G2A as a Threshold Regulator of Inflammatory Hyperalgesia Modulates Chronic Hyperalgesia

Tissue injury, pathogen infection, and diseases are often accompanied by inflammation to release mediators that sensitize nociceptors and further recruit immune cells, which can lead to chronic hyperalgesia and inflammation. Tissue acidosis, occurring at the inflammatory site, is a major factor contributing to pain and hyperalgesia. The receptor G2 accumulation (G2A), expressed in neurons and immune cells, responds to protons or oxidized free fatty acids such as 9-hydroxyoctadecadienoic acid produced by injured cells or oxidative stresses. We previously found increased G2A expression in mouse dorsal root ganglia (DRG) at 90 min after complete Freund’s adjuvant (CFA)-induced inflammatory pain, but whether G2A is involved in the inflammation or hyperalgesia remained unclear. In this study, we overexpressed or knocked-down G2A gene expression in DRG to explore the roles of G2A. G2A overexpression reduced the infiltration of acute immune cells (granulocytes) and attenuated hyperalgesia at 90 to 240 min after CFA injection. G2A knockdown increased the number of immune cells before CFA injection and prolonged the inflammatory hyperalgesia after CFA injection. G2A may serve as a threshold regulator in neurons to attenuate the initial nociceptive and inflammatory signals, modulating the chronic state of hyperalgesia.     

Mu opioid receptor-containing neurons mediate electroacupuncture-produced anti-hyperalgesia in rats with hind paw inflammation

Previous studies showed that electroacupuncture (EA) significantly attenuates inflammatory hyperalgesia in a complete Freund's adjuvant (CFA)-induced inflammatory pain rat model. The present study demonstrates that pretreatment with Derm-sap, a selective toxin for neurons that contain mu opioid receptor (MOR), specifically decreases MOR and blocks EA anti-hyperalgesia. These data suggest that spinal MOR-containing neurons are involved in the processes by which EA produces anti-hyperalgesia.     

IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat

The function of populations of nociceptors in muscle pain syndromes remain poorly understood. We compared the contribution of two major classes, isolectin B4-positive (IB4(+)) and IB4-negative (IB4(-)) nociceptors, in acute and chronic inflammatory and ergonomic muscle pain. Baseline mechanical nociceptive threshold was assessed in the gastrocnemius muscle of rats treated with IB4-saporin, which selectively destroys IB4(+) nociceptors. Rats were then submitted to models of acute inflammatory (intramuscular carrageenan)- or ergonomic intervention (eccentric exercise or vibration)-induced muscle pain, and each of the three models also evaluated for the transition from acute to chronic pain, manifest as prolongation of prostaglandin E2 (PGE(2))-induced hyperalgesia, after recovery from the hyperalgesia induced by acute inflammation or ergonomic interventions. IB4-saporin treatment did not affect baseline mechanical nociceptive threshold. However, compared to controls, IB4-saporin treated rats exhibited shorter duration mechanical hyperalgesia in all three models and attenuated peak hyperalgesia in the ergonomic pain models. And, IB4-saporin treatment completely prevented prolongation of PGE(2)-induced mechanical hyperalgesia. Thus, IB4(+) and IB4(-) neurons contribute to acute muscle hyperalgesia induced by diverse insults. However, only IB4+ nociceptors participate in the long term consequence of acute hyperalgesia.     

Cutaneous inflammation regulates THIK1 expression in small C-like nociceptor dorsal root ganglion neurons

