The goal of this proposal is to develop a simplified mammalian preparation with which to examine mechanisms of behavioral tolerance to opiates. The approach taken in these studies is derived from a substantial body of evidence demonstrating that tolerance to the analgesic effect of opiates is profoundly modified by the context in which the analgesic responses are assessed. Such responses include the defensive tail-withdrawal (flick), which can be elicited in both, intact rats, and in rats who have undergone a complete spinal transection. This fact provides an opportunity to examine environmental modulation of opiate tolerance in a chronic, unanesthetized spinal animal, a preparation which may subsequently be amenable to neurophysiological analysis. These experiments will therefore utilize standard nociceptive procedures (the hot plate and tail flick) to evaluate the contribution of environmental contingencies, both associative and nonassociative, to tolerance. Three preparations will be studied: a. intact, unoperated rats, b. intact rats sustaining spinal catheters for the intathecal administration of morphine and c. spinally transected rats. The extend to which behavioral tolerance can be modulated by environmental contingenices will be determined in each of these successively reduced preparations. In concert, these investigations will provide a valuable approach with which to gain insight into both, drug tolerance as well as the biological bases of learning and memory.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002845-06
Application #
3207588
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1989-09-01
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
6
Fiscal Year
1991
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
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
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
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

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