Although substantial progress has been made in our understanding of the role of spinal delta opioid receptors in the production of antinociception, the role of supraspinal delta receptors remains ill- defined.
The first aim of this proposal is to identify the supraspinal sites at which delta1 and delta2 receptor agonists act to produce antinociception in the rat. A systematic analysis will be made of the sites in the CNS at which microinjection of delta1 or delta2 receptor agonists alters nociceptive threshold as measured by tail flick and hot plate tests. These sites will include brainstem nuclei conventionally implicated in descending modulation of nociception, as well as more rostral nuclei implicated in ascending modulation of nociception. The pharmacologic specificity of the effect will be confirmed by concurrent microinjection of delta1 or delta2 receptor antagonists.
The second aim of this proposal is to identify the neural pathways mediating this antinociception. CoCl2 will be microinjected in select brainstem nuclei to interrupt afferent transmission and determine whether neurons in these nuclei mediate the antinociception produced by intracerebral administration of delta1 or delta2 receptor agonists. In addition, serotonergic and noradrenergic receptor antagonists will be administered i.t. to determine whether delta receptor agonists activate a bulbospinal inhibitory system akin to that previously identified for morphine.
The third aim of this proposal is to conduct a rigorous, isobolographic analysis of the manner in which spinal and supraspinal delta1 and delta2 receptors interact to produce antinociception. The final aspect of this proposal addresses methodological aspects of the thermally-induced paw flick and tail flick tests. These studies will measure the tissue temperature at which reflex withdrawal occurs as a function of stimulus intensity (heating rate) and dose of opioid agonist. They will test the hypothesis that the efficacy of an opioid, as measured by the degree to which it increases threshold tissue temperature, rather than response latency, for reflex withdrawal is independent of stimulus intensity. Collectively, these studies will provide important new information about the supraspinal sites, neural pathways and mechanisms by which subtypes of the delta opioid receptor modulate nociceptive transmission. In addition, studies are proposed to examine the relationships among stimulus intensity, opioid efficacy, and tissue temperature for three commonly used thermal models of nociception.
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