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.