MECHANISMS OF PERIPHERALLY-MEDIATED NICOTINIC ANALGESIA

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The proposed studies will test the hypothesis that neuronal nicotinic receptor agonists produce antinociception at peripheral sites of action. The specific aims of these studies will be to assess the antinociceptive effects of neuronal nicotinic receptor activation in the complete Freund's adjuvant (CFA) and chronic constriction injury (CCI) models of experimental pain. In addition, molecular biological techniques will be utilized to determine the expression and distribution of neuronal nicotinic receptors along peripheral sensory neuronal processes originating in the trigeminal ganglion. The effects on neuronal nicotinic receptor expression under conditions of inflammatory and neuropathic experimental pain and the extent to which these alterations are dependent upon nerve growth factor will also be assessed. Thus, the present studies will examine the role that peripheral neuronal nicotinic receptors play in the antinociceptive effects seen due to nicotinic agonists. The development of analgesic drugs with distinct mechanisms than those of opioids or non-steroidal anti inflammatory drugs (NSAIDS) is important due to the undesirable side effects of these drugs and their ineffectiveness in certain types of neuropathic pain. Establishing a peripheral site of action for nicotinic analgesic drugs holds out the advantage of eliminating any potential central nervous system side effects of centrally acting nicotinic analgesics.