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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA001949-16
Application #
3482634
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1978-02-01
Project End
1994-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Clarke, R W; Morgan, M M; Heinricher, M M (1994) Identification of nocifensor reflex-related neurons in the rostroventromedial medulla of decerebrated rats. Brain Res 636:169-74
Morgan, M M; Heinricher, M M; Fields, H L (1994) Inhibition and facilitation of different nocifensor reflexes by spatially remote noxious stimuli. J Neurophysiol 72:1152-60
Morgan, M M; Fields, H L (1993) Activity of nociceptive modulatory neurons in the rostral ventromedial medulla associated with volume expansion-induced antinociception. Pain 52:1-9
Levine, J D; Fields, H L; Basbaum, A I (1993) Peptides and the primary afferent nociceptor. J Neurosci 13:2273-86
Fields, H L; Heinricher, M M; Mason, P (1991) Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14:219-45
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
Kaplan, H; Fields, H L (1991) Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla. J Neurosci 11:1433-9
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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