OPIOIDS AND STRESS: THE PAG

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This application proposes using combined anatomical and electrophysiological means to understand how opioids function to modulate neuronal activity in the ventrolateral periaqueductal gray (PAG) and furthermore to understand mechanisms of plasticity within the PAG-opioid system. The applicant is an experienced ultrastructural neuroanatomist and will be trained under this support mechanism in electrophysiological techniques, as well as in stress neurobiology. The PAG subserves several behavioral functions but has been most well characterized as a site of morphine-produced and stress-induced analgesia. Mu opioids are thought to act in the PAG by inhibiting local GABAergic interneurons and subsequently disinhibiting PAG output, however, several anatomical observations suggest the mu opioids may act through additional mechanisms. Most strikingly, mu opioid receptor (MOR) is present on a large subpopulation (approx. 40%) of medullary projecting neurons in the ventrolateral PAG. Here we hypothesize the MOR may function distinctly on GABAergic vs. nonGABAergic PAG neurons. This hypothesis will be tested by determining the effects of MOR agonists on PAG cells using intracellular recording techniques. Studied cells will be filled with neurobiotin and immunohistochemically labeled for GABA. Certain stress paradigms, for example a prolonged exposure to intermittent and inescapable shock (IS) have long lasting effects on the opioid system. Specifically, exposure to IS potentates the analgesic effects of low doses of morphine 24 hours later. The PAG is involved in both the acute response to stressors, and morphine and stress induced analgesia. This suggests the hypothesis that changes in MOR and/or delta opioid receptor (DOR) functioning in the PAG may participate in IS produced changes in morphine's analgesic potency. In Specific Aims 2 and 3, anatomical and electrophysiological methods will be used in concert to determine the changes in MOR and DOR function relating to this phenomenon. These studies will shed insight into the cellular mechanisms that underlie morphine's analgesic effects. Furthermore, understanding stress effects on the opioid system are particularly important since stress has been implicated as a major factor contributing to addiction and relapse to drug seeking behavior.