The long-term objective of this research is to understand how morphine acts acutely in the central nervous system to produce analgesia and how these effects are modified by chronic pain and/or morphine exposure, to produce tolerance. Previous investigations led to a model, which postulates that 1) the analgesic effect of morphine at the spinal cord is normally suppressed by a mechanism originating in the brain, and that 2) this suppression is eliminated when the spinal cord is transected or when morphine is simultaneously administered to the brain and the spinal cord. The removal of this inhibitory influence on the spinal effect of morphine accounts for the profound potency of systemically administered morphine relative to the effect of morphine at each of these two sites separately.
The specific aim of the proposed experiments is to determine which transmitter(s) are responsible for the postulated inhibition exerted by the brain on the analgesic effect of spinal morphine. Representative agonists and antagonists of several transmitter systems will be administered to the spinal cord (intrathecally) of intact rats and rats that have received an acute spinal transection. These compounds will be injected 1)alone - to determine whether they are directly involved in pain (nociceptive) processes at the level of the spinal cord and 2) in combination with a) spinal morphine b) spinal and supraspinal morphine and c) systemic morphine - to determine whether they modulate opiate analgesia. The nociceptive response will consist of the tail withdrawal reflex (tail flick) to a noxious thermal stimulus. The transmitter systems that will be examined include the 1) opioids 2) adenosine 3) gamma-amino butyric acid 4) glutamate 5) acetylcholine 6) serotonin and 7) norepinephrine. If morphine-induced analgesia is modified, as predicted, by compounds that act through any of these systems, then our knowledge of opiate analgesia will be enhanced and subsequent studies can explore the role of these transmitters in opiate tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002845-08
Application #
3207589
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1989-09-01
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Louisiana State University A&M Col Baton Rouge
Department
Type
Schools of Arts and Sciences
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803
Advokat, C; Duke, M; Zeringue, R (1999) Dissociation of (-) baclofen-induced effects on the tail withdrawal and hindlimb flexor reflexes of chronic spinal rats. Pharmacol Biochem Behav 63:527-34
Advokat, C; Duke, M (1999) Comparison of morphine-induced effects on thermal nociception, mechanoreception, and hind limb flexion in chronic spinal rats. Exp Clin Psychopharmacol 7:219-25
Advokat, C; Mosser, H; Hutchinson, K (1997) Morphine and dextrorphan lose antinociceptive activity but exhibit an antispastic action in chronic spinal rats. Physiol Behav 62:799-804
Advokat, C; Rhein, F Q (1995) Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan. Brain Res 699:157-60
Bertman, L J; Advokat, C (1995) Comparison of the antinociceptive and antispastic action of (-)-baclofen after systemic and intrathecal administration in intact, acute and chronic spinal rats. Brain Res 684:8-18
Ghorpade, A; Advokat, C (1994) Evidence of a role for N-methyl-D-aspartate (NMDA) receptors in the facilitation of tail withdrawal after spinal transection. Pharmacol Biochem Behav 48:175-81
Advokat, C; Prejean, J; Bertman, L (1994) Intrathecal co-administration of morphine and excitatory amino acid agonists produce differential effects on the tail-flick of intact and spinal rats. Brain Res 641:135-40
Advokat, C (1993) Intrathecal coadministration of serotonin and morphine differentially modulates the tail-flick reflex of intact and spinal rats. Pharmacol Biochem Behav 45:871-9
Advokat, C; Pellegrin, A I (1992) Excitatory amino acids and memory: evidence from research on Alzheimer's disease and behavioral pharmacology. Neurosci Biobehav Rev 16:13-24
Advokat, C; McInnis, C (1992) Environmental modulation of behavioral tolerance in spinal rats. Brain Res 581:46-52

Showing the most recent 10 out of 20 publications