The efficacy and potency of various classes of analgesic drugs is often dependent on the experimental model of pain used. For example, drugs that' act at serotonin(1a) receptors produce a strong antinociceptive effect on the hot-plate test, but are ineffective or produce hyperalgesic effects on the tail flick test. Similar differences have been observed for the antinociception produced by stimulation of various brain sites. One explanation for these different effects is that the drugs or the neurotransmitters released by brain stimulation produce selective effects on the nociception mediated by different types of nociceptors. Such a differential effect has been demonstrated for morphine, which selectively inhibits nociceptive responses produced by the activation of unmyelinated polymodal nociceptors. We have developed a rodent behavioral model which appears to selectively assess responses mediated by the activation of either C-polymodal or myelinated A-fiber nociceptors. Preliminary experiments have shown a preferential antinociceptive effect of serotonin(1a) agonists and morphine on responses produced by the activation of C-polymodal nociceptors and a preferential effect of alpha2- adrenoceptor agonists on responses produced by activation of myelinated nociceptors. We propose to perform behavioral and electrophysiological experiments to further establish the selectivity of this model. The model will then be used to examine the effects of opiate, sertonergic, and alpha-adrenergic agonists, and brainstem- stimulation, on nociceptive responses evoked by the activation of either C-polymodal or A nociceptors. To investigate whether the selectivity of these agents is mediated by inhibition of nociceptor afferent fibers, we will determine whether these treatments reduce the release of putative primary afferent neurotransmitters. These studies could provide important insights into the basic mechanisms underlying the antinociception produce by a variety of analgesic drugs. In addition, these studies may lead to the discovery of clinically useful drugs with selective analgesic effects on pain mediated by different nociceptors.
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