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Social adversity not only causes severe psychological diseases but also may improve people’s ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 ( SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A + neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

Light modulates mood through various retina-brain pathways. We showed that mice treated with short-term acute bright light exposure displayed anxiety-related phenotypes in a prolonged manner even after the termination of the exposure. Such a postexposure anxiogenic effect depended upon melanopsin-based intrinsically photosensitive retinal ganglion cell (ipRGC) activities rather than rod/cone photoreceptor inputs. Chemogenetic manipulation of specific central nuclei demonstrated that the ipRGC–central amygdala (CeA) visual circuit played a key role in this effect. The corticosterone system was likely to be involved in this effect, as evidenced by enhanced expression of the glucocorticoid receptor (GR) protein in the CeA and the bed nucleus of the stria terminalis and by the absence of this effect in animals treated with the GR antagonist. Together, our findings reveal a non-image forming visual circuit specifically designed for “the delayed” extinction of anxiety against potential threats, thus conferring a survival advantage.

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light–mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino–ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)–positive neurons in the vLGN (vLGN Penk ). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGN Penk neurons. In addition, activation of the projections from vLGN Penk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGN Penk -DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.

Chronic pain patients often complain their decreased cognitive function. However, the comorbidity mechanism between neuropathic pain and cognitive dysfunction still remains largely unknown. Here, we examined changes in the transciptomic profiles in the medial prefrontal cortex (mPFC) of mice with chronic pain and cognitive impairment using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was induced via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery. Comparing with the naïve group, RNA-seq identified a total 309 and 222 differentially expressed genes (DEGs) in ipsilateral and contralateral mPFC of CCI model mice, respectively. GO analysis indicated that the functions of these gene families are mainly enriched in immune and inflammation-related processes such as interferon-gamma production, cytokine secretion etc. KEGG analysis further showed the enriched neuroactive ligand-receptor interaction signaling pathway and Parkinson disease pathway that have been reported to be importantly involved in chronic neuralgia and cognitive dysfunction. Our study may provide insights into understanding the possible mechanisms underlying pain-related cognitive disorders.

Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear.Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia.Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1β (IL-1β) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1β mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment.These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

BACKGROUND Major depressive disorder (MDD) is a highly disabling psychiatric syndrome associated with deficits of specific subpopulations of cortical GABAergic interneurons; however, the underlying molecular mechanism remains unknown. Type 3 adenylyl cyclase (ADCY3, AC3), which is important for neuronal excitability, has been implicated in MDD in a genome-wide association study in humans. Moreover, a study reported that ablation of AC3 in mice caused similar symptoms as MDD patients. AIM To determine if disruption of the AC3 gene in different subtypes of GABAergic interneurons of mice causes depression-like behaviors. METHODS Using immunohistochemistry, we investigated the expression of AC3 in two major subtypes GABAergic interneurons: Somatostatin-positive (SST+) and parvalbumin-positive (PV+) neurons. Genetic manipulations were used to selectively disrupt AC3 expression in SST+ or PV+ interneurons. A series of behavior tests including rotarod test, open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) were used to evaluate the motor ability, anxiety- and depression- like behaviors, respectively. RESULTS Our results indicate that approximately 90.41% of SST+ and 91.22% of PV+ interneurons express AC3. After ablation of AC3 in SST+ interneurons, the mice spent comparable time in the center area in OFT, but significantly less time in the open arms and low frequency of entries to the open arms in EPM. Furthermore, these mice showed prolonged immobility in FST and more freezing in TST. However, there were no significant changes in these behaviors after specific disruption of AC3 in PV+ interneurons. CONCLUSION This study indicates that ablation of AC3 in SST+ interneurons of mice increases anxiety- and depression-like behaviors in mice, supporting the general hypothesis that decreased AC3 activity may play a role in human depression.

Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Whether and how microglia are involved in TN-induced anxiodepressive remains unclear. Here, we unconventionally report that TN activates ipsilateral but not contralateral hippocampal microglia, upregulates ipsilateral hippocampal ATP and interleukin1β (IL-1β) levels, impairs ipsilateral hippocampal long-term potentiation (LTP), and induces anxiodepressive-like behaviors in a time-dependent manner in rodents. Specifically, activation of ipsilateral hippocampal microglia is necessary for TN-induced anxiodepressive-like behaviors; and unilateral activating hippocampal microglia is sufficient to elicit an anxiodepressive state and impair LTP. Knockdown of ipsilateral hippocampal P2X7 receptor prevented TN-induced microglial activation and anxiodepressive-like behaviors. Furthermore, we demonstrate that microglia-derived IL-1β mediates microglial activation-induced anxiodepressive-like behaviors and LTP impairment. Together, these findings suggest that priming of microglia with ATP/P2X7R in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviors via IL-1β. Our results also reveal an asymmetric role of the bilateral hippocampus in TN-induced anxiety and depression.

Pain is a common symptom among patients with cancer. Adequate pain assessment and management are critical to improve the quality of life and health outcomes in this population. In this review, the authors provide a framework for safely and effectively managing cancer-related pain by summarizing the evidence for the importance of controlling pain, the barriers to adequate pain management, strategies to assess and manage cancer-related pain, how to manage pain in patients at risk of substance use disorder, and considerations when managing pain in a survivorship population. CA Cancer J Clin 2018;68:182-196. © 2018 American Cancer Society.

Background Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. Methods Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-d-aspartate–mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. Results The administration of the estrogen receptor-β antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein–coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): −7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): −4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-β knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α–short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-β–short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein–coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-β/protein kinase A or G protein–coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-d-aspartate–mediated excitatory postsynaptic currents. Conclusions These findings indicate that estrogen receptor-β and G protein–coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-d-aspartate receptor–mediated excitatory synaptic transmission. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Patients with diabetic peripheral neuropathy experience debilitating pain that significantly affects their quality of life (Abbott et al., 2011), by causing sleeping disorders, anxiety, and depression (Dermanovic Dobrota et al., 2014). The primary clinical manifestation of painful diabetic neuropathy (PDN) is mechanical hypersensitivity, also known as mechanical allodynia (MA) (Callaghan et al., 2012). MA’s underlying mechanism remains poorly understood, and so far, based on symptomatic treatment, it has no effective therapy (Moore et al., 2014).

Painful diabetic neuropathy (PDN) is a diabetes mellitus complication. Unfortunately, the mechanisms underlying PDN are still poorly understood. Adenosine triphosphate (ATP)-gated P2X7 receptor (P2X7R) plays a pivotal role in non-diabetic neuropathic pain, but little is known about its effects on streptozotocin (STZ)-induced peripheral neuropathy. Here, we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia (MA) in STZ-induced type 1 diabetic neuropathy in mice. MA was assessed by measuring paw withdrawal thresholds and western blotting. Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R. STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA. Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout (KO) mice both presented attenuated progression of MA. Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1 (a microglia marker). Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.

cAMP (Cyclic Adenosine monophosphate), one of the most highly studied second messengers, is regulated by a family of adenylyl cyclase (AC) enzymes. Type 3 adenylyl cyclase (abbreviated as AC3), a subtype of adenylyl cyclase, is reported to be expressed in cilia in the olfactory and central nervous system and plays an important role in many physiological functions such as olfaction, development. However, expression of AC3 in the dorsal root ganglion (DRG) is not reported. In the present study, using immunohistochemical method, we discovered that AC3 immunoreactivity (IR) is predominantly expressed in the cytoplasm of small to medium sized DRG neurons. Double labelling revealed that the majority of AC3 IR are colocalized with CGRP (a peptidergic nociceptor marker), rarely with NF200 (a myelinated neuronal marker) or IB4 (a nonpeptidergic nociceptor marker). Furthermore, dense AC3 IR exists in the superficial dorsal horn, especially in laminaⅠand dorsal part of lamina II, where CGRP-positive DRG neurons terminate. The expression pattern of AC3 is similar between C57/BL6 J mouse and Sprague Dawley rat. For instance, AC3 is primarily expressed in the cell bodies of small to medium sized DRG neurons and the majority of AC3 IR is also in CGRP-containing neurons in rat. Taken together, our data suggest that AC3 is primarily expressed in the small to medium sized cell bodies and central terminals of CGRP-positive DRG neurons, implying AC3 enzyme might potentially function in nociception.

