neurons and in satellite glial cells. Treatment with the MAPK kinase 1/2 inhibitor, U0126, suppressed CCI-induced mechanical allodynia and partially reversed the increase in neuropeptide Y (NPY) expression in damaged DRG neurons. In contrast, the CCI induced the activation of p38, mainly in uninjured small-to-medium-diameter DRG neurons and in satellite glial cells. The p38 inhibitor, SB203580, reversed the CCI-induced heat hyperalgesia and also the increase in brain-derived neurotrophic factor (BDNF) expression in intact DRG neurons. On the other hand, the nerve growth factor (NGF)-induced increase in BDNF expression in small-to-medium-diameter neurons was reversed by SB203580, whereas the anti-NGF-induced increase in NPY in medium-sized and large-sized neurons was partially blocked by U0126. Taken together, our results demonstrate that the activation of ERK and p38 and also the changes in NPY and BDNF expression may occur in different populations of DRG neurons after CCI, partially through alterations in the target-derived NGF. These changes in injured and intact primary afferents are likely to have a substantial role in pathological states, and MAPK pathways in nociceptors may be potential targets for the development of novel analgesics.
- Published
- 2004
25. Contribution of degeneration of motor and sensory fibers to pain behavior and the changes in neurotrophic factors in rat dorsal root ganglion
- Author
-
Yi Dai, Koichi Noguchi, Toshiyuki Mizushima, Atsushi Tokunaga, Hiroki Yamanaka, Tetsuo Fukuoka, Hideki Yoshikawa, and Koichi Obata
- Subjects
Male ,Wallerian degeneration ,medicine.medical_treatment ,Presynaptic Terminals ,Motor nerve ,Rhizotomy ,Rats, Sprague-Dawley ,Developmental Neuroscience ,Dorsal root ganglion ,Ganglia, Spinal ,Nerve Growth Factor ,Animals ,Medicine ,Nerve Growth Factors ,Neurons, Afferent ,Ganglionectomy ,Receptor, trkA ,Cell Size ,Motor Neurons ,Brain-derived neurotrophic factor ,Behavior, Animal ,business.industry ,Brain-Derived Neurotrophic Factor ,Lumbosacral Region ,Membrane Proteins ,Peripheral Nervous System Diseases ,Nerve injury ,medicine.disease ,Denervation ,Rats ,Up-Regulation ,Disease Models, Animal ,medicine.anatomical_structure ,nervous system ,Neurology ,Hyperalgesia ,Neuralgia ,medicine.symptom ,Carrier Proteins ,Spinal Nerve Roots ,Wallerian Degeneration ,business ,Neuroscience ,Sensory nerve - Abstract
To elucidate the role of the degeneration of motor and sensory fibers in neuropathic pain, we examined the pain-related behaviors and the changes of brain-derived neurotrophic factor (BDNF) in the L4/5 dorsal root ganglion (DRG) and the spinal cord after L5 ventral rhizotomy. L5 ventral rhizotomy, producing a selective lesion of motor fibers, produced thermal hyperalgesia and increased BDNF expression in tyrosine kinase A-containing small- and medium-sized neurons in the L5 DRG and their central terminations within the spinal cord, but not in the L4 DRG. Furthermore, L5 ventral rhizotomy up-regulated nerve growth factor (NGF) protein in small to medium diameter neurons in the L5 DRG and also in ED-1-positive cells in the L5 spinal nerve, suggesting that NGF synthesized in the degenerative fibers is transported to the L5 DRG and increases BDNF synthesis. On the other hand, L5 ganglionectomy, producing a selective lesion of sensory fibers, produced heat hypersensitivity and an increase in BDNF and NGF in the L4 DRG. These data indicate that degeneration of L5 sensory fibers distal to the DRG, but not motor fibers, might influence the neighboring L4 nerve fibers and induce neurotrophin changes in the L4 DRG. We suggest that these changes of neurotrophins in the intact primary afferents of neighboring nerves may be one of many complex mechanisms, which can explain the abnormal pain behaviors after nerve injury. The ventral rhizotomy and ganglionectomy models may be useful to investigate the pathophysiological mechanisms of neuropathic pain after Wallerian degeneration in motor or sensory or mixed nerve.
- Published
- 2004
26. Activation of extracellular signal-regulated protein kinase in dorsal horn neurons in the rat neuropathic intermittent claudication model
- Author
-
Yi Liu, Hiroki Yamanaka, Koichi Noguchi, Koichi Obata, Tetsuo Fukuoka, Atsushi Tokunaga, and Yi Dai
- Subjects
Male ,MAPK/ERK pathway ,medicine.medical_specialty ,MAP Kinase Signaling System ,Cauda equina syndrome ,Walking ,Rats, Sprague-Dawley ,Spinal Stenosis ,Internal medicine ,Nitriles ,Butadienes ,medicine ,Noxious stimulus ,Animals ,Alprostadil ,Enzyme Inhibitors ,Protein kinase A ,Analysis of Variance ,business.industry ,Intermittent Claudication ,Spinal cord ,medicine.disease ,Immunohistochemistry ,Intermittent claudication ,Sensory neuron ,Rats ,Posterior Horn Cells ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Endocrinology ,Neurology ,Anesthesia ,Neurology (clinical) ,Mitogen-Activated Protein Kinases ,medicine.symptom ,Claudication ,business - Abstract
Extracellular signal-regulated protein kinase (ERK) is a mitogen-activated protein kinase (MAPK) that mediates several cellular responses to mitogenic and differentiation signals, and activation of ERK in dorsal horn neurons by noxious stimulation is known to contribute to pain hypersensitivity. In order to elucidate the pathophysiological mechanisms of the cauda equina syndrome, secondary to spinal canal stenosis, we evaluated walking dysfunction triggered by forced exercise and activation of ERK in the dorsal horn using a rat model of neuropathic intermittent claudication. Rats in the lumbar canal stenosis (LCS) group showed a shorter running distance from 1 to 14 days after surgery. Two minutes after running on the treadmill apparatus, phosphorylation of ERK was induced in neurons in the superficial laminae in the LCS group but not in the sham group, whereas there was no change in the deeper laminae. Intrathecal administration of the MAPK kinase inhibitor, U0126, 30 min before running, clearly increased the running distance, whereas there was no significant change in the vehicle control group 3 days after surgery. In addition, a prostaglandin E1 analog, OP-1206 α-CD, administered orally, improved the walking dysfunction, and further, inhibited activation of ERK following running 7 days after surgery. These findings suggest that intermittent claudication triggered by forced walking might affect the phosphorylation of ERK in the superficial laminae, possibly via transient (partial) ischemia of the spinal cord. ERK activation in the dorsal horn neurons may be involved in the transient pain in the neuropathic intermittent claudication model.
- Published
- 2004
27. Enhancement of stimulation-induced ERK activation in the spinal dorsal horn and gracile nucleus neurons in rats with peripheral nerve injury
- Author
-
Yi Dai, Atsushi Tokunaga, Koichi Noguchi, Hiroki Yamanaka, Tetsuo Fukuoka, Hu Wang, and Koichi Obata
- Subjects
medicine.medical_specialty ,SNi ,Gracile nucleus ,business.industry ,General Neuroscience ,medicine.medical_treatment ,Stimulation ,Nerve injury ,Sciatic nerve injury ,medicine.disease ,Endocrinology ,nervous system ,Internal medicine ,Peripheral nerve injury ,medicine ,Sciatic nerve ,medicine.symptom ,Axotomy ,business ,Neuroscience - Abstract
It has been suggested that low-threshold sensory pathways have an important role in the formation and maintenance of sensory abnormalities which are observed after peripheral nerve injury. In the present study, we examined the involvement of these pathways in the development of hyperexcitability after sciatic nerve injury (SNI) by detecting the intracellular signal molecule. The rats that received a transection of the sciatic nerve 7 days before were electrically stimulated at 0.1 mA and 3 mA in the proximal region of the nerve injury site. We found a small number of phosphorylated extracellular signal-regulated kinase (pERK)-labelled neurons in laminae I-II and III-IV of the spinal dorsal horn in the control rats after 0.1 mA stimulation. By contrast, there was a marked increased of pERK-labelled neurons both in the superficial laminae and laminae III-IV after the same stimulation in the SNI rats. Enhancement of ERK activation induced by 3 mA stimulation was also observed. Immunoreactivity of pERK in gracile nucleus neurons was also dramatically increased after 0.1 mA stimulation to the injured nerve. These data suggest that the rats with peripheral nerve injury had an increased responsiveness to the low- or high-threshold peripheral stimuli in I-II, III-IV and gracile nucleus neurons. Furthermore, SNI rats that received neonatal capsaicin treatment showed a decreased number of pERK neurons after 0.1 mA stimulation in the dorsal horn and gracile nucleus neurons compared to the control rats. Thus, C-fibres may contribute to the enhanced excitability of the low-threshold sensory neurons after peripheral nerve injury.
- Published
- 2004
28. Activation of extracellular signal-regulated protein kinase in the dorsal root ganglion following inflammation near the nerve cell body
- Author
-
Yi Dai, Koichi Noguchi, Hiroki Yamanaka, Koichi Obata, Toshiyuki Mizushima, Atsushi Tokunaga, and Tetsuo Fukuoka
- Subjects
Male ,MAPK/ERK pathway ,medicine.medical_specialty ,Time Factors ,Blotting, Western ,Freund's Adjuvant ,Carbazoles ,Pain ,Cell Count ,Tropomyosin receptor kinase A ,Functional Laterality ,Indole Alkaloids ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Dorsal root ganglion ,Ganglia, Spinal ,Internal medicine ,Nerve Growth Factor ,Nitriles ,Butadienes ,Reaction Time ,medicine ,Animals ,Drug Interactions ,Enzyme Inhibitors ,Phosphorylation ,Radiculopathy ,Protein kinase A ,In Situ Hybridization ,Pain Measurement ,Neurons ,Brain-derived neurotrophic factor ,Behavior, Animal ,Dose-Response Relationship, Drug ,Brain-Derived Neurotrophic Factor ,General Neuroscience ,Immunohistochemistry ,Rats ,Endocrinology ,Nerve growth factor ,medicine.anatomical_structure ,Gene Expression Regulation ,nervous system ,chemistry ,Trk receptor ,K252a ,Mitogen-Activated Protein Kinases ,Spinal Nerve Roots - Abstract
Inflammation of the primary afferent proximal to the dorsal root ganglion (DRG) and the DRG itself is known to produce radicular pain. Here, we examined pain-related behaviors and the activation of extracellular signal-regulated protein kinase (ERK) in the DRG after inflammation near the DRG somata. Inflammation of the L4/5 nerve roots and DRG induced by complete Freund's adjuvant (CFA) produced mechanical allodynia on the ipsilateral hindpaw and induced an increase in the phosphorylation of ERK, mainly in tyrosine kinase (trk) A-expressing small- and medium-size neurons. This CFA-induced increase in ERK phosphorylation was mediated through trk receptors, because intrathecal treatment with the tyrosine kinase inhibitor, K252a, reduced the activation of ERK. On the other hand, an increase in brain-derived neurotrophic factor (BDNF) mRNA/protein in the DRG concomitant with the ERK activation was also observed. Furthermore, we found that nerve growth factor (NGF) injection directly into the L4/5 nerve roots and DRG produced mechanical allodynia, and an increase in the phosphorylation of ERK and BDNF expression in the DRG, but the mitogen-activated protein kinase (MAPK) kinase1/2 inhibitor, U0126, inhibited the effects induced by NGF. Therefore, we suggest that after inflammation near the cell body, NGF synthesized within the nerve root and DRG induces BDNF expression through trkA receptors and intracellular ERK-MAPK. The activation of MAPK in the primary afferents may be involved in the pathophysiological mechanisms of inflammation-induced radiculopathy and MAPK pathways in the primary afferents may be potential targets for pharmacological intervention for neuropathic pain produced by inflammation near the DRG somata.
