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To examine the specific roles of group I metabotropic glutamate receptors (mGluRs) in nociceptive processing, we examined the effects of intrathecal (i.t.) treatment with antibodies raised against the C-terminals of mGluR1 and mGluR5 in various rat pain models. The effects of anti-mGluR1 IgG and anti-mGluR5 IgG were assessed in a model of persistent pain induced by intrathecal administration of the mGluR1/5 agonist DHPG, as well as in models of heat pain (plantar test), chemical pain (formalin test) and neuropathic pain. DHPG-induced spontaneous nociceptive behaviours (SNB) were significantly attenuated by i.t. treatment with either anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (10 and 30 microg). Neither anti-mGluR1 IgG (30 microg) nor anti-mGluR5 IgG (30 microg) significantly increased response latencies to noxious heat in the plantar test, compared with anti-rat IgG (control IgG). Moreover, neither antibody (30 microg) significantly reduced formalin pain scores as compared to control IgG. However, i.t. treatment with anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (30 microg) significantly reduced cold hypersensitivity exhibited 8 days after constriction injury of the sciatic nerve, supporting the contention that group I mGluRs play a role in the development of neuropathic pain. Because these antibodies were effective against neuropathic pain, and not acute heat or chemical noxious stimuli, these results suggest that mGluRs are involved in nociceptive processing in chronic pain states rather than signaling acute noxious stimuli, and that DHPG-induced pain may be mediated by similar mechanisms as neuropathic pain.

Background: It has been proposed that the measure of noxious stimulus-induced Fos (the protein product of the immediate early gene c-fos) expression in the spinal cord dorsal horn of laboratory animals may provide an estimate of the potential of specific treatments to produce preemptive analgesia. The present study examined this hypothesis by comparing the effects of intrathecal lidocaine given before and after hindpaw formalin injection on persistent nociceptive responses and Fos expression in spinal cord dorsal horn of rats., Methods: Formalin-induced nociception and Fos expression in the spinal cord, in response to a 50-microl injection of 2.5% formalin into the hind paw, were assessed in rats given an intrathecal injection of 50 microl 2% lidocaine by lumbar puncture between the L5 and L6 vertebrae, either 3 min before (pretreatment) or 5 min after (post-treatment) formalin injection., Results: Pain behaviors (hindpaw licking, elevation, and favoring) in the second phase of the formalin test were significantly reduced by pretreatment, but were unaffected by post-treatment. The number of immunocytochemically stained Fos-positive cells and the immunoprecipitation of the Fos antibodies were reduced by pretreatment, and were also reduced, to a lesser extent, by post-treatment., Conclusions: The finding that persistent nociceptive behaviors and Fos expression were suppressed by intrathecal lidocaine pretreatment suggests that nociception in the second phase of the formalin test depends on increases in central hyperexcitability generated during the first phase. On the other hand, the finding that the intrathecal injection of lidocaine after formalin treatment reduced Fos expression but not nociceptive responses indicates an uncoupling of the behavioral and Fos protein responses to formalin and suggests that changes in Fos expression may not be a good predictor of the ability of agents to produce preemptive analgesia.

Low frequency electrical stimulation of high threshold sensory afferents elicits a prolonged inhibition of nociceptive mechanisms in the lightly anaesthetized rat. The present study was to determine the role of NMDA receptor activation in mediation of this inhibition. The latency of the tail withdrawal from a noxious thermal test stimulus to the tip of the tail was taken as an indication of the excitability of nociceptive pathways. Conditioning electrical stimulation at 20 times threshold for muscle twitch with 2 ms pulses at 4 Hz for 20 min applied to previously defined meridian points in the hindlimb evoked a 70% inhibition of the tail withdrawal reflex in rats which received an intrathecal injection of CSF (n = 11) compared with unstimulated controls (n = 10). This inhibition lasted > 1 h after the end of the conditioning stimulus. The competitive NMDA receptor antagonist 5-amino-2-phosphonovaleric acid (APV) blocked the inhibition during the stimulus and during the post-stimulation period. It is concluded that activation of NMDA receptors is critical for the expression of the long-term plastic changes in the central nervous system which result in the persistent inhibition of the nociceptive tail withdrawal reflex.

To determine whether a lumbar spinal mechanism mediates the late phase of the nociceptive response in the formalin test, we compared the effects of intrathecal (i.t.) lidocaine given pre- or post-formalin at the lumbar or thoracic level. Pre- but not post-formalin administration of lidocaine to the lumbar level significantly attenuated late phase nociceptive responses. In contrast, neither pre- nor post-formalin administration of lidocaine to the mid-thoracic level altered nociceptive responses. In rats chronically spinalized at the mid-thoracic level, nociceptive responses to formalin were observed which were blocked by i.t. pre-treatment with lidocaine at the lumbar level. These results suggest that a specific lumbar spinal mechanism is involved in the initiation of persistent nociception in the formalin test.

The effect of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel blocker, glibenclamide, on adenosine-induced postsynaptic hyperpolarization was studied by means of intracellular recording techniques in TTX-treated CA1 neurones in the rat hippocampal slice. Glibenclamide applied in the CSF perfusion fluid at 30 microM reversibly depressed the 2-chloroadenosine-induced hyperpolarization and the increase in the membrane conductance. It is suggested that adenosine induces the opening of potassium channels in the postsynaptic membrane of CA1 neurones, including KATP channels in the mammalian central nervous system (CNS).