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Objective To compare postural balance ability in patients with low back pain between groups with and without lumbosacral radiculopathy. Methods Patients who were referred for electromyography because of low back pain during the period from April 2017 through June 2018 were chosen as subjects. They were divided into groups with and without lumbosacral radiculopathy based on the results of electromyography. We used Tetrax (Sunlight Medical Ltd., Ramat Gan, Israel) to objectively evaluate postural balance ability, and to measure the fall risk, stability index, weight distribution index, and Fourier index. Results Patients in the lumbosacral radiculopathy group showed significantly higher fall risk (73.25 vs. 38.00; p<0.05), weight distribution index (8.57 vs. 5.00; p<0.05), and stability index (21.19 vs. 13.16; p<0.05) than those in the group without lumbosacral radiculopathy. The Fourier index at high-medium frequency was significantly increased in the lumbosacral radiculopathy group (8.27 vs. 5.56; p<0.05), whereas weight-bearing on the side of radiculopathy was significantly decreased. Conclusion Patients with lumbosacral radiculopathy have decreased postural balance compared with patients without this condition. Somatosensory disturbances in lumbosacral radiculopathy might cause postural balance impairment. Assessment and treatment plan not only for pain reduction but also for postural balance improvement should be considered in the management of patients with lumbosacral radiculopathy. [ABSTRACT FROM AUTHOR]

Spinal D-serine plays an important role in nociception via an increase in phosphorylation of the N-Methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). However, the cellular mechanisms underlying this process have not been elucidated. Here, we investigate the possible role of neuronal nitric oxide synthase (nNOS) in the D-serine-induced potentiation of NMDA receptor function and the induction of neuropathic pain in a chronic constriction injury (CCI) model. Intrathecal administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt (LSOS) or the D-serine degrading enzyme, D-amino acid oxidase (DAAO) on post-operative days 0-3 significantly reduced the CCI-induced increase in nitric oxide (NO) levels and nicotinamide adenine dinucleotide phosphate-diaphorase staining in lumbar dorsal horn neurons, as well as the CCI-induced decrease in phosphorylation (Ser847) of nNOS (pnNOS) on day 3 post-CCI surgery. LSOS or DAAO administration suppressed the CCI-induced development of mechanical allodynia and protein kinase C (PKC)-dependent (Ser896) phosphorylation of GluN1 on day 3 post-surgery, which were reversed by the co-administration of the NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1). In naıve mice, exogenous D-serine increased NO levels via decreases in pnNOS. D-serine-induced increases in mechanical hypersensitivity, NO levels, PKCdependent pGluN1, and NMDA-induced spontaneous nociception were reduced by pretreatment with the nNOS inhibitor, 7-nitroindazole or with the NMDA receptor antagonists, 7-chlorokynurenic acid and MK-801. Collectively, we show that spinal D-serine modulates nNOS activity and concomitant NO production leading to increases in PKC-dependent pGluN1 and ultimately contributing to the induction of mechanical allodynia following peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Background: Self-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in Shank2−/− (Shank2 knock-out, KO) mice. Results: Intrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn. Conclusion: Shank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study provides new clues into the mechanisms underlying pain deficits associated with SIB and deserves further study in patients with ASD. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether the combination of muscle motor evoked potentials (mMEPs) and somatosensory evoked potentials (SEPs) measured during spinal surgery can predict immediate and permanent postoperative motor deficits. Methods mMEP and SEP was monitored in patients undergoing spinal surgery between November 2012 and July 2014. mMEPs were elicited by a train of transcranial electrical stimulation over the motor cortex and recorded from the upper/lower limbs. SEPs were recorded by stimulating the tibial and median nerves. Results Combined mMEP/SEP recording was successfully achieved in 190 operations. In 117 of these, mMEPs and SEPs were stable and 73 showed significant changes. In 20 cases, motor deficits in the first 48 postoperative hours were observed and 6 patients manifested permanent neurological deficits. The two potentials were monitored in a number of spinal surgeries. For surgery on spinal deformities, the sensitivity and specificity of combined mMEP/ SEP monitoring were 100% and 92.4%, respectively. In the case of spinal cord tumor surgeries, sensitivity was only 50% but SEP changes were observed preceding permanent motor deficits in some cases. Conclusion Intraoperative monitoring is a useful tool in spinal surgery. For spinal deformity surgery, combined mMEP/SEP monitoring showed high sensitivity and specificity; in spinal tumor surgery, only SEP changes predicted permanent motor deficits. Therefore, mMEP, SEP, and joint monitoring may all be appropriate and beneficial for the intraoperative monitoring of spinal surgery. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAa receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic. [ABSTRACT FROM AUTHOR]

Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4. [ABSTRACT FROM AUTHOR]

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or withAβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. [ABSTRACT FROM AUTHOR]

Background We previously developed a thrombus-induced ischemic pain (TIIP) animal model, which was characterized by chronic bilateral mechanical allodynia without thermal hyperalgesia (TH). On the other hand we had shown that intraplantar injection of acidic saline facilitated ATPinduced pain, which did result in the induction of TH in normal rats. Because acidic pH and increased ATP are closely associated with ischemic conditions, this study is designed to: (1) examine whether acidic saline injection into the hind paw causes the development of TH in TIIP, but not control, animals; and (2) determine which peripheral mechanisms are involved in the development of this TH. Results Repeated intraplantar injection of pH 4.0 saline, but not pH 5.5 and 7.0 saline, for 3 days following TIIP surgery resulted in the development of TH. After pH 4.0 saline injections, protein levels of hypoxia inducible factor-1α (HIF-1α) and carbonic anhydrase II (CA II) were elevated in the plantar muscle indicating that acidic stimulation intensified ischemic insults with decreased tissue acidity. At the same time point, there were no changes in the expression of TRPV1 in hind paw skin, whereas a significant increase in TRPV1 phosphorylation (pTRPV1) was shown in acidic saline (pH 4.0) injected TIIP (AS-TIIP) animals. Moreover, intraplantar injection of chelerythrine (a PKC inhibitor) and AMG9810 (a TRPV1 antagonist) effectively alleviated the established TH. In order to investigate which proton- or ATP-sensing receptors contributed to the development of TH, amiloride (an ASICs blocker), AMG9810, TNP-ATP (a P2Xs antagonist) or MRS2179 (a P2Y1 antagonist) were pre-injected before the pH 4.0 saline. Only MRS2179 significantly prevented the induction of TH, and the increased pTRPV1 ratio was also blocked in MRS2179 injected animals. Conclusion Collectively these data show that maintenance of an acidic environment in the ischemic hind paw of TIIP rats results in the phosphorylation of TRPV1 receptors via a PKC-dependent pathway, which leads to the development of TH mimicking what occurs in chronic ischemic patients with severe acidosis. More importantly, peripheral P2Y1 receptors play a pivotal role in this process, suggesting a novel peripheral mechanism underlying the development of TH in these patients. [ABSTRACT FROM AUTHOR]

Background: We previously developed a thrombus-induced ischemic pain (TIIP) animal model, which was characterized by chronic bilateral mechanical allodynia without thermal hyperalgesia (TH). On the other hand we had shown that intraplantar injection of acidic saline facilitated ATP-induced pain, which did result in the induction of TH in normal rats. Because acidic pH and increased ATP are closely associated with ischemic conditions, this study is designed to: (1) examine whether acidic saline injection into the hind paw causes the development of TH in TIIP, but not control, animals; and (2) determine which peripheral mechanisms are involved in the development of this TH. Results: Repeated intraplantar injection of pH 4.0 saline, but not pH 5.5 and 7.0 saline, for 3 days following TIIP surgery resulted in the development of TH. After pH 4.0 saline injections, protein levels of hypoxia inducible factor-1α (HIF-1α) and carbonic anhydrase II (CA II) were elevated in the plantar muscle indicating that acidic stimulation intensified ischemic insults with decreased tissue acidity. At the same time point, there were no changes in the expression of TRPV1 in hind paw skin, whereas a significant increase in TRPV1 phosphorylation (pTRPV1) was shown in acidic saline (pH 4.0) injected TIIP (AS-TIIP) animals. Moreover, intraplantar injection of chelerythrine (a PKC inhibitor) and AMG9810 (a TRPV1 antagonist) effectively alleviated the established TH. In order to investigate which proton- or ATP-sensing receptors contributed to the development of TH, amiloride (an ASICs blocker), AMG9810, TNP-ATP (a P2Xs antagonist) or MRS2179 (a P2Y1 antagonist) were pre-injected before the pH 4.0 saline. Only MRS2179 significantly prevented the induction of TH, and the increased pTRPV1 ratio was also blocked in MRS2179 injected animals. Conclusion: Collectively these data show that maintenance of an acidic environment in the ischemic hind paw of TIIP rats results in the phosphorylation of TRPV1 receptors via a PKC-dependent pathway, which leads to the development of TH mimicking what occurs in chronic ischemic patients with severe acidosis. More importantly, peripheral P2Y1 receptors play a pivotal role in this process, suggesting a novel peripheral mechanism underlying the development of TH in these patients. [ABSTRACT FROM AUTHOR]