- Published
- 2004
29. Expression of hepatocyte growth factor in primary sensory neurons of adult rats
- Author
-
Norio Hashimoto, Tetsuo Fukuoka, Hiroki Yamanaka, Takashi Mashimo, Koichi Obata, and Koichi Noguchi
- Subjects
medicine.medical_specialty ,Central nervous system ,Sensation ,Nerve Tissue Proteins ,In situ hybridization ,Tropomyosin receptor kinase A ,Biology ,Synaptic Transmission ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Dorsal root ganglion ,Ganglia, Spinal ,Internal medicine ,medicine ,Animals ,Neurons, Afferent ,RNA, Messenger ,Receptor, trkA ,Molecular Biology ,In Situ Hybridization ,Hepatocyte Growth Factor ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Proto-Oncogene Proteins c-met ,Spinal cord ,Sensory neuron ,Rats ,Lumbar Spinal Cord ,medicine.anatomical_structure ,Endocrinology ,Liver ,Spinal Cord ,nervous system ,Hepatocyte growth factor ,Neuroscience ,medicine.drug - Abstract
We examined the expression of hepatocyte growth factor (HGF) mRNA and its receptor, c-met mRNA, in the dorsal root ganglia (DRG) and spinal cord of naive adult rats using in situ hybridization histochemistry (ISHH) and the reverse transcription-polymerase chain reaction (RT-PCR) technique. HGF mRNA was expressed in 25.0% of DRG neurons and 80.5% of HGF mRNA-positive neurons expressed trkA mRNA. In the lumbar spinal cord, c-met mRNA signals were observed in the superficial layer of dorsal horn. These results suggest that the HGF/cMet system may be involved in sensory transmission.
- Published
- 2001
30. Improvement of Emissions and Therrmal Efficiency in Diesel Combustion with Oxygenated Agents as Main Fuel
- Author
-
Teruyoshi Arima, Noboru Miyamoto, Hideyuki Ogawa, NabiMohammad Nurun, and Koichi Obata
- Subjects
Noise ,Mechanical Engineering ,Acoustics ,Environmental science ,Condensed Matter Physics - Published
- 1998
31. Clinical evaluation of combined treatment with amfenac sodium(Fenazox) and ethyl loflazepate(Meilax) according to the type of temporomandibular disorder
- Author
-
Tetsuya Yoda, Shin Morita, Hiroyasu Tsukahara, Ichiro Sakamoto, Koichi Obata, and Shoji Enomoto
- Subjects
medicine.medical_specialty ,Combined treatment ,business.industry ,Internal medicine ,Temporomandibular disorder ,medicine ,business ,Clinical evaluation ,Gastroenterology ,Ethyl loflazepate ,medicine.drug ,Surgery ,Amfenac sodium - Abstract
The efficacy of combined treatment with amfenac sodium (150 mg/day for 14 days) and ethyl loflazepate (2 mg/day for 14 days) was clinically evaluated in 44 patients with temporomandibular disorders in comparison with 77 patients with temporomandibular disorders who were given amfenac sodium (150 mg/day for 14 days) alone.The 121 temporomandibular disorder patients were classified into four types (I-IV) according to the criteria proposed by the Japanese Society for the Temporomandibular Joint.The usefulness of combined treatment with amfenac sodium and ethyl loflazepate was excellent in 14 cases (31.8%), good in 14 cases (31.8%), and fair in 12 cases (27.3%).The usefulness of amfenac sodium alone was excellent in 6 cases (7.8%), good in 34 cases (44.1%), and fair in 31 cases (40.3%).
- Published
- 1995
32. [Intensity-dependent activation of extracellular signal-regulated protein kinases (ERK) 5 in sensory neurons contributes to pain hypersensitivity]
- Author
-
Toshiyuki, Mizushima, Koichi, Obata, Koichi, Noguchi, and Takashi, Mashimo
- Subjects
Enzyme Activation ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Sensory Receptor Cells ,Hyperalgesia ,Animals ,Humans ,Extracellular Signal-Regulated MAP Kinases ,Mitogen-Activated Protein Kinase 7 ,Rats - Published
- 2012
33. Systematic Diagnosis and Treatment Method for Temporomandibular Disorders. New Chart for Primary Diagnosis and Treatment
- Author
-
Tetsuya Yoda, Ichiro Sakamoto, Hiroyasu Tsukahara, Junko Onaka, Noriko Akimoto, Tomoe Ide, Yasushi Yoda, Koichi Obata, Atsushi Takano, Juichi Miyamura, Shin Morita, Maimi Mitsui, Toaki Ono, and Shoji Enomoto
- Subjects
medicine.medical_specialty ,Crepitus ,business.industry ,medicine.medical_treatment ,Treatment method ,Disc disorders ,General Medicine ,Temporomandibular Joint Disorders ,Temporomandibular joint ,Surgery ,Derangement ,medicine.anatomical_structure ,Clinical Protocols ,Chart ,Humans ,Medicine ,medicine.symptom ,business ,Masticatory muscle ,Reduction (orthopedic surgery) - Abstract
In this study, the classification of temporomandibular disorders of Japanese Society for Temporomandibular Joint was subdivided into ten types for the purpose of connecting directly with treatment, then a new chart for primary diagnosis and treatment were expressed. Ten types, i.e. type I (masticatory muscle disorders), type II (micro traumatic synovitis), type IIIc- (disk disorders except internal derangement; open lock, eminense click and crepitus), type IIIc+ (internal derangement; disc anterior displacement with reduction), type III L (internal derangement; disc anterior displacement without reduction, type IVo (osteoarthrosis with no TMJ symptoms), type IVp (osteoarthrosis with TMJ pain and no disc disorders), type IVc- (osteoarthrosis with crepitus, eminense click and open lock), type IVc+ (osteoarthrosis with internal derangement; disc anterior displacement with reduction), type IV L (osteoarthrosis with internal derangement; disc anterior displacement without reduction) 605 patients who visited our clinic from January 1994 to June 1994 were classified by the new chart for primary diagnosis; type I: 37 cases, type II: 142 cases, type IIIc-:56 cases, type III c+: 215 cases, type III L: 82 cases, type IVo: 8 cases, type IVp: 11 cases, type IVc-: 10 cases, type IV+: 19 cases, type IVL: 25 cases.