Background: Neuropathic pain seriously affects people’s life, but its mechanism is not clear. Interleukin-17 (IL-17) is a proinflammation cytokine and involved in pain regulation. Our previous study found that IL-17 markedly enhanced the excitatory activity of spinal dorsal neurons in mice spinal slices. The present study attempts to explore if IL-17 contributes to neuropathic pain and spinal synapse plasticity.Methods：A model of spared nerve injury (SNI) was established in C57BL/6J mice and IL-17a mutant mice. The pain-like behaviors was tested, and the expression of IL-17 and its receptor, IL-17RA, was detected. C-fiber evoked field potentials were recorded in vivo. Results: In the spinal dorsal horn, IL-17 predominantly expressed in the superficial spinal astrocytes and IL-17RA expressed mostly in neurons and slightly in astrocytes. The SNI-induced static and dynamic allodynia was significantly prevented by pretreatment of neutralizing IL-17 antibody (intrathecal injection, 2 μg/10 μL) and attenuated in IL-17a mutant mice. Post-treatment of IL-17 neutralizing antibody also partially relieved the established mechanical allodynia. Moreover, spinal long-term potentiation (LTP) of C-fiber evoked field potentials, a substrate for central sensitization, was suppressed by IL-17 neutralizing antibody. Intrathecal injection of IL-17 recombinant protein (0.2 μg/10 μL) mimicked the mechanical allodynia and facilitated the spinal LTP. Conclusions: These data implied that IL-17 in the spinal cord played a crucial role in neuropathic pain and central sensitization.

We proposed a PVDF airflow sensor array based on the principle of wind cavity vibration like a whistle, which enlarged the responding amplitude of the PVDF cantilever beam. The PVDF airflow sensor array consisted of eight array units that were arranged in a circumferential configuration. Each unit consisted of a PVDF cantilever beam anchored onto a cavity structure. Circumferential array elements were used to sense wind signals from different directions. Within a certain range, the flow velocity showed a linear relationship with the response voltage. When the flow velocity was 5.32 m/s, the flow velocity error was less than 2.3%, and the flow direction error was less than 2.88%. This sensor array can calculate the airflow velocity and direction, which can assist the actuator to complete the escape movement.

Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activated Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer–induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD-1 signaling suppresses bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delays the development of bone cancer pain via suppressing TRPV1 function., PD-L1/PD-1 signaling suppresses TRPV1 activity and alleviates pain-like behaviors via phosphorylation of SHP-1 in nociceptive primary sensory neurons in a mouse bone cancer model.

Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve–induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus–VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism–based therapeutic strategy for the anxiodepressive consequences of neuropathic pain., Activating excitatory neurons or inhibiting GABAergice neurons of the VLO improved anxiodepressive consequences of neuropathic pain in a trigeminal neuralgia mouse model.

As the most common symptomatic reason to seek medical consultation, pain is a complex experience that has been classified into different categories and stages. In pain processing, noxious stimuli may activate the anterior cingulate cortex (ACC). But the function of ACC in the different pain conditions is not well discussed. In this review, we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain, neuropathic pain, and cancer pain in the ACC, and discuss the cellular receptors and signaling molecules from animal studies. We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management. The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

