Opiates are the most powerful analgesic agents presently available. The general goal of the proposed research is to elucidate the circuitry underlying opiate actions that produce analgesia. This proposal is specifically focussed on the mechanisms of opiate analgesia at the level of the brainstem. The rostral ventromedial medulla (RVM) is involved in opioid-sensitive mechanisms that underlie brainstem control of nociceptive transmission. Opiate receptors and endogenous opioid peptides are found in this region, and microinjection of opiate agonists into RVM suppresses behavioral responses to noxious stimulation. Two classes of putative nociceptive modulating neurons have been identified in the RVM. Off-cells, which are thought to suppress nociceptive transmission, are activated by morphine. On-cells, which appear to facilitate nociceptive processing, are depressed by morphine. Other RVM neurons, neutral cells, are unaffected by morphine. We propose to use intracranial microinjection techniques, behavioral tests of nociceptive responsiveness, single unit recording and microiontophoresis to investigate the neurotransmitters involved in opiate control of the activity of physiologically-identified RVM neurons. We plan to investigate the actions of morphine, norepinephrine, serotonin and excitatory amino acids. We are particularly interested in determining how cells containing these transmitters contribute to the antinociceptive action of opiates. Hopefully, by increasing knowledge of how opiates produce analgesia, new drugs or pharmacological strategies can be devised to produce analgesia more selectively.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Drug Abuse Biomedical Research Review Committee (DABR)
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Yun, I A; Fields, H L (2003) Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121:747-57
Heinricher, M M; Morgan, M M; Tortorici, V et al. (1994) Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla. Neuroscience 63:279-88
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Heinricher, M M; Drasner, K (1991) Lumbar intrathecal morphine alters activity of putative nociceptive modulatory neurons in rostral ventromedial medulla. Brain Res 549:338-41
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Haws, C M; Heinricher, M M; Fields, H L (1990) Alpha-adrenergic receptor agonists, but not antagonists, alter the tail-flick latency when microinjected into the rostral ventromedial medulla of the lightly anesthetized rat. Brain Res 533:192-5

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