- Published
- 1994
34. Role of transient receptor potential A1 in gastric nociception
- Author
-
Tadayuki Oshima, Takayuki Matsumoto, Jun Sakurai, Takashi Kondo, Koichi Obata, Hiroto Miwa, Charles H. Knowles, and Koichi Noguchi
- Subjects
Male ,medicine.medical_specialty ,TRPV1 ,Gastric Dilatation ,Calcitonin gene-related peptide ,Oligodeoxyribonucleotides, Antisense ,Rats, Sprague-Dawley ,Transient receptor potential channel ,Dorsal root ganglion ,Internal medicine ,Ganglia, Spinal ,Nitriles ,medicine ,Butadienes ,Animals ,Enzyme Inhibitors ,Extracellular Signal-Regulated MAP Kinases ,TRPA1 Cation Channel ,TRPC Cation Channels ,Neurogenic inflammation ,Chemistry ,Stomach ,Gastroenterology ,Nociceptors ,Visceral pain ,Nodose Ganglion ,Denervation ,Rats ,Enzyme Activation ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Gastric Mucosa ,Nociceptor ,medicine.symptom ,Neurogenic Inflammation - Abstract
Afferent fibers innervating the gastrointestinal tract have major roles in consciously evoked sensations including pain. However, little is known about the molecules involved in mechanonociception from the upper gastrointestinal tract. We recently reported that activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase cascade in primary afferent neurons, was induced by noxious gastric distention in the rat, and that the activation of ERK1/2 in dorsal root ganglion (DRG) neurons can be implicated in acute visceral pain. Transient receptor potential (TRP) A1, a member of the TRP family of cation channels, was expressed in both DRG and nodose ganglion (NG) neurons innervating the stomach and in nerve fibers in the gastric wall. TRPA1 was coexpressed with ERK1/2 in gastric primary afferent neurons, and attenuation of TRPA1 activation using antisense peptides and a specific blocker led to suppression of both ERK1/2 activation and visceromotor responses. TRPA1 also significantly colocalized with substance P (SP) and calcitonin gene-related peptide (CGRP) in the thoracolumbar DRG, NG and stomach. These data indicate that SP and CGRP may also be released by TRPA1 activation in primary afferent neurons to elicit neurogenic inflammation and promote visceral hyperalgesia.
- Published
- 2010
35. Genetic algorithm based parameters adjustments for micron-order image analysis of metal fracture
- Author
-
Masanobu Mizoguchi, Koichi Obata, Kazuya Ogata, and Yuki Kato
- Subjects
Imagination ,Accuracy and precision ,Digital image ,Materials science ,Scanning electron microscope ,media_common.quotation_subject ,Genetic algorithm ,Fracture (geology) ,Forensic engineering ,Fractography ,Image segmentation ,Algorithm ,media_common - Abstract
A brittle fracture, which is a kind of metal fractures, accompanies little or no plastic deformations of the metal, The origin of the fracture is one of the most important clues to identify the cause of it, and can be located by observing the surface. Here, fractography is an area of study to analyze fracture mechanisms and/or causes by using electron microscope images. The method to locate the origins has been established through it. However, they have been done mainly by visual observations. At MHS2007, we proposed a method to improve its measurement accuracy to micron order by introducing computer vision techniques on Scanning Electron Microscope, or SEM, digital images [1]. However, some parameters were manually determined and required to be automated. This is a continued research of it. We propose, in this paper, a new method to determine proper parameters for image segmentation using Genetic Algorithms (GAs.) Through experiments, we proved the scheme worked properly, and suboptimal parameters were determined so that the greatest number of cleavage steps was obtained. It is expected that these proposed methods will enable non-experts to analyze metal fractures accurately in micron scale.
- Published
- 2009
36. Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats
- Author
-
Koichi Noguchi, Jun Sakurai, Junji Tanaka, Kan Miyoshi, Takashi Kondo, Koichi Obata, and Hiroto Miwa
- Subjects
Male ,medicine.medical_specialty ,Visceral Afferents ,Receptor potential ,Neuropeptide ,Stimulation ,Gastric Dilatation ,Splanchnic nerves ,Rats, Sprague-Dawley ,Transient receptor potential channel ,Dorsal root ganglion ,Internal medicine ,Medicine ,Animals ,TRPA1 Cation Channel ,TRPC Cation Channels ,Afferent Pathways ,Mitogen-Activated Protein Kinase 3 ,Staining and Labeling ,business.industry ,Gastroenterology ,food and beverages ,Nodose Ganglion ,Visceral pain ,Splanchnic Nerves ,Abdominal Pain ,Rats ,Enzyme Activation ,Endocrinology ,medicine.anatomical_structure ,nervous system ,medicine.symptom ,business ,psychological phenomena and processes - Abstract
Background: Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats. Methods: We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats. Results: TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD. Conclusions: The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.
- Published
- 2009
37. Interleukin-18-Mediated Microglia/Astrocyte Interaction in the Spinal Cord Enhances Neuropathic Pain Processing after Nerve Injury
- Author
-
Haruki Okamura, Koichi Obata, Takashi Kondo, Koichi Noguchi, and Kan Miyoshi
- Subjects
Male ,MAP Kinase Signaling System ,Rats, Sprague-Dawley ,Mice ,Peripheral Nerve Injuries ,medicine ,Animals ,Peripheral Nerves ,Injections, Spinal ,Mice, Knockout ,Receptors, Interleukin-18 ,Microglia ,business.industry ,General Neuroscience ,Interleukin-18 ,NF-kappa B ,Interleukin ,Peripheral Nervous System Diseases ,Articles ,Nerve injury ,Spinal cord ,Rats ,Up-Regulation ,Mice, Inbred C57BL ,Posterior Horn Cells ,medicine.anatomical_structure ,Spinal Cord ,Hyperalgesia ,Astrocytes ,Neuropathic pain ,Interleukin 18 ,medicine.symptom ,Signal transduction ,business ,Neuroscience ,Astrocyte ,Signal Transduction - Abstract
Interleukin (IL)-18 is an important regulator of innate and acquired immune responses. Here we show that both the IL-18 and IL-18 receptor (IL-18R), which are induced in spinal dorsal horn, are crucial for tactile allodynia after nerve injury. Nerve injury induced a striking increase in IL-18 and IL-18R expression in the dorsal horn, and IL-18 and IL-18R were upregulated in hyperactive microglia and astrocytes, respectively. The functional inhibition of IL-18 signaling pathways suppressed injury-induced tactile allodynia and decreased the phosphorylation of nuclear factor κB in spinal astrocytes and the induction of astroglial markers. Conversely, intrathecal injection of IL-18 induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Our results indicate that IL-18-mediated microglia/astrocyte interactions in the spinal cord have a substantial role in the generation of tactile allodynia. Thus, blocking IL-18 signaling in glial cells might provide a fruitful strategy for treating neuropathic pain.