The gap junction is essential for the communication between astrocytes and neurons by various connexins. Connexin43 hemichannels (Cx43 HCs), one of important subunits of gap junction protein, is highly expressed in astrocytes. It has been demonstrated that Cx43 HCs is involved in synaptic plasticity and learning and memory. However, whether the role of Cx43 HCs in the prefrontal cortex (PFC), a key brain region mediating cognitive and executive functions including working memory, still remains unclear. Here, we investigate that the role of Cx43 HCs in working memory through pharmacological inhibition of Cx43 HCs in the PFC. Gap26, a specific hemichannels blocker for Cx43 HCs, was bilaterally infused into the prelimbic (PrL) area of the PFC and then spatial working memory was examined in delayed alternation task in T-maze. Furthermore, the effect of Gap26 on synaptic transmission of prefrontal pyramidal neurons was examined using whole-cell patch recording in slice containing PFC. The demonstrate that inhibition of prefrontal cortex Cx43 HCs impairs the working memory and excitatory synaptic transmission of PFC neurons, suggesting that Cx43 HCs in the PFC contributes to working memory and excitatory synaptic transmission of neurons in rats.

Response inhibition is a critical executive control function in many species. Deficits in response inhibition have been observed in many disorders, eg, attention deficit/hyperactivity disorder (ADHD). The stop-signal task (SST) is a unique behavior task for evaluating response inhibition via measuring the covert latency of a stop process, and it is widely used in studies of humans, nonhuman primates and rodents. Methylphenidate (MPH; Ritalin(®)) is a psychostimulant that is widely used for the treatment of ADHD and that effectively improves response inhibition in individuals with ADHD and normal subjects. However, its mechanism of improving response inhibition remains unknown. In this study we adopted a rodent nose-poking version of the SST to examine response inhibition by estimating the stop signal reaction time (SSRT) in rats. Administration of MPH (1 mg/kg, sc) 25 min before the SST test exerted a baseline-dependent effect of MPH on response inhibition, ie, it shortened the SSRTs only in the rats with larger baseline SSRTs, thereby improving response inhibition in these rats. The effect of MPH on response inhibition remained 3 h after MPH administration. Co-administration of PP2 (1 mg/kg, sc), a Src-protein tyrosine kinase (Src-PTKs) inhibitor that inhibited the upregulation of glutamate receptor expression on the plasma membrane of the prefrontal cortex (PFC), abolished the MPH-caused improvement in response inhibition. Furthermore, intra-PFC infusion of a selective AMPAR antagonist.NASPM (0.3 mmol/L, per side) via stainless guide cannulas implanted earlier abolished the effect of MPH on SSRT. These results suggest that AMPA receptors in the PFC are involved in the effect of MPH on response inhibition in rats.

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus. However, the treatment for PDN is limited in clinical practice. In the present study, we investigated the effect of systemic administration dexmedetomidine (DEX), a selective alpha 2 adrenergic receptor (α2AR) agonist, on mechanical allodynia and its underlying mechanism in db/db mice, an animal model of type 2 diabetes mellitus. Our data demonstrated that db/db mice develop mechanical allodynia at the early stage of diabetes. During the period of mechanical allodynia, we detected increased release of norepinephrine (NE) and decreased levels of α2A-Adrenoceptors in db/db mice. Immunohistochemistry showed that the α2A-Adrenoceptor is predominantly expressed in neurons in the spinal cord. Acute injection of dexmedetomidine significantly decreased mechanical allodynia, which was blocked by its selective antagonist BRL44408. Furthermore, the upregulation of pERK1 and pERK2 in db/db mice were attenuated by preadministration of dexmedetomidine. We provide the first evidence that the functional alternation of spinal noradrenergic system might underlie exaggerated nociception in PDN. Systemic dexmedetomidine inhibits the mechanical allodynia which is related to ERK signaling pathway in type 2 diabetes, implying that the α2-Adrenoceptor might be a potential therapeutic strategy for PDN.

Tetanic stimulation of the sciatic nerve (TSS) triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1–CX3CR1 signaling is an important pathway in neuronal–microglial activation. Nuclear factor κB (NF-κB) is a key signal transduction molecule that regulates neuroinflammation and neuropathic pain. Here, we set out to determine whether and how NF-κB and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-κB (pNF-κB) and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammonium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down-regulated the expression of CX3CL1–CX3CR1 signaling, and conversely the CX3CR1-neutralizing antibody also down-regulated pNF-κB. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR1-neutralizing antibodies in treating pathological pain.

Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K+ channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.

Objective. Postincision pain often occurs after surgery and is an emergency to be treated in clinic. Electroacupuncture (EA) is a Chinese traditional treatment widely used to cure acute or chronic pain, but its mechanism is not clear. Interleukin-10 (IL-10) is a powerful anti-inflammatory cytokine that shows neuroprotective effects in inflammation and injury in the CNS. The present study attempts to reveal that IL-10 is crucial for EA analgesia on postincision pain. Methods. A model of incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of IL-10 and its receptor was detected by an immunohistochemical method. C-fiber-evoked field potentials were recorded by in vivo analysis. Results. The mechanical allodynia induced by paw incision was significantly inhibited by pretreatment of EA in mice. Intrathecal injection of IL-10 neutralizing antibody (2 µg/10 µL) but not intraplantar injection (10 µg/10 µL) reversed the analgesia of EA. The upregulations of IL-10 mRNA and protein were induced by EA at 6 h and 1 d after incision, respectively. Spinal long-term potentiation (LTP), a substrate for central sensitization, was also suppressed by EA with IL-10. IL-10 recombinant protein (1 µg/10 µL, i.t.) mimicked the analgesia of EA on mechanical allodynia and inhibition on the spinal LTP. Posttreatment of EA after incision also transitorily relieved the mechanical allodynia, which can be blocked by spinal IL-10 antibody. IL-10 and its receptor, IL-10RA, are predominantly expressed in the superficial spinal astrocytes. Conclusions. These results suggested that pretreatment of EA effectively prevented postincision pain and IL-10 in spinal astrocytes was critical for the analgesia of EA and central sensitization.

Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2+]i in DRG neurons from wild-type mice. However, the enhancement of [Ca2+]i was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain. SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

Postmenopausal depression is mainly caused by the deprivation of ovarian hormones during menopausal transition, it is of great importance to study on the treatment that could effectively relieve symptoms of menopausal depression with fewer side effects. Activation of G-protein-coupled estrogen receptor (GPER) has long been reported to facilitate neuronal plasticity and improve cognition in animals. Meanwhile, it could participate in regulation of intracellular signaling pathways through the characteristic of GPER, ameliorate intracellular mitochondrial function and oxidative stress. However, the impact of GPER on regulating estrogen deprived-depressant and anxious behaviors is still largely unknown. Here we used the ovariectomized female rats to imitate the condition of menopause. Owing to the lateral ventricle administration of G-1 which specifically react with GPER receptor intracerebrally, Ovariectomized (OVX) female rats showed depressive- or anxiety-like phenotypes with attenuated mitochondrial function. In addition, G-1 facilitated PKA activation, which further accelerated TSPO phosphorylation and alleviated menopausal depression- and anxiety-like behaviors. Moreover, PKA inhibitor PKI could partially antagonized the anti-anxiety and anti-depression effects of G-1. Taken together, we concluded that GPER activation might exhibit antidepressant and anxiolytic effect by elevating TSPO phosphorylation via protein kinase A signaling and rescuing the redox status in menopausal female rats.

Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant sodium channel Nav1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA1 (also known as EDG2) and Nav1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in naïve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Nav1.8 expression in L4-6 DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Nav1.8 expression in ipsilateral L4-6 DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Nav1.8 and LPA remarkably enhanced Nav1.8 currents in DRG neurons, and this was blocked by either a protein kinase C (PKC) inhibitor or a PKCε inhibitor. Overall, we demonstrated the modulation of Nav1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.

The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins, and maresins. We also discuss a possible role of microglia in chronic itch.

