Previous studies of the pharmacologic and physiologic mechanisms of antinociception have focused primarily on the involvement of opioid peptides and monoamines. Although several lines of evidence implicate GABA in the modulation of nociception, limitations in our understanding of the pharmacology of GABA receptors and a paucity of drugs with which to manipulate these receptors have severely hampered studies of the role of GABA to date. However, recent advances in the pharmacology of both GABAA and GABAB receptors now provide the tools with which to more thoroughly characterize the role of GABA in antinociception. This proposal will systematically characterize involvement of GABAA and GABAB receptors in the modulation of nociception by neurons in three regions of the CNS for which the pharmacologic and physiologic mechanisms of antinociception have been best characterized: the spinal cord, n. raphe magnus and n. reticularis gigantocullaris pars alpha. These studies will first assess the effects of GABAA and GABAB agonists and antagonists on nociceptive sensitivity and motor function following intracerebral microinjection and intrathecal injection. The pharmacologic specificity of these effects will then be determined. With respect to the GABAA receptor, these studies will determine whether benzodiazepine agonists in a manner consonant with GABAA receptor pharmacology. Of particular interest will be the determination of (1) whether GABAA receptors involved in nociception are linked to a benzodiazepine modulatory site as it now appears that not all GABAA sites are linked to benzodiazepine sites and (2) whether a specific subtype of the GABAA receptor mediates antinociception. With respect to the GABAB receptor, these studies will determine, using the newly introduced GABAB antagonists, whether the antinociception produce by baclofen is truly mediated by a GABAB receptor or by a """"""""baclofen"""""""" receptor. Finally, this proposal will also examine the pharmacology of the neuronal pathways that mediate the effects of GABAA and GABAB receptor agonists and antagonists on nociception. Using a multidisciplinary approach, these studies will determine whether GABAergic modulation of nociception is mediated by activation or inhibition of a bulbospinal serotonergic projection originating in the n. raphe magnus. The results of these studies will provide new insights into non-opioid mechanisms of antinociception.
