The PI has made significant advances in her research and drug education activities to the present time, and has the potential to answer significant questions as to the mechanism of tolerance and physical dependence if given a sustained commitment by NIDA to the goals of this research. Specifically, the objective of this research is to determine the role of free intracellular calcium and cyclic-AMP in the auction of antinociception, tolerance, and physical dependence by two classes of drugs, opiates and cannabinoids. Opiate tolerance is accompanied by increased levels of intracellular free calcium measured directly with the indicator fura-2/AM. Some possible mechanisms for this rise include modulation of calcium channel activation or number, potassium channel modulation, activation of c-AMP, or the influence of endogenous calcium modulators. These possibilities will be examined in both synaptosomes and dorsal root ganglia (DRG). In addition, we hypothesize that the chronic administration of opiates alters the functionality, specific binding, or mRNA for the endogenous calcium modulatory peptides calcitonin (CT) and calcitonin gene-related peptide (CGRP) leading directly to compensatory modulation of intracellular calcium in neurons or indirectly via activation of adenylyl cyclase. This hypothesis will be examined by the use of receptor binding assay for the hormones, radioimmunoassays, autoradiography, immunohistochemistry, and the measurement of c-AMP accumulation in synaptosomes from brain regions and the spinal cord. The novel profile of pharmacological activity of the cannabinoids indicates that these drugs may be useful tools in the elucidation of what may prove to be a unique mechanism for the relief of pain. Our data indicate that the antinociceptive effects of the cannabinoids occur due to interaction at both supraspinal and spinal sites, although the mechanism of action of the drugs is not known. Using methods similar to those described for the opiates, we propose to perform a systematic study of the role of calcium and cyclic-AMP in the antinociceptive effects of the cannabinoids in order to compare and contrast the mechanism of action of the drugs in the brain versus in the spinal cord using synaptosomes and DRG cells. We have shown that the cannabinoids significantly potentiate the antinociceptive effects of opiates at spinal and supraspinal site. In addition, we have found that the antinociceptive effects of cannabinoids are blocked by the kappa opiate antagonist, nor-BNI, but not mu and delta receptor blockers. We hypothesize that the mechanism of action of the cannabinoids may have similarities to the opiates in the alteration of neuronal second messengers. We propose to determine the interaction of the cannabinoids and the opiates with intracellular calcium and c-AMP production. The outcome of all of these studies could lead to a better understanding of the process of addiction and interventions in the addiction process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000186-03
Application #
2116084
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1993-09-30
Project End
1998-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Cox, Melinda L; Haller, Victoria L; Welch, Sandra P (2007) The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat involves the CB(2) cannabinoid receptor. Eur J Pharmacol 570:50-6
Haller, Victoria L; Cichewicz, Diana L; Welch, Sandra P (2006) Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice. Eur J Pharmacol 546:60-8
Williams, I Jovan; Edwards, Sherita; Rubo, Alex et al. (2006) Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by delta9-tetrahydrocannabinol. Eur J Pharmacol 539:57-63
Cichewicz, Diana L; Welch, Sandra P; Smith, Forrest L (2005) Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Eur J Pharmacol 525:74-82
Cox, Melinda L; Welch, Sandra P (2004) The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat. Eur J Pharmacol 493:65-74
Bass, Caroline E; Welch, Sandra P; Martin, Billy R (2004) Reversal of delta 9-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors. Eur J Pharmacol 496:99-108
Cichewicz, Diana L; Welch, Sandra P (2003) Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther 305:812-7
Lee, Matthew C; Smith, Forrest L; Stevens, David L et al. (2003) The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther 305:593-9
Cichewicz, Diana L; McCarthy, Erin A (2003) Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther 304:1010-5
Anikwue, Rene; Huffman, John W; Martin, Zachary L et al. (2002) Decrease in efficacy and potency of nonsteroidal anti-inflammatory drugs by chronic delta(9)-tetrahydrocannabinol administration. J Pharmacol Exp Ther 303:340-6

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