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive-but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. [ABSTRACT FROM AUTHOR]

The ability to distinguish between similar experiences is a critical feature of episodic memory and is primarily regulated by the dentate gyrus (DG) region of the hippocampus. However, the molecular mechanisms underlying such pattern separation tasks are poorly understood. We report a novel role for the small GTPase ADP ribosylation factor 4 (Arf4) in controlling pattern separation by regulating dendritic spine development. Arf4-/2 mice at 4-5 months of age display severe impairments in a pattern separation task, as well as significant dendritic spine loss and smaller miniature excitatory post- synaptic currents (mEPSCs) in granule cells of the DG. Arf4 knockdown also decreases spine density in primary neurons, whereas Arf4 overexpression promotes spine development. A constitutively active form of Arf4, Arf4-Q71L, promotes spine density to an even greater extent than wildtype Arf4, whereas the inactive Arf4-T31N mutant does not increase spine density relative to controls. Arf49s effects on spine development are regulated by ASAP1, a GTPase-activating protein that modulates Arf4 GTPase activity. ASAP1 overexpression decreases spine density, and this effect is partially rescued by concomitant overexpression of wildtype Arf4 or Arf4-Q71L. In addition, Arf4 overexpression rescues spine loss in primary neurons from an Alzheimer's disease-related apolipoprotein (apo) E4 mouse model. Our findings suggest that Arf4 is a critical modulator of DG-mediated pattern separation by regulating dendritic spine development. [ABSTRACT FROM AUTHOR]

Background: Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methodology and Principal Findings: We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)-a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions and Significance: Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer’s disease. However, the underlying mechanisms are unclear.We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABAA receptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABAA receptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancingGABAsignaling are potential strategies to treat or prevent apoE4-related Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Background and purpose: The neurosteroid, dehydroepiandrosterone sulphate (DHEAS) and its non-sulphated form, DHEA, are considered as crucial endogenous modulators of a number of important physiological events. Evidence suggests that DHEAS and DHEA modulate central nervous system-related functions by activating sigma-1 receptors and/or allosterically inhibiting γ-aminobutyric acic receptor type A (GABAA) receptors. As both the sigma-1 receptor and the GABAA receptor play important roles in spinal pain transmission, the present study was designed to examine whether intrathecally injected DHEAS or DHEA affect nociceptive signalling at the spinal cord level. Experimental approach: We first determined whether intrathecal (i.t.) DHEA or DHEAS injection was able to affect nociceptive thresholds to peripheral mechanical stimulation and subsequently examined whether this effect was mediated by sigma-1 or the GABAA receptors. Key results: The i.t. DHEAS injection dose-dependently decreased the nociceptive threshold to mechanical stimulation, thus producing mechanical allodynia. Moreover, this DHEAS-induced mechanical allodynia was significantly reduced by administration of the sigma-1 receptor antagonist, BD-1047 or the GABAA receptor agonist, muscimol. Conversely, i.t. DHEA had no effect on mechanical sensitivity. However, when i.t. DHEA was combined with the GABAA receptor antagonist bicuculline, DHEA dose-dependently produced mechanical allodynia similar to that of DHEAS. This effect was blocked by BD-1047 and by muscimol. Conclusions and implications: These findings indicate that i.t. injection of DHEAS produces mechanical allodynia and that the development of this mechanical allodynia is mediated by sigma-1 and GABAA receptors. The findings of this study raise several interesting questions for further investigations into the mechanisms underlying neurosteroid modulation of spinal pain transmission. British Journal of Pharmacology (2009) 157, 666–673; doi:10.1111/j.1476-5381.2009.00197.x; published online 30 April 2009 [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is pentacyclic triterpenoic acid that naturally occurs in many medicinal herbs and plants. In this study, we examined the possible suppressive effect of UA extracted from Oldenlandia diffusa on zymosan-induced acute inflammation in mice and complete Freund's adjuvant (CFA)-induced arthritis in rats. UA treatment (per oral) dose-dependently (25–200 mg kg−1) suppressed zymosan-induced leucocyte migration and prostaglandin E2 (PGE2) production in the air pouch exudates. Since the maximal effective dose of UA was 50 mg kg−1 in the zymosan experiment, we used this dose of UA in a subsequent study using an adjuvant-induced rheumatoid arthritis model. UA treatment (50 mg kg−1, per oral, once a day for 10 days) was started from day 12 after adjuvant injection. UA dramatically inhibited paw swelling, plasma PGE2 production and radiological changes in the joint caused by CFA injection. Moreover, UA significantly suppressed the arthritis-induced mechanical and thermal hyperalgesia as well as the spinal Fos expression, as determined by immunohistochemistry, which was increased by CFA injection. In addition, overall anti-arthritic potency of UA was comparable with ibuprofen (100 mg kg−1, oral) while UA did not induce significant gastric lesions as compared with the ibuprofen treatment group. These findings strongly suggest that UA is a useful suppressive compound for rheumatoid arthritis treatment with low risk of gastric problems. [ABSTRACT FROM AUTHOR]