Tandem pore-domain Halothane Inhibited K⁺ channel (THIK1) is a two-pore-domain potassium channel (K2P) present in dorsal root ganglia (DRG). We previously demonstrated that THIK1 mRNA levels in the DRG dropped ipsilaterally 1 day after CFA-induced cutaneous inflammation (CFA1). In this study we aimed to identify the currently unknown DRG subpopulations expressing THIK1, and to investigate the relationship between the channel and both inflammatory and spontaneous pain in normal rats. Using a combination of immunohistochemistry, western blotting and behavioural tests, we found that all small neurons and large groups of medium and large DRG neurons express THIK1. Myelinated and unmyelinated fibers, nerve endings in the skin and lamina I and II of the spinal cord also express the channel. THIK1 staining co-localizes with IB4-binding and trkA suggesting that the channel is expressed by nociceptors. At CFA1, both cytoplasmic and edge (membrane-associated) THIK1 staining were significantly reduced only in small neurons ipsilaterally compared to normal. At 4 days after inflammation (CFA4), edge THIK1 staining levels in small neurons decreased bilaterally compared to normal. Medium and large size DRG neurons showed no change in THIK1 expression either at CFA1 or CFA4. Ipsilateral (but not contralateral) mean %intensities of THIK1 in small neurons at CFA1 correlated strongly negatively with spontaneous foot lifting (SFL) duration (a marker of spontaneous pain). Thus, nociceptors express THIK1 that can be regulated by cutaneous inflammation. Finally, in vivo siRNA knockdown of THIK1 resulted in longer SFL duration than siRNA scramble-treated rats. Taken together our evidence suggests a potential involvement for THIK1 in pain processing following inflammation.     

Effects of pertussis toxin on electroacupuncture-produced anti-hyperalgesia in inflamed rats

Our previous study showed that electroacupuncture (EA) significantly attenuated hyperalgesia in an animal model of persistent inflammatory pain. The present study was designed to show if Gi/o protein is involved in EA-produced anti-hyperalgesia. Spinal Gi/o-protein function was destroyed by intrathecal pretreatment with pertussis toxin (PTX). Seven days after the placement of an intrathecal PE-10 tube, PTX was injected into the intrathecal space of the lumbar spinal cord of rats. Seven days after PTX, complete Freund's adjuvant (CFA) was injected into the plantar surface of one hind paw of the rat to induce hyperalgesia in the injected paw. EA treatment was given at acupoint GB30 immediately post-CFA and then hyperalgesia was assessed by measuring the degree of decreased paw withdrawal latency (PWL) to a noxious thermal stimulus. The results showed that PTX pretreatment prevented EA-produced anti-hyperalgesia in the CFA inflammatory pain model but did not affect either baseline pain threshold or CFA-induced hyperalgesia. The data suggest that EA-produced anti-hyperalgesia is mediated by PTX-sensitive Gi/o proteins and the relevant signaling pathways.     

Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain

Opioid peptides have been proven effective in reducing the sign of hyperalgesia associated with inflammation. Electroacupuncture (EA) produces antinociception via release of endogenous opioid peptides in normal rats. Moreover, intrathecal injection of dynorphin has antinociceptive effect in rats. The present study was designed to examine whether EA has effect on the thermal and mechanical hyperalgesia in rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. The results are the following: (1) single session of 100Hz EA (0.5-1.0-1.5 mA, 10 min for each intensity) at both Zusanli (ST 36) and Sanyinjiao acupoints (SP 6) significantly increased mechanical withdrawal threshold determined by von Frey filaments but not with thermal withdrawal latency that is determined by hot plate (52 +/- 0.2 degrees C); (2) 100 Hz EA applied twice a week for 4 weeks and showed a significant decrease in the mechanical hyperalgesia at the third and fourth week, with no effect on thermal hyperalgesia; (3) naloxone (20 mg kg(-1)) had the ability to reverse the inhibition of the mechanical hyperalgesia produced by a single session of EA. In conclusion, the present results indicate that a single or repetitive EA could reduce mechanical hyperalgesia, but not thermal hyperalgesia, in CFA-inflammatory pain rats, and the opioid system might be involved in these effects.     

Electroacupuncture attenuates visceral hyperalgesia and inhibits the enhanced excitability of colon specific sensory neurons in a rat model of irritable bowel syndrome

Abstract  The causes of irritable bowel syndrome remain elusive and there are few effective treatments for pain in this syndrome. Electroacupunture (EA) is used extensively for treatment of various painful conditions including chronic visceral hyperalgesia (CVH). However, mechanism of its analgesic effect remains unknown. This study was designed to investigate effect of EA on colon specific dorsal root ganglion (DRG) neurons in rats with CVH. CVH was induced by intracolonic injection of acetic acid (AA) in 10-day-old rats. Electromyography and patch clamp recordings were performed at age of 8–10 weeks. Colon DRG neurons were labelled by injection of DiI into the colon wall. EA was given at ST36 in both hindlimbs. As adults, neonatal AA-injected rats displayed an increased sensitivity to colorectal distension (CRD) and an enhanced excitability of colon DRG neurons. EA treatment for 40 min significantly attenuated the nociceptive responses to CRD in these rats; this attenuation was reversed by pretreatment with naloxone. EA treatment for 40 min per day for 5 days produced a prolonged analgesic effect and normalized the enhanced excitability of colon DRG neurons. Furthermore, in vitro application of [D-Ala², N -MePhe⁴, Gly⁵-Ol] enkephalin (DAMGO) suppressed the enhanced excitability of colon neurons from rats with CVH. These findings suggest that EA produced-visceral analgesia, which might be mediated in a large part by endogenous opioids pathways, is associated with reversal of the enhanced excitability of colon DRG neurons in rats with CVH.     

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E₂ (PGE₂) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (<30 µm) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE₂ (10 nm), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4–) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE₂ (100 nm) was enhanced. The sensitizing effect of 10 nm PGE₂ was attenuated in weakly IB4+ and IB4– neurons cultured from rats whose OIHP was reversed in vivo. Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4– nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE₂ in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.SIGNIFICANCE STATEMENT Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an in vitro model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E₂ (PGE₂) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE₂-induced sensitization was observed in vitro, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4–)] nociceptors.     

Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain

Brain-derived neurotrophic factor (BDNF) released within the spinal cord induces phosphorylation of N-methyl-D-aspartate (NMDA) receptors on the spinal cord neurons. This process is necessary for maintaining pain hypersensitivity after nerve injury. However, little is known about the role of BDNF and NMDA receptors in cancer-induced bone pain (CIBP), whose features are unique. This study demonstrates a critical role of the BDNF-modulated NMDA subunit 1 (NR1) in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP, both in the spinal cord and in the dorsal root ganglia (DRG). We selectively suppressed BDNF expression by RNA interference (RNAi) using intrathecal administration of BDNF small interfering RNA (siRNA). Then, we assessed mechanical threshold and spontaneous pain in CIBP rats. Real-time PCR, Western blotting, and fluorescent immunohistochemical staining were used to detect BDNF or NR1 both in vivo and in vitro. BDNF and phospho-NR1 were expressed under CIBP experimental conditions, with expression levels peaking at day 6 (BDNF) or 9 (NR1). Intrathecal BDNF siRNA prevented CIBP at an early stage of tumor growth (days 4-6). However, at later stages (days 10-12), intrathecal BDNF siRNA only attenuated, but did not completely block, the established CIBP. BDNF-induced NMDA receptor activation in the spinal cord or DRG leads to central sensitization and behavioral hypersensitivity. Thus, BDNF might provide a targeting opportunity for alleviating CIBP.     

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock‐down of NMDA receptors in primary afferents decreased NMDA‐induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin‐related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75^NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA‐12 but not by the p75^NTR inhibitor TAT‐Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full‐length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr¹⁴⁷² phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch‐clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA‐induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain.     

Two N-methyl-D-aspartate receptors in rat dorsal root ganglia with different subunit composition and localization

