Reduction of stress‐induced analgesia but not of exogenous opioid effects in mice lacking CB 1 receptors

CB 1 cannabinoid receptors are widely distributed in the central nervous system where they mediate most of the cannabinoid‐induced responses. Here we have evaluated the interactions between the CB 1 cannabinoid receptors and the endogenous opioid system by assaying a number of well‐characterized opioid responses, e.g. antinociception and stress‐mediated effects, on mutant mice in which the CB 1 receptor gene was invalidated. The spontaneous responses to various nociceptive stimuli (thermal, mechanical and visceral pain) were not changed in mutant CB 1 mice. Furthermore, the absence of the CB 1 cannabinoid receptor did not modify the antinociceptive effects induced by different opioid agonists: morphine (preferential mu opioid agonist), d ‐Pen 2 ‐ d ‐Pen 5 ‐enkephalin (DPDPE) and deltorphin II (selective delta opioid agonists), and U‐50,488H (selective kappa opioid agonist) in the hot‐plate and tail‐immersion tests. In contrast, the stress‐induced opioid mediated responses were modified in CB 1 mutants. Indeed, these mutants did not exhibit antinociception following a forced swim in water at 34 °C and presented a decrease in the immobility induced by the previous exposure to electric footshock. However, the antinociception induced by a forced swim in water at 10 °C was preserved in CB 1 mutants. These results indicate that CB 1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid‐mediated responses to stress.