- Published
- 2008
38. Changes in DRG Neurons and Spinal Excitability in Neuropathy
- Author
-
Koichi Obata, Koichi Noguchi, and Yi Dai
- Subjects
MAPK/ERK pathway ,business.industry ,medicine.medical_treatment ,Stimulation ,medicine.anatomical_structure ,Nerve growth factor ,nervous system ,Dorsal root ganglion ,Neurotrophic factors ,medicine ,Noxious stimulus ,Sciatic nerve ,Axotomy ,business ,Neuroscience - Abstract
An intracellular signalling pathway in the dorsal root ganglion (DRG) and spinal neurons is a popular target in pain research that is relevant to the neuroplastic changes that occur during chronic pain conditions. First, we examined the phosphorylation of ERK in DRG neurons after peripheral inflammation and sciatic nerve transection without any stimulation to the receptive field. We found an activation of ERK in different populations of DRG neurons after peripheral inflammation and axotomy, which developed from alterations in target-derived nerve growth factor (NGF). We observed that the ERK signalling regulates the brain-derived neurotrophic factor (BDNF) expression in DRG neurons in both conditions. We also demonstrated that very rapid phosphorylation of ERK occurred in DRG neurons that were involved in the transmission of various noxious signals under normal conditions. Further, we examined the pERK labelling after the mechanical stimuli into the inflamed tissue and found that the pERK labelling occurred through the P2X3 receptors in the terminals. This activity-dependent activation of the ERK signal pathway may be useful for identifying which DRG neurons are involved in transmission of noxious stimuli under normal and pathological conditions.
- Published
- 2008
39. [Contribution of primary sensory neurons and spinal glial cells to pathomechanisms of neuropathic pain]
- Author
-
Koichi, Obata and Koichi, Noguchi
- Subjects
Transient Receptor Potential Channels ,Spinal Cord ,Peripheral Nerve Injuries ,Neuropeptides ,Animals ,Gene Expression ,Humans ,Neuralgia ,Nerve Growth Factors ,Neurons, Afferent ,Enzyme Inhibitors ,Mitogen-Activated Protein Kinases ,Neuroglia - Abstract
Injury to the peripheral nerves often induces produces spontaneous pain, hyperalgesia (increased responsiveness to noxious stimuli), and allodynia (painful responses to normally innocuous stimuli). In contrast to inflammatory pain, the currently available therapeutics for neuropathic pain are either relatively ineffective or accompanied by considerable side effects. Numerous animal models of chronic pain following nerve injury have been introduced. All these neuropathic pain models are generated by partial nerve injury, where a few primary afferents are axotomized, while the others are spared. Among these models, the L5 spinal nerve ligation (SNL) model is unique because in this model, the L4 dorsal root ganglion (DRG) neurons are clearly separated from the axotomized L5 DRG neurons. Previous studies have focused considerable attention on the directly damaged primary afferents and their influence on the activity of the dorsal horn neurons. However, increasing evidence suggests that DRG neurons with intact axons also exhibit alterad excitability and gene expression, and these changes might play functional roles in the pathomechanisms of neuropathic pain. For example, L5 SNL increases the expression of substance P, calcitonin gene-related peptide, brain-derived neurotrophic factor, and the transient receptor potential ion channels TRPV1 and TRPA1 in the uninjured L4 DRG neurons. Furthermore, compelling evidence suggests that the glial cells in the spinal cord may also play a role in the pathogenesis of neuropathic pain. Recent studies have shown that peripheral nerve injury results in the activation of mitogen-activated protein kinases (MAPK) in spinal glial cells and that MAPK inhibitors diminish nerve injury-induced pain hypersensitivity. This review mainly focuses on the DRG neurons and spinal glial cells and will review the roles of MAPK in the nociceptive pathways for neuropathic pain.
- Published
- 2008
40. P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain
- Author
-
Kimiko Kobayashi, Tetsuo Fukuoka, Koichi Noguchi, Yi Dai, Koichi Obata, and Hiroki Yamanaka
- Subjects
MAPK/ERK pathway ,Male ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,Purinergic P2 Receptor Antagonists ,Medicine ,Animals ,Pain Measurement ,Microglia ,business.industry ,Receptors, Purinergic P2 ,General Neuroscience ,Membrane Proteins ,P2RX7 ,Articles ,Nerve injury ,Receptors, Purinergic P2Y12 ,Rats ,Up-Regulation ,medicine.anatomical_structure ,Metabotropic receptor ,Neuropathic pain ,Neuralgia ,Sciatic nerve ,medicine.symptom ,business ,Neuroscience - Abstract
Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y12, has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury.Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y12mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y12mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y12antagonist and antisense knockdown of P2Y12expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y12agonist 2-(methythio) adenosine 5′-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors.These data suggest a new mechanism of neuropathic pain, in which the increased P2Y12works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.
- Published
- 2008
41. Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity
- Author
-
Hiroshi Kamo, Shinichi Yoshiya, Koichi Obata, Koichi Noguchi, Xiuyu Cui, Hiroki Yamanaka, Shenglan Wang, Kimiko Kobayashi, Yi Dai, Koichi Iwata, and Tomokazu Fukui
- Subjects
Male ,MAPK/ERK pathway ,Stimulation ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Extracellular ,lcsh:Pathology ,Animals ,Medicine ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Posterior Horn Cell ,business.industry ,Research ,Spinal cord ,Sciatic Nerve ,Electric Stimulation ,Rats ,Cell biology ,Electrophysiology ,Posterior Horn Cells ,medicine.anatomical_structure ,Anesthesiology and Pain Medicine ,nervous system ,NMDA receptor ,Molecular Medicine ,Sciatic nerve ,business ,Neuroscience ,lcsh:RB1-214 - Abstract
The phosphorylation of extracellular signal-regulated kinase (pERK) in DRG and dorsal horn neurons is induced by the C-fiber electrical stimulation to the peripheral nerve. The present study was designed to investigate the expression and modulation of pERK in the rat dorsal horn neurons produced by repetitive electrical stimulation, and its involvement in the electrophysiological activity of dorsal horn neurons. Electrical stimulation of C-fiber intensity at different frequencies was applied to the sciatic nerve; the stimuli-induced pERK expression and the activity in dorsal horn neurons were studied by immunohistochemistry and extracellular recording, respectively. Electrical stimulation of C-fibers (3 mA) induced pERK expression in dorsal horn neurons in a frequency-dependent manner, indicating that the frequency of electrical stimulation is an important factor which activates the intracellular signal pathway in the spinal cord. To demonstrate the underlying mechanism of this frequency-dependent pERK expression, an NMDA receptor antagonist, MK-801, and a voltage sensitive calcium channel antagonist, nifedipine, were administrated intrathecally before the stimulation. We found that high frequency (0.5 Hz and 10 Hz) but not low frequent (0.05 Hz) stimulus-evoked pERK was partially inhibited by MK-801. Both high and low frequency stimulus-evoked pERK were inhibited by the nifedipine treatment. The extracellular single unit activities were recorded from the laminae I-II and V of the L4-5 dorsal horn, and we found that blockage of the intracellular ERK signal suppressed the wind-up responses in a dose-dependent manner. In contrast, any change in the mechanically evoked responses was not observed following the administration of ERK inhibitor. These observations indicate that ERK activation plays an important role in the induction of the wind-up responses in dorsal horn nociceptive neurons.
