Involvement of the Cannabinoid CB1 Receptor in the Oppioid Inhibition of the Response to Cholecystochinin and Acute Withdrawal Response

Numerous recent studies have reported major functional interactions between cannabinoid and opioid systems. These interactions can be studied in the myenteric plexus-longitudinal muscle isolated preparations. We had previously shown that in the guinea-pig ileum (GPI), the opioid acute withdrawal response is under the inhibitory control of several systems; mu-opioid agonist exposure indirectly activates the kappa-opioid system; conversely, exposure to a kappa-opioid agonist indirectly activates the mu-system; the indirectly activated opioid system inhibits the withdrawal response. The adenosine A1 system is also indirectly activated by opioids and it inhibits the withdrawal response. We had also shown that indirect activation is prevented or antagonized by cholecystokinin (CCK-8). In GPI preparations briefly exposed to the mu-agonist, dermorphine (DERM) and then challenged with naloxone (NL), the cannabinoid CB1 antagonist, SR141716 (SR), increased the withdrawal responses to NL, but only did so in presence of a kappa-opioid and an adenosine A(1) antagonist. Under similar experimental conditions, SR also enhances the kappa-opioid withdrawal response. In opioid agonist/CCK-8/NL tests, SR antagonized the inhibition of the tissue response to CCK-8 induced by the mu- or kappa-opioid agonist and increased the kappa-withdrawal response, but not the mu-withdrawal response. However, the dose-response curve against dermorphine inhibition of the response to CCK-8 was bell-shaped and the highest SR concentration also significantly decreased the mu-withdrawal response. In preparations exposed to dermorphine or to the kappa-agonist, