Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Abstract

Several lines of evidence indicate that Group II metabotropic glutamate receptor (mGluR) activation can depress sensory transmission. We have reported the expression of Group II mGluRs on unmyelinated axons, many of which were presumed to be nociceptors, in the rat digital nerve (Carlton et al., 2001b). The goals of the present study are to further our understanding of Group II modulation of nociceptor processing in the periphery, documenting behavioral changes using inflammatory models and documenting, for the first time, cutaneous single fiber activity following exposure to a Group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and antagonist LY341495 (LY). The data indicate that peripheral Group II mGluR activation does not depress nociceptive behaviors or nociceptor fiber responses in the non-sensitized state (i.e. following brief nociceptive mechanical or thermal stimulation) but can depress these responses when nociceptors are sensitized by exposure to formalin or inflammatory soup. Group II mGluR agonist-induced inhibition can be blocked by a selective Group II antagonist. Peripheral Group II mGluR-induced inhibition evoked in these studies occurs through activation of local receptors and not through spinal or supraspinal mechanisms. The data indicate that administration of selective Group II agonists may be potent therapeutic agents for prevention of peripheral sensitization and for treatment of inflammatory pain. KeywordsGroup II mGluR; pain; APDC; LY341495; formalin; inflammation; inflammatory soup Glutamate and glutamate receptors play an important role in peripheral pain mechanisms in animals (Carlton, 2001;Carlton et al., 2003) and humans (McNearney et al., 1999;McNearney et al., 2000;Cairns et al., 2001;Alfredson et al., 2001;Alfredson and Lorentzon, 2002;Svensson et al., 2003;Cairns et al., 2003). To date, ionotropic glutamate receptors (iGluRs) including N-methyl-D-aspartate (NMDA) and non-NMDA receptors are implicated in peripheral cutaneous pain mechanisms Bleakman et al., 2006).More recent studies indicate that metabotropic glutamate receptors (mGluRs) can modulate peripheral nociceptor function. In contrast to iGluRs, which are ligand-gated ion channel receptors, mGluRs mediate their function via G-protein coupled receptors which trigger Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 June 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript intracellular second-messenger systems (Pin and Duvoisin, 1995). Accordin...

Group II mGluRs suppress hyperexcitability in mouse and human nociceptors

“…Previous work demonstrated that application of APDC into the rodent skin reduced the duration and magnitude of inflammatory pain responses, indicating a peripheral mechanism for the analgesic action [16; 54]. Group II mGluR activation also prevented PGE 2 -induced potentiation of capsaicin-evoked calcium responses [53], and reduced capsaicin-evoked nociceptive fiber activity, suggesting that the anti-nociceptive effect may be related to inhibition of the heat- and capsaicin-sensitive ion channel TRPV1 [3; 6].…”

“…In several rodent models of inflammatory and neuropathic pain, pharmacological activation of group II mGluRs reduced nocifensive behaviors [33; 35; 43; 54]. Immunoreactivity for group II mGluRs has been observed in rodent DRG neurons [4; 5], and cutaneous administration of a group II mGluR agonist suppressed capsaicin-evoked activity in nociceptors, indicating a peripheral mechanism of action [3; 16; 53]. Interestingly, pharmacological inhibition of peripheral group II mGluRs prolonged hyperalgesia and nociceptor activity, suggesting that group II mGluRs act endogenously to reverse hypersensitivity [6; 54].…”

Group II/III Metabotropic Glutamate Receptors Exert Endogenous Activity-Dependent Modulation of TRPV1 Receptors on Peripheral Nociceptors

“…Group II and III mGluRs are expressed by primary sensory neurons (Carlton et al, 2001a; Carlton and Hargett, 2007), and peripheral injection of a Group II agonist inhibits peripheral nociceptor activity (Du et al, 2008), in particular transient receptor potential vanilloid 1 (TRPV1)-induced pain behaviors and TRPV1-induced excitation and sensitization of peripheral nociceptors (Carlton et al, 2009a). Thus, exogenous activation of peripheral mGluRs modifies pain transmission.…”

Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain

“…Some of them are found to be therapeutically active, but are associated with side effects like psychomimetic symptoms, cognitive impairment, dizziness and sedation [7,48]. Newer approaches have been identified to overcome these side effects, which include, inhibiting other binding sites of NMDA receptor like the NR2B, glycine B site [49][50][51][52][53][54][55][56][57][58][59][60][61][62], targeting other receptors like AMPA [63][64][65][66][67], kainate [68][69][70][71][72] and mGluR1 -5 [73][74][75][76][77][78][79][80][81][82], enhancing the activity of glutamate transporters that sequester the extracellular glutamate [23,24,83] and inhibiting glutamate release by designing various enzyme inhibitors [84][85][86][87][88][89][90][91...…”

“…Among the drugs acting on group II mGlu receptor, a mGluR2/3 agonist LY379268 (35, Figure 5) and mGluR7 agonist AMN082 (36, Figure 5) have been shown to attenuate allodynia and hyperalgesia on day seven after CCI in swiss albino mice [77]. A selective group-II mGluR agonist, 4-aminopyrrolidine-2-,4-dicarboxylate (APDC) (37, Figure 5) attenuated peripheral sensitization in inflammatory states [80] and mechanical hyperalgesia in neuropathic pain model [81]. ACPT-I (38, Figure 5), a selective group III mGluR agonist has also been found to inhibit hyperalgesia in various animal models of inflammation and neuropathic pain [82].…”