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
Summary
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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