Opioids are the most powerful analgesic agents presently available. However, there are significant limitations to their effectiveness. The general goal of the proposed research is to elucidate the circuitry underlying opioid analgesia and to determine the factors that limit the analgesic efficacy of opioids. This proposal is focused on opioid activated circuitry at the level of the brainstem and spinal cord. The rostral ventromedial medulla (RVM) is involved in brainstem control of nociceptive transmission. Opioid receptors and endogenous opioid peptides are found in this region, and microinjection of opioid agonists into RVM suppresses behavioral responses to noxious stimulation. Three classes of putative nociceptive modulating neurons have been identified in the RVM: Off cells, which suppress nociceptive transmission, are activated by morphine. On cells, which facilitate nociceptive processing, are inhibited by morphine. The other RVM neurons, neutral cells, are unaffected by morphine. We will use intracranial microinjection techniques, behavioral tests of nociceptive responsiveness, in vivo and in vitro single unit recording and application of putative neurotransmitter receptor agonists and antagonists to investigate RVM circuitry. We plan to determine how each class of RVM neuron modulates spinal cord dorsal horn nociceptive transmission. Another important goal of these studies is to determine the contribution of the mu, kappa, delta and orphanin opioid receptors to RVM-mediated modulation of nociception. Hopefully, by increasing knowledge of what limits the efficacy of opioid analgesia, new pharmacological strategies can be devised to produce more potent and selective analgesics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001949-26
Application #
6634149
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (02))
Program Officer
Thomas, David A
Project Start
1978-02-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2006-03-31
Support Year
26
Fiscal Year
2003
Total Cost
$378,040
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
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

Showing the most recent 10 out of 30 publications