N-methyl-D-aspartate (NMDA) receptors in sensory afferents participate in chronic pain by mediating peripheral and central sensitization. We studied the presence of NMDA receptor subunits in different types of primary afferents. Western blots indicated that rat dorsal root ganglia (DRG) contain NR1, NR2B, NR2C, and NR2D but not NR2A. Real-time RT-PCR showed that NR2B and NR2D were expressed at higher levels than NR2A and NR2C in DRG. Immunofluorescence with an antibody that recognized NR1 and another that recognized NR2A and NR2B showed that NR1 and NR2B colocalized in 90% of DRG neurons, including most A-fibers (identified by the presence of neurofilament 200 kDa). In contrast, an antibody recognizing NR2C and NR2D labeled only neurofilament-negative DRG profiles. This antibody stained practically all DRG cells that contained calcitonin gene-related peptide and neurokinins and those that bound isolectin B4. The percentage of cells immunoreactive for NR1, NR2A/NR2B, and NR2C/NR2D were the same in the T9, T12, L4, and L6 DRG. The intracellular distribution of the NR2 subunits was strikingly different: Whereas NR2A/NR2B immunoreactivity was found in the Golgi apparatus and occasionally at the plasma membrane, NR2C/NR2D immunoreactivity was found in the cytoplasm but not in the Golgi. The NR1 subunit was present throughout the cytoplasm and was more intense in the Golgi. These findings indicate that DRG neurons have two different NMDA receptors, one containing the NR1, NR2D, and possibly the NR2C subunits, found only in C-fibers, and the diheteromer NR1/NR2B, present in the Golgi apparatus of both A- and C-fibers.     

The distribution of kisspeptin and its receptor GPR54 in rat dorsal root ganglion and up-regulation of its expression after CFA injection

Kisspeptin/GPR54 system plays a crucial role in the control of puberty onset and reproductive function. In the present study, we gave the first report that kisspeptin and GPR54 were expressed in the small- to large-sized neurons, and co-localized with Bandeiraea simplicifolia isolectin B4 (IB4), calcitonin-gene-related peptide (CGRP) and neurofilament 200 (NF200) in the L4/5 dorsal root ganglion (DRG) of naïve rats, detected by the double immunofluorescent staining. Interestingly, a marked elevation in the levels of KiSS-1 and GPR54 mRNA as well as protein was observed in the spinal dorsal horn and DRG 4 and 14 days following intra-articular injection of complete Freund's adjuvant (CFA), indicating a possible involvement of the kisspeptin/GPR54 system in chronic inflammatory pain.     

NGF and GDNF differentially regulate TRPV1 expression that contributes to development of inflammatory thermal hyperalgesia

The transient receptor potential ion channel, TRPV1 plays an essential role in the development of inflammatory thermal hyperalgesia. We investigated the dependence of inflammatory TRPV1 induction on neurotrophic factor. Rat dorsal root ganglia (DRG) neurons were classified according to immunostaining for trk-A and IB4 and the effects of antibodies against NGF or GDNF on TRPV1 expression within the groups were then analysed by immunohistochemical means. The data were compared with the time course of trophic factor expression and the effects of their antibodies on thermal hyperalgesia against radiant heat after inflammation. Although the levels of both NGF and GDNF were increased by inflammation, NGF rapidly and transiently increased whereas GDNF increased gradually over a period of approximately one week. TRPV1 expression was increased within both trk-A positive and IB4 positive neurons after inflammation. Increased TRPV1 expression within trk-A positive neurons was prevented by anti-NGF but not by anti-GDNF, whereas TRPV1 induction within the IB4 positive group was blocked by anti-GDNF but not by anti-NGF. Both antibodies prevented the short latency of withdrawing an inflamed paw from radiant heat. These results suggest that inflammation differentially increases both NGF and GDNF, which facilitate TRPV1 expression within distinctive neurons to induce thermal hyperalgesia.     

The behavioral and neuroanatomical effects of IB4-saporin treatment in rat models of nociceptive and neuropathic pain

