Abstract

We examined whether enhanced glutamate release contributes to the expression of persistent spontaneous nociceptive behaviours (SNBs) in rats induced by intrathecal (i.t.) administration of the selective group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine ((RS)-DHPG). Pretreatment with drugs that have been shown to inhibit glutamate release, including a group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4), or the use-dependent sodium channel blockers 3,5-diamino-6-(2,3-diclorophenyl)-1,2,4-triazine (lamotrigine) and 2-amino-6-trifluoromethoxybenzothiazole (riluzole), produced dose-dependent reductions in (RS)-DHPG-induced SNBs. We have also shown that incubation of rat lumbar spinal cord slices with (RS)-DHPG potentiates 4-aminopyridine-evoked (4-AP) release of glutamate. Furthermore, we found that destruction of unmyelinated primary afferent C-fibres by neonatal capsaicin treatment significantly reduced (RS)-DHPG-induced SNBs in adult rats. Together, these results suggest that (RS)-DHPG-induced nociception is dependent on spinal glutamate release, probably from primary afferent C-fibres.

Highlights

  • Metabotropic glutamate receptors, in particular group I metabotropic glutamate receptor (mGluR), have been implicated in persistent nociception

  • We examined whether enhanced glutamate release contributes to the expression of persistent spontaneous nociceptive behaviours (SNBs) in rats induced by intrathecal (i.t.) administration of the selective group I mGluR agonist, (RS)-3,5dihydroxyphenylglycine ((RS)-DHPG)

  • To test the above hypotheses, we examined the effects of i.t. pretreatment with the selective group II agonist (2R,4R)4-aminopyrrolidine-2,4-dicarboxylate (2R,4R)-APDC)) [13] and the selective group III mGluR agonist (L-2-amino-4phosphonobutyrate (L-AP4)) [14] on (RS)-DHPG-induced SNBs

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Summary

Introduction

Metabotropic glutamate receptors (mGluRs), in particular group I mGluRs (mGluR1 and mGluR5), have been implicated in persistent nociception. In contrast to group I mGluR agonists, i.t. application of mGluR group II and III agonists do not have any nociceptive effects [4], and have been shown to decrease mechanical and cold allodynia in a rat model of neuropathic pain [8]. Activation of the group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6±8) mGluRs has been shown to decrease EAA release in the CNS [11,12]. It is possible group II and III mGluRs may be effective at alleviating persistent nociception by inhibiting glutamate release in the spinal cord dorsal horn

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