- Published
- 2007
42. Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation
- Author
-
Hirokazu, Katsura, Koichi, Obata, Toshiyuki, Mizushima, Jun, Sakurai, Kimiko, Kobayashi, Hiroki, Yamanaka, Yi, Dai, Tetsuo, Fukuoka, Masafumi, Sakagami, and Koichi, Noguchi
- Subjects
Inflammation ,Male ,Time Factors ,Behavior, Animal ,Freund's Adjuvant ,TRPV Cation Channels ,Oligonucleotides, Antisense ,Rats ,Enzyme Activation ,Rats, Sprague-Dawley ,Hyperalgesia ,Neurofilament Proteins ,Ganglia, Spinal ,Animals ,Neurons, Afferent ,Receptor, trkA ,Mitogen-Activated Protein Kinase 7 ,Pain Measurement - Abstract
Heat and cold hyperalgesia is a common feature of inflammatory pain. To investigate whether activation of extracellular signal-regulated protein kinase 5 (ERK5), also known as big mitogen-activated protein kinase 1, in primary sensory neurons participates in inflammatory pain, we examined the phosphorylation of ERK5 in the dorsal root ganglion (DRG) after peripheral inflammation. Inflammation induced by complete Freund's adjuvant produced heat and cold hyperalgesia on the ipsilateral hind paw and induced an increase in the phosphorylation of ERK5, mainly in tyrosine kinase A-expressing small- and medium-size neurons. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. ERK5 antisense, but not mismatch, oligodeoxynucleotide decreased the activation of ERK5 and suppressed inflammation-induced heat and cold hyperalgesia. Furthermore, the inhibition of ERK5 blocked the induction of transient receptor potential channel TRPV1 and TRPA1 expression in DRG neurons after peripheral inflammation. Our results show that ERK5 activated in DRG neurons contribute to the development of inflammatory pain. Thus, blocking ERK5 signaling in sensory neurons that has the potential for preventing pain after inflammation.
- Published
- 2007
43. Activation of fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to neuropathic pain
- Author
-
Kimiko Kobayashi, Koichi Noguchi, Hiroki Yamanaka, Yi Dai, Koichi Obata, and Tetsuo Fukuoka
- Subjects
MAPK/ERK pathway ,Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Nerve Tissue Proteins ,p38 Mitogen-Activated Protein Kinases ,Functional Laterality ,Rats, Sprague-Dawley ,Sciatica ,Growth factor receptor ,Dorsal root ganglion ,Internal medicine ,Ganglia, Spinal ,medicine ,Animals ,Pyrroles ,Enzyme Inhibitors ,Phosphorylation ,Pain Measurement ,Behavior, Animal ,Chemistry ,General Neuroscience ,Fibroblast growth factor receptor 1 ,Axotomy ,Receptors, Fibroblast Growth Factor ,Rats ,Enzyme Activation ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Gene Expression Regulation ,Fibroblast growth factor receptor ,Peripheral nerve injury ,Sciatic nerve ,Neuroscience - Abstract
The possible involvement of fibroblast growth factor receptor (FGFR) activation in the dorsal root ganglion (DRG) was examined following peripheral nerve injury in the rat. Ligation of the sciatic nerve down-regulated FGFR2, -3 and -4 mRNA; however, the expression of FGFR1 mRNA showed no change. Activation of FGFR was examined by immunohistochemistry using an antibody of the phosphorylated form of FGFR1-4. Ligation of the sciatic nerve produced phosphorylation of FGFR in the L4 and 5 DRG ipsilateral to the injury, starting at 3 days after the lesion and persisting for more than 30 days. Substantial activation of FGFR was observed, mainly in unmyelinated small DRG neurons that co-expressed phosphorylated p38 mitogen-activated protein kinase (MAPK). Continuous intrathecal infusion of the FGFR1 inhibitor, 3-[3-(2-carboxyethyl)-4-methylpyrrol-2-methylidenyl]-2-indolinone, reduced p38 MAPK phosphorylation in the DRG and pain-related behaviors in the partial sciatic nerve model rat without affecting on the activation of spinal glia cells (microglia and astrocyte). In the injured small DRG neurons, activation of FGFR1 may contribute to the generation of neuropathic pain by activating p38 MAPK.
- Published
- 2007
44. Alteration of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain
- Author
-
Hiroki, Yamanaka, Koichi, Obata, Kimiko, Kobayashi, Yi, Dai, Tetsuo, Fukuoka, and Koichi, Noguchi
- Subjects
Male ,animal structures ,Time Factors ,dorsal root ganglion ,dorsal horn ,Cell Count ,Nerve Tissue Proteins ,Neural Cell Adhesion Molecule L1 ,Research Reports ,synaptic reorganization ,Rats ,Rats, Sprague-Dawley ,Sciatica ,Gene Expression Regulation ,Ganglia, Spinal ,Animals ,peripheral nerve injury ,rat ,Neurons, Afferent - Abstract
The cell adhesion molecule L1 (L1-CAM) plays important functional roles in the developing and adult nervous systems. Here we show that peripheral nerve injury induced dynamic post-transcriptional alteration of L1-CAM in the rat dorsal root ganglia (DRGs) and spinal cord. Sciatic nerve transection (SCNT) changed the expression of L1-CAM protein but not L1-CAM mRNA. In DRGs, SCNT induced accumulation of the L1-CAM into the surface of somata, which resulted in the formation of immunoreactive ring structures in a number of unmyelinated C-fiber neurons. These neurons with L1-CAM-immunoreactive ring structures were heavily colocalized with phosphorylated p38 MAPK. Western blot analysis revealed the increase of full-length L1-CAM and decrease of fragments of L1-CAM after SCNT in DRGs. Following SCNT, L1-CAM-immunoreactive profiles in the dorsal horn showed an increase mainly in pre-synaptic areas of laminae I–II with a delayed onset and colocalized with growth-associated protein 43. In contrast to DRGs, SCNT increased the proteolytic 80-kDa fragment of L1-CAM and decreased full-length L1-CAM in the spinal cord. The intrathecal injection of L1-CAM antibody for the extracellular domain of L1-CAM inhibited activation of p38 MAPK and emergence of ring structures of L1-CAM immunoreactivity in injured DRG neurons. Moreover, inhibition of extracellular L1-CAM binding by intrathecal administration of antibody suppressed the mechanical allodynia and thermal hyperalgesia induced by partial SCNT. Collectively, these data suggest that the modification of L1-CAM in nociceptive pathways might be an important pathomechanism of neuropathic pain.
