Abstract

The long-term objective of this proposal is to understand the brain's natural pain-inhibitory capacity. It is felt that this objective can best be met by pursuing studies of stimulation-produced analgesia (SPA) and stress-induced analgesia (SIA) in rats. Because sub-systems of SPA and SIA are now known to exist, some mediated by opioid peptides, others, not, it is felt that particularly significant progress can now be made in defining the anatomy and neurochemistry of these systems. SPA and SIA are tools for investigating mechanisms of endogenous analgesia that have proven useful so far and should prove more useful still now that their separate substrates are beginning to be understood.
The specific aims of this proposal are: 1. To investigate the neurochemistry of opioid and nonopioid forms of SPA and SIA by studying the susceptibilities of each form to modification by certain drugs. Using standard analgesiometric tests such as the rodent tail-flick assay, the effects of drugs known to modify central serotonin and histamine systems will be studied. 2. To investigate the anatomy of opioid and nonopioid forms of SPA and SIA by studying the effects on the different forms of SIA of lesions in those areas of the periaqueductal gray matter known to be important in mediating opioid and nonopioid forms of SPA. 3. To investigate peripheral vs. central and cerebral vs. spinal sites of opioid binding concerned with the several opioid forms of SPA and SIA by making discrete microinjections of opiate antagonists into ventricular and spinal areas. 4. To investigate the effects of anesthesia on SPA and to study SPA's effects on the immune system (natural killer cell cytotoxicity). 5. To investigate the bulbar relay mediating the different forms of SIA by making bulbar lesions. Studies of SPA have already led to successful clinical trials with deep brain stimulation for pain relief in humans. It is hoped that continued studies of SPA and SIA will assure further progress in this direction by disclosing both noninvasive means of activating natural analgesia systems and nonopioid mechanisms lacking unwanted opiate effects.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS007628-22
Application #
3393613
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1976-12-01
Project End
1992-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
22
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Sternberg, W F; Mogil, J S; Pilati, M L et al. (1994) Neurochemical quality of nonopioid stress-induced analgesia is not altered by estrous phase in female mice. Proc West Pharmacol Soc 37:141-3
Kest, B; Mogil, J S; Sternberg, W F et al. (1994) Haloperidol increases pain behavior following peripheral tissue injury. Proc West Pharmacol Soc 37:89-90
Mogil, J S; Marek, P; O'Toole, L A et al. (1994) Mu-opiate receptor binding is up-regulated in mice selectively bred for high stress-induced analgesia. Brain Res 653:16-22
Page, G G; Ben-Eliyahu, S; Liebeskind, J C (1994) The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain Behav Immun 8:241-50
Vaccarino, A L; Marek, P; Kest, B et al. (1993) Morphine fails to produce tolerance when administered in the presence of formalin pain in rats. Brain Res 627:287-90
Vaccarino, A L; Marek, P; Kest, B et al. (1993) NMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin. Brain Res 615:331-4
Kest, B; Mogil, J S; Shamgar, B E et al. (1993) The NMDA receptor antagonist MK-801 protects against the development of morphine tolerance after intrathecal administration. Proc West Pharmacol Soc 36:307-10
Page, G G; Ben-Eliyahu, S; Yirmiya, R et al. (1993) Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 54:21-8
Kest, B; Mogil, J S; Sternberg, W F et al. (1993) Evidence for the up-regulation of kappa opiate mechanisms in mice selectively bred for high analgesia. Proc West Pharmacol Soc 36:249-53
Marek, P; Mogil, J S; Belknap, J K et al. (1993) Levorphanol and swim stress-induced analgesia in selectively bred mice: evidence for genetic commonalities. Brain Res 608:353-7

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