One distinguishing feature of primary afferent neurons is their ability to bind the lectin IB(4). Previous work suggested that neurons in the inner part of lamina II (IIi), onto which IB(4)-positive sensory neurons project, facilitate nociceptive transmission following tissue or nerve injury. Using an IB(4)-saporin conjugate (IB(4)-SAP), we examined the contribution of IB(4)-positive neurons to nociceptive processing in rats with and without nerve injury. Intrasciatic injection of IB(4)-SAP (5 mug/5 mul) significantly decreased IB(4)-labeling and immunoreactive P(2)X(3) in the spinal cord and delayed the behavioral and neuroanatomical consequences of L5 spinal nerve ligation (SNL) injury. In the absence of injury, thermal and mechanical nociceptive thresholds increased 2 weeks post-treatment only in IB(4)-SAP-treated, but not control (saline or saporin only), rats. Acute NGF-induced hyperalgesia was also attenuated following IB(4)-SAP treatment. In the SNL model, mechanical allodynia failed to develop 1 and 2 weeks post-injury, but was fully established by 4 weeks. Moreover, neuropeptide Y immunoreactivity (NPY-ir), which increases in the spinal cord after nerve injury, was unchanged in IB(4)-SAP-treated animals whereas immunoreactive PKCgamma decreased 2, but not 4, weeks post-injury. Quantitative RT-PCR revealed a reduction in P(2)X(3) mRNA in L4 DRG of IB(4)-SAP-treated animals, but no change in TrkA expression. Our results suggest that IB(4)-positive neurons in L4 are required for the full expression of NGF-induced hyperalgesia and participate in the behavioral and anatomical consequences that follow injury to the L5 spinal nerve.     

Hepatocyte growth factor improves synaptic localization of the NMDA receptor and intracellular signaling after excitotoxic injury in cultured hippocampal neurons

To examine the effects of HGF on synaptic densities under excitotoxic conditions, we investigated changes in the number of puncta detected by double immunostaining with NMDA receptor subunits and presynaptic markers in cultured hippocampal neurons. Exposure of hippocampal neurons to excitotoxic NMDA (100 muM) decreased the synaptic localization of NMDA receptor subunit NR2B, whereas synaptic NR1 and NR2A clusters were not altered. Colocalization of PSD-95, a scaffolding protein of the receptor, with the presynaptic protein synapsin I was also decreased after excitotoxicity. Treatment with HGF attenuated these decreases in number. The decrease in the levels of surface NR2B subunits following the addition of the excitotoxic NMDA was also attenuated by the HGF treatment. The decrease in CREB phosphorylation in response to depolarization-evoked NMDA receptor activation was prevented by the HGF treatment. These results suggest that HGF not only prevented neuronal cell death but also attenuated the decrease in synaptic localization of NMDA receptor subunits and prevented intracellular signaling through the NMDA receptor.     

Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation

Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by mu and delta opioid receptors at 2-15 Hz and by kappa opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against mu (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta (naltrinodole, NTI) and kappa (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by mu- and delta- but not kappa-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of mu and delta, but not kappa, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.     

Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia

In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. Upon long-term exposure to IL-17A, isolated and cultured rat DRG neurons showed a significant upregulation of extracellular-regulated kinase (ERK) and nuclear factor κB (NFκB). Long-term exposure of neurons to IL-17A did not upregulate the expression of TRPV1. However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.     

Involvement of nociceptin/orphanin FQ and its receptor in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation

The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (NOP receptor), has been demonstrated to be involved in many physiological and pathological functions including pain regulation. In the present study, the involvement of N/OFQ-NOP receptor system in electroacupuncture (EA)-produced anti-hyperalgesia was investigated in rats with peripheral inflammation. Intrathecal (i.t.) administration of N/OFQ (15 nmol) or EA at acupoints GB30 and GB34 could significantly attenuate hyperalgesia which was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into one hindpaw of rats, manifesting as decreased paw withdrawal latency (PWL) to the noxious thermal stimulus. The anti-nociceptive effect of N/OFQ or EA was significantly blocked by intrathecal injection of [Nphe(1)]nociceptin(1-13)NH(2) (20 nmol), a selective antagonist of the NOP receptor, indicating the NOP-receptor-mediated mechanism. Additionally, the combination of N/OFQ injection with EA treatment could enhance anti-hyperalgesia compared to that produced by each component alone. These findings suggested that the spinal N/OFQ-NOP system might be involved in EA analgesia, which may be one of the mechanisms underlying the anti-nociceptive effect of EA in rat's peripheral inflammatory pain.