Changes in opioid and cannabinoid receptor protein following short-term combination treatment with delta(9)-tetrahydrocannabinol and morphine.
Recent studies in our laboratory have shown that in mice, low doses of morphine in combination with Delta(9)-tetrahydrocannabinol (Delta(9)-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 mu-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 (mu, delta, kappa) and cannabinoid (CB1) receptor protein were evaluated in mouse models of short-term exposure to Delta(9)-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 mu-, delta-, and kappa-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 Delta(9)-THC and morphine retains high antinociceptive effect without causing changes in receptor protein that may contribute to tolerance.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
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Cichewicz
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VL
Haller
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Welch
D000818:Animals; D015153:Blotting, Western; D013759:Dronabinol / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000032:analysis / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000032:analysis / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000032:analysis / Q000187:drug effects*
D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine; D013759:Dronabinol