Abstract
Recent studies in our laboratory have shown that in mice, low doses of morphine in combination with Δ9-tetrahydrocannabinol (Δ9-THC) have a similar antinociceptive effect to high doses of morphine alone. After short-term administration of this combination, there is no behavioral tolerance to the opioid. Previous binding studies and Western analyses following chronic morphine exposure in rodent models indicate significant μ-receptor down-regulation, as well as decreased levels of receptor protein, in both brain and spinal cord regions. We hypothesized that combination-treated animals would show no receptor protein down-regulation. The levels of opioid (μ, δ, κ) and cannabinoid (CB1) receptor protein were evaluated in mouse models of short-term exposure to Δ9-THC, morphine, or both drugs in combination. Western blot analysis revealed that all three types of opioid receptor protein are significantly decreased in morphine-tolerant mouse midbrain. This down-regulation was not seen in combination-treated animals. In the spinal cord, there was an up-regulation of μ-, δ-, and κ-opioid receptor protein in combination-treated mice when compared with morphine-tolerant mice. There were no apparent changes in levels of CB1 receptor protein in midbrain regions, and there was an up-regulation of CB1 protein in the spinal cord. The data presented here indicate that there is a correlation between morphine tolerance and receptor protein regulation. A combination of Δ9-THC and morphine retains high antinociceptive effect without causing changes in receptor protein that may contribute to tolerance.
Footnotes
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Send reprint requests to: Sandra P. Welch, Ph.D., Dept. of Pharmacology/Toxicology, P.O. Box 980613, MCV Station, Richmond, VA 23298. E-mail: swelch{at}hsc.vcu.edu
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This work was supported by National Institute on Drug Abuse Grants DA-07027, DA-05274, and K02-DA-00186.
- Abbreviations:
- Δ9-THC
- Δ9-tetrahydrocannabinol
- CB1
- cannabinoid receptor 1
- O.D.
- optical density
- Received July 17, 2000.
- Accepted December 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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