- Published
- 2007
45. Axotomy increases plasma membrane Ca2+ pump isoform4 in primary afferent neurons
- Author
-
Shinichi Yoshiya, Hiroyuki Ogura, Yi Dai, Toshiya Tachibana, Kimiko Kobayashi, Hiroki Yamanaka, Koichi Noguchi, and Koichi Obata
- Subjects
Male ,Time Factors ,Calcium pump ,ATPase ,medicine.medical_treatment ,Diaphragm pump ,Rats, Sprague-Dawley ,Plasma Membrane Calcium-Transporting ATPases ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Animals ,Neurons, Afferent ,RNA, Messenger ,In Situ Hybridization ,biology ,Chemistry ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Axotomy ,Immunohistochemistry ,Cell biology ,Rats ,medicine.anatomical_structure ,Gene Expression Regulation ,Spinal Cord ,Peripheral nerve injury ,biology.protein ,Plasma membrane Ca2+ ATPase ,Neuron ,Neuroscience - Abstract
The expression of plasma membrane Ca 2+ -ATPase, a calcium pump located in cell membrane regulating intracellular Ca 2+ levels by Ca 2+ extrusion from cells, was examined in dorsal root ganglion neurons in naive rats and after spinal nerve ligation.The mRNAs and proteins in plasma membrane Ca 2+ -ATPase 1-3 were expressed in all size neurons with intense labeling in medium to large neurons. After spinal nerve ligation, these three isoforms showed downregulation of their expression. In contrast, plasma membrane Ca 2+ -ATPase 4 was expressed mainly in small neurons, and the number and signal intensity were significantly increased after spinal nerve ligation. These data suggest that plasma membrane Ca 2+ -ATPase isoforms have a distinct pattern of expression and regulation by axotomy in dorsal root ganglion neurons in normal and pathological conditions.
- Published
- 2007
46. Agonist of proteinase-activated receptor 2 increases painful behavior produced by alpha, beta-methylene adenosine 5'-triphosphate
- Author
-
Shenglan Wang, Tetsuo Fukuoka, Hiroki Yamanaka, Koichi Noguchi, Koichi Obata, Yi Dai, Wan-Jun Zhu, and Kimiko Kobayashi
- Subjects
Agonist ,Male ,medicine.drug_class ,Central nervous system ,Gene Expression ,Pain ,Pharmacology ,Rats, Sprague-Dawley ,Adenosine Triphosphate ,Dorsal root ganglion ,medicine ,Noxious stimulus ,Animals ,Receptor, PAR-2 ,Receptor ,Pain Measurement ,Behavior, Animal ,Chemistry ,Receptors, Purinergic P2 ,General Neuroscience ,Drug Synergism ,Adenosine ,Immunohistochemistry ,Rats ,Posterior Horn Cells ,medicine.anatomical_structure ,Nociception ,Oncogene Proteins v-fos ,nervous system ,Nociceptor ,Neuroscience ,Oligopeptides ,Receptors, Purinergic P2X3 ,medicine.drug - Abstract
Proteinase-activated receptor (PAR) 2 is expressed in a subset of primary afferent neurons and is involved in inflammatory nociception. The P2X3 ion channel is localized on nociceptors of sensory neurons. Using immunohistochemistry, we showed that many P2X3s are co-expressed with the PAR2 in rat dorsal root ganglia neurons. Nocifensive behavior induced by alphabeta-methylene adenosine 5'-triphosphate (ATP) injection to the hind paw was significantly augmented after the application of PAR2 agonists. Fos expression induced by the alphabeta-methylene ATP injection in dorsal horn neurons was also increased after the pre-application of PAR2 agonists. These findings indicate that PAR2 agonists may potentiate the sensitivity of P2X3 ion channel to noxious stimuli, and the interaction between PAR2 and P2X3 may be an important mechanism underlying inflammatory pain.
- Published
- 2006
47. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury
- Author
-
Jun Sakurai, Hirokazu Katsura, Yi Dai, Kimiko Kobayashi, Masafumi Sakagami, Koichi Obata, Toshiyuki Mizushima, Tetsuo Fukuoka, Koichi Noguchi, and Hiroki Yamanaka
- Subjects
MAPK/ERK pathway ,Ankyrins ,Male ,Hot Temperature ,p38 mitogen-activated protein kinases ,TRPV1 ,TRPV Cation Channels ,p38 Mitogen-Activated Protein Kinases ,Rats, Sprague-Dawley ,medicine ,Animals ,Trauma, Nervous System ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,TRPA1 Cation Channel ,TRPC Cation Channels ,Microglia ,Chemistry ,General Neuroscience ,Lumbosacral Region ,Long-term potentiation ,Articles ,Nerve injury ,Rats ,Cold Temperature ,Enzyme Activation ,medicine.anatomical_structure ,Spinal Nerves ,src-Family Kinases ,nervous system ,Spinal Cord ,Hyperalgesia ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Peripheral nerve injury ,Calcium Channels ,medicine.symptom ,Neuroscience ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signal-regulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.
- Published
- 2006
48. BDNF in sensory neurons and chronic pain
- Author
-
Koichi Noguchi and Koichi Obata
- Subjects
Nervous system ,Gene Expression ,Pain ,Sensory system ,Calcitonin gene-related peptide ,Models, Biological ,Dorsal root ganglion ,Neurotrophic factors ,medicine ,Animals ,Humans ,Neurons, Afferent ,Mitogen-Activated Protein Kinase Kinases ,business.industry ,General Neuroscience ,Brain-Derived Neurotrophic Factor ,Chronic pain ,General Medicine ,medicine.disease ,Spinal cord ,Enzyme Activation ,Posterior Horn Cells ,medicine.anatomical_structure ,nervous system ,Neuropathic pain ,Chronic Disease ,business ,Neuroscience - Abstract
Neurotrophic factors, which support neuronal survival and growth during development of the nervous system, have been shown to play significant roles in the transmission of physiologic and pathologic pain. Brain-derived neurotrophic factor (BDNF), synthesized in the primary sensory neurons, is anterogradely transported to the central terminals of the primary afferents in the spinal dorsal horn, where it is involved in the modulation of painful stimuli. In models of inflammatory and neuropathic pain, BDNF synthesis is greatly increased in different populations of dorsal root ganglion (DRG) neurons. Furthermore, it is now known that the activation of mitogen-activated protein kinases occurs in these sensory neurons and contributes to persistent inflammatory and neuropathic pain by regulating BDNF expression. The recent discovery that BDNF upregulation in the DRG and spinal cord contributes to chronic pain hypersensitivity indicates that blocking BDNF in sensory neurons could provide a fruitful strategy for the development of novel analgesics.
