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.
Cichewicz
D L
DL
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
Haller
V L
VL
Welch
S P
SP
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