ANESTHETIC ACTION ON OPIATE PEPTIDE GENE EXPRESSION

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Potent analgesics and general anesthetics can act on primary pain-modulatin circuits in the spinal cord to alter the flow of nociceptive information. These drugs can change primary afferent input, alter descending activity, o directly impact the firing of modulating interneurons. However, in blockin the perception of pain during the period when they are administered, these exogenous agents could also change the activities of the endogenous brain systems that would normally be recruited to modulate nociceptive inputs. Recent evidence strongly suggests that anesthetic- and analgesic-induced changes in neuronal function could exert significant impact on the activiti s of the principal segmental and endogenous CNS pain-modulating systems that use opioid peptides as neurotransmitters. Therefore, we will focus on neurons which express the preproenkephalin and preprodynorphin genes and which use the translation products of these genes as pain-modulating transmitters to investigate the inter-relationship between exogenous and endogenous analgesia. Neurotransmitter-specific monitoring of the functional activity of specific neuronal populations is difficult to achieve. However, quantitated in situ hybridization techniques allow assessment of the extent of neuronal expressional of preproenkephalin and preprodynorphin genes in the appropria e cell populations. These approaches can detect substantial and rapid change in the cellular expression of these genes in pain-responsive neurons with enhancement or reductions in primary afferent inputs. The studies proposed here will monitor the neuronal expression of these gen s during anesthetic/analgesic regimens that are thought to act by: (a) blocking conduction of afferent impulses, (b) simulating activity in descending endogenous analgesic systems, (c) mimicking activity in the segmental opiate peptide analgesic systems, and (d) blocking conscious perception of pain. The studies will evaluate drug-induced changes in the function-related expression of the opioid peptide genes under baseline and stimulated conditions as one index of the impact of these clinically-used exogenous analgesic agents on the function of endogenous analgesic systems. This work should improve understanding of how these therapeutic agents affe t the capacity for endogenous analgesia in a way that might yield significant y improved clinical strategies for pain management.