- Published
- 2005
49. Noxious cold stimulation induces mitogen-activated protein kinase activation in transient receptor potential (TRP) channels TRPA1- and TRPM8-containing small sensory neurons
- Author
-
Takashi Mashimo, Kimiko Kobayashi, Hiroki Yamanaka, Tetsuo Fukuoka, Koichi Noguchi, Atsushi Tokunaga, Toshiyuki Mizushima, Yi Dai, Koichi Obata, and Hirokazu Katsura
- Subjects
Ankyrins ,Male ,medicine.medical_specialty ,TRPM Cation Channels ,Stimulation ,Biology ,Rats, Sprague-Dawley ,Transient receptor potential channel ,Dorsal root ganglion ,Internal medicine ,Ganglia, Spinal ,medicine ,TRPM8 ,Noxious stimulus ,Animals ,Neurons, Afferent ,Protein kinase A ,TRPA1 Cation Channel ,Pain Measurement ,TRPC Cation Channels ,Kinase ,General Neuroscience ,Sensory neuron ,Cell biology ,Rats ,Cold Temperature ,Enzyme Activation ,medicine.anatomical_structure ,Endocrinology ,Enzyme Induction ,Calcium Channels ,Mitogen-Activated Protein Kinases - Abstract
Two cold-sensitive transient receptor potential (TRP) channels, TRPA1 and TRPM8, have been identified and considered interesting because of their possible roles in thermosensation, nociception and other functions. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase and p38 mitogen-activated protein kinase occurred in primary afferent neurons in response to noxious heat stimulation of the peripheral tissue, i.e. activity-dependent activation of extracellular signal-regulated protein kinase and p38 in dorsal root ganglion neurons. In the present study, we investigated the phosphorylation of extracellular signal-regulated protein kinase, p38, and c-Jun N-terminal kinase in the rat dorsal root ganglion by cold stimulation using immunohistochemistry. Cold stimuli (28-4 degrees C) were applied by immersion of the hind paw into a water bath (six times of 10 s stimulation and 10 s interval, total 2 min). Noxious cold stimulation induced phosphorylated-extracellular signal-regulated protein kinase and phosphorylated-p38, but not phosphorylated-c-Jun N-terminal kinase, in small to medium diameter sensory neurons with a peak at 2 min after stimulation. We found that a cold stimulation at 4 degrees C showed a marked increase in the number of activated neurons. Furthermore, double staining for phosphorylated-extracellular signal-regulated protein kinase and phosphorylated-p38 showed no colocalization in the dorsal root ganglion neurons. We then performed double-labeling experiments for TRPA1 and TRPM8 mRNA and phosphorylation of mitogen-activated protein kinase. The majority of phosphorylated-extracellular signal-regulated protein kinase-positive neurons also expressed TRPM8 mRNA, whereas phosphorylated-p38 heavily colocalized with TRPA1 mRNA after noxious cold stimulation. Our data suggest that the noxious, but not innocuous, cold stimulation in vivo induced differential activation of extracellular signal-regulated protein kinase and p38 pathways in each subpopulation containing TRPA1 or TRPM8 in dorsal root ganglion.
- Published
- 2005
50. The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior
- Author
-
Hirokazu Katsura, Yi Dai, Atsushi Tokunaga, Koichi Obata, Hiroki Yamanaka, Koichi Noguchi, Tetsuo Fukuoka, Kimiko Kobayashi, and Toshiyuki Mizushima
- Subjects
Male ,medicine.medical_treatment ,Pain ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Neurotrophic factors ,Ganglia, Spinal ,medicine ,Animals ,Neurons, Afferent ,In Situ Hybridization ,Motor Neurons ,Behavior, Animal ,business.industry ,General Neuroscience ,Brain-Derived Neurotrophic Factor ,Rhizotomy ,Peripheral Nervous System Diseases ,Anatomy ,Nerve injury ,Spinal cord ,Immunohistochemistry ,Rats ,Allodynia ,medicine.anatomical_structure ,Spinal Nerves ,Spinal Cord ,Hyperalgesia ,Spinal nerve ,Neuropathic pain ,medicine.symptom ,business ,Neuroscience - Abstract
A number of rat neuropathy models have been developed to simulate human neuropathic pain conditions, such as spontaneous pain, hyperalgesia, and allodynia. In the present study, to determine the relative importance of injury site (proximal or distal to the primary afferent neurons) and injury type (motor or sensory), we examined pain-related behaviors and changes of brain-derived neurotrophic factor expression in the dorsal root ganglion in sham-operated rats, and in the L5 dorsal rhizotomy, L5 ventral rhizotomy, L5 dorsal rhizotomy+ventral rhizotomy, and L5 spinal nerve transection models. L5 ventral rhizotomy and spinal nerve transection produced not only mechanical and heat hypersensitivity, but also an increase in brain-derived neurotrophic factor mRNA/protein in the L5 dorsal root ganglion at 7 days after surgery. In contrast, rats in the L5 dorsal rhizotomy and dorsal rhizotomy+ventral rhizotomy groups did not show both pain behaviors at 7 days after surgery, despite brain-derived neurotrophic factor upregulation in medium- and large-size neurons in the L5 dorsal root ganglion. On the other hand, L5 spinal nerve transection, but not dorsal rhizotomy, dorsal rhizotomy+ventral rhizotomy or ventral rhizotomy, increased the expression of brain-derived neurotrophic factor in the L4 dorsal root ganglion at 7 days after surgery. Taken together, these findings suggest that the upregulation of brain-derived neurotrophic factor expression in the L4 and L5 dorsal root ganglion neurons may be, at least in part, involved in the pathophysiological mechanisms of neuropathic pain and that the selective nerve root injury models may be useful for studying the underlying mechanisms of chronic pain after nerve injury.
- Published
- 2005
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