Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors

CB1 cannabinoid receptors are widely distributed in the central nervous sys tem where they mediate most of the cannabinoid-induced responses. Here we h ave evaluated the interactions between the CB1 cannabinoid receptors and th e endogenous opioid system by assaying a number of well-characterized opioi d responses, e.g. antinociception and stress-mediated effects, on mutant mi ce in which the CB1 receptor gene was invalidated. The spontaneous response s to various nociceptive stimuli (thermal, mechanical and visceral pain) we re not changed in mutant CB1 mice. Furthermore, the absence of the CB1 cann abinoid receptor did not modify the antinociceptive effects induced by diff erent opioid agonists: morphine (preferential mu opioid agonist), d-Pen(2)- d-Pen(5)-enkephalin (DPDPE) and deltorphin II (selective delta opioid agoni sts), and U-50,488H (selective kappa opioid agonist) in the hot-plate and t ail-immersion tests. In contrast, the stress-induced opioid mediated respon ses were modified in CB1 mutants. Indeed, these mutants did not exhibit ant inociception following a forced swim in water at 34 degrees 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 a t 10 degrees C was preserved in CB1 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 cannab inoid systems is necessary to allow the development of opioid-mediated resp onses to stress.