Although previous reports have suggested that the sigma 1 (σ1) receptor may be involved in pain sensation, its specific site of action has not been elucidated. The aim of present study was to determine the role of the spinal σ1 receptor in formalin-induced pain behavior, spinal cord Fos expression and phosphorylation of N-methyl-D-aspartate receptor subunit 1 (pNR1).Intrathecal (i.t.) pretreatment with the selective σ1 receptor antagonist, BD-1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) (10–100 nmol) dose dependently reduced formalin-induced pain behaviors in second phase, but not first phase, of the formalin test. I.t. injection of BD-1047 also reduced formalin-evoked Fos expression and pNR1 at the protein kinase C-dependent site, serine-896 (Ser896) and the protein kinase A-dependent site, serine-897 (Ser897) in spinal dorsal horn.i.t. BMY-14802 ((α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride) (10–100 nmol, σ1 receptor antagonist and 5-HT1A receptor agonist) dose dependently reduced formalin-induced pain behaviors in both phases. However, the 5-HT1A receptor might not be involved in the antinociceptive effect of BMY-14802 on the second phase, since i.t. pretreatment with the 5-HT1A receptor antagonist propranolol ((S)-1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride) (injected 10 min prior to i.t. BMY-14802) partially blocked the effect of BMY-14802 on the first phase of the formalin test but did not affect the inhibitory effect of BMY-14802 on the second phase. In addition, i.t. BMY-14802 significantly reduced formalin-evoked Fos expression and pNR1 (Ser896 and Ser897) expression in spinal dorsal horn.The results of this study suggest that selective blockage of spinal σ1 receptors can reduce pain behaviors, spinal cord Fos expression and pNR1 (Ser896 and Ser897) expression associated with the second phase of the formalin test.British Journal of Pharmacology (2006) 148, 490–498. doi:10.1038/sj.bjp.0706764; published online 8 May 2006 [ABSTRACT FROM AUTHOR]

Background: Although acupuncture has been widely used for complementary therapeutic approaches to treat inflammatory diseases and inflammation-induced pain, the potential anti-inflammatory effects of acupuncture treatment remain controversial in clinical trials, and the underlying mechanisms are still unclear. Objective: The objective was to determine whether electroacupuncture (EA) is able to suppress the peripheral inflammatory response (e.g., zymosan-induced leukocyte migration into air pouch). As part of a mechanistic approach, it was further evaluated whether endogenous opioid systems are involved in the "EA-induced anti-inflammatory effect" (EA-AI). Methods: EA (1 or 120 Hz) was performed bilaterally in the Zusanli acupoint (ST36) or in a nonacupoint (gluteal muscle) for 30 min in ICR mice under anesthetic condition. The number of leukocytes that migrated into the air pouch was counted 4 hours after zymosan injection. EA was performed at 0, 0.5, 1, or 2 hours prior to zymosan injection, respectively. To evaluate opioid involvement in EA-AI, intrathecal naloxone (36 μg/mouse) and intraperitoneal naloxone methiodide (30 mg/kg) were administered 10 min before EA stimulation. Results: Both the 1 and 120 Hz frequencies of EA into Zusanli acupoint at the same time with zymosan injection significantly reduced leukocyte migration into the air pouch as compared with those of control groups (i.e., anesthetic control and needling control into Zusanli acupoint without electrical stimulation). The EA stimulation into nonacupoint did not produce any significant anti-inflammatory effect. EA treatment at 0.5 hours prior to zymosan injection also produced an anti-inflammatory effect but 1 and 2 hours prior to zymosan injection did not elicit any effect. Peripheral opioid blockage significantly reversed EA-AI, whereas spinal opioid blockage did not alter EA-AI. Conclusion: EA can suppress peripheral inflammation through a peripheral opioid mechanism. To achieve the full effectiveness of EA, repeated application is recommended for the treatment of a variety of inflammatory diseases. [ABSTRACT FROM AUTHOR]