The proinflammatory cytokine Interleukin-17 (IL-17) is produced mainly by Th17 cells and has been implicated in pain regulation. However, synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We observed respective expression of IL-17 and its receptor IL-17R in spinal cord astrocytes and neurons. Patch clamp recording in spinal cord slices revealed that IL-17 not only enhanced EPSCs but also suppressed IPSCs and GABA-induced currents in lamina IIo somatostatin-expressing neurons. Spinal IL-17 was upregulated after paclitaxel treatment, and intrathecal IL-17R blockade reduced paclitaxel-induced neuropathic pain. In dorsal root ganglia, respective IL-17 and IL-17R expression in satellite glial cells and neurons was sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate both central and peripheral neuron-glial interactions in chemotherapy-induced peripheral neuropathy.

Pain is a complex experience including sensory-discriminative and emotional-affective components. Base on the intensity and chronification of pain, pain is divided into physiological and pathological pain. Anterior cingulate cortex (ACC), which is activated by noxious and contextual stimuli, is involved in pain processing, especially affective pain, the neural mechanisms of the ACC involvement in affective pain have yet to be elaborated. This review summarizes the main progresses and recent findings from our and other laboratories regarding the ACC and affective pain. Most evidence provided new insights into the neural mechanisms underlying affective pain. Excitation of ACC pyramidal neurons is necessary and sufficient for the pain-related negative emotion. We also sketched other brain regions associated with the ACC and discussed the role of these brain regions in affective pain. Actually, it is likely that the neural network between these brain regions is critical for the negative affect of pain. In particular, the important advances within the optogenetic filed provide new opportunities to deepen and expand our understanding of the affective pain.

Increasing evidence suggests that T cells and glia participate in the process of neuropathic pain. However, little is known about the involvement of T cells or the interaction between glia and T cells at the molecular level. Here we investigated the phenotype of T cell infiltration into the spinal cord in inflammatory pain and explored potential crosstalk between glia and T cells. The establishment of monoarthritis produced T cell infiltration and astrocyte activation, exhibiting similar kinetics in the spinal cord. T-cell-deficient (Rag1−/−) mice significantly attenuated MA-induced mechanical allodynia and GFAP upregulation. Double immunofluorescence staining showed that CD3 mainly colocalized with interferon-gamma (IFN-γ). Western blot and flow cytometry showed that multiple intrathecal administrations of astrocytic inhibitor fluorocitrate decreased IFN-γ-production without decreasing T cell number in the spinal cord. Spinal IFN-γ blockade reduced MA-induced mechanical allodynia and astroglial activation. In contrast, treatment with rIFN-γ directly elicited persistent mechanical allodynia and upregulation of GFAP and pJNK1/2 in naïve rats. Furthermore, rIFN-γ upregulated the phosphorylation of NF-κB p65 in cultured astrocytes vitro and spinal dorsal horn vivo. The results suggest that Th1 cells and astrocytes maintain inflammatory pain and imply that there may be a positive feedback loop between these cells via IFN-γ.

Clinically, pain and anxiety frequently coexist; however, these two conditions' interaction is limited and contradictory in animal studies. In this study, we combined social defeat (SD) stress with Freund's adjuvant (CFA)-induced persistent inflammatory pain to investigate the reciprocal relationship between anxiety-like and nociceptive behaviors in two mouse strains. C57BL/6J mice subjected to the 10-day period of SD stress by repeated CD-1 mice aggression exhibited significant social interaction avoidance behaviors in the social interaction (SI) test, which is believed to represent the symptoms of anxiety. These mice also displayed anxiety-like behaviors in elevated plus maze (EPM) and open field (OF) tests. Compared to C57BL/6J mice, FVB/NJNju mice showed less basal social contact, but their behavioral responses to 10-day SD stress were more resilient. CFA-inflammatory mice showed robust mechanical allodynia and thermal hyperalgesia in both strains, but did not develop obvious social avoidance and anxiety-like behaviors 10 days after CFA-inflammation. Interestingly, CFA-inflammatory mice exposed to SD stress were not accompanied by a worsening of pain and anxiety-like behaviors in most tests. In contrast, the SD stress-induced social avoidance was significantly antagonized by combining with CFA-inflammatory pain. These findings suggest that persistent inflammatory pain and SD stress-induced anxiety may not necessarily exacerbate one another in animal models of comorbidity.