Opiates are potent pain-killers and are essential in clinical practice, yet it is not entirely clear how they produce analgesia. Opiate analgesia has been hypothesized to result, at least in part, from the activation of spinally projecting antinociceptive neurons located in or near nucleus raphe magnus (NRM). This activation may be partly due to a direct action of opiates on NRM and partly due to actions on the periaqueductal gray (PAG), which innervates NRM. In both NRM and PAG there is evidence for opioids activating cells by their reducing GABAergic tone; serotonergic cells in NRM have been proposed as having an antinociceptive role as well. Thus there are specific populations of cells in NRM and PAG that would be expected to be associated with opioid receptors. To date though, it has not been possible to test whether this is the case due to the technical difficulty of combining tract-tracing and immunocytochemistry with receptor-binding techniques. Recently, mRNA's encoding delta, mu, and kappa opioid receptors have been sequenced, allowing the raising of antibodies against the deduced sequences of the receptor proteins. Using these antisera in rats, we have demonstrated that some serotonergic neurons (and also non-serotonergic raphe-spinal neurons) in NRM are apposed by opioid receptor-stained varicosities; we have also found opioid receptor staining in the ventrolateral PAG, from which region many neurons project to NRC Using these same techniques, it should be possible to confirm and extend these findings in primates including (in at least some cases) humans. In the present application, we propose: 1) To determine the anatomical relationship between opioid receptors and the PAG neurons that project to NRM. 2) To determine the anatomical relationship between opioid receptors and the NRM neurons projecting to the spinal dorsal horn. 3) To determine the relationships between opioid receptors and serotonergic neurons, and between opioid receptors and GABAergic neurons. Addressing these questions will clarify how opiate analgesia occurs in humans, and may suggest strategies by which less-addictive substitutes for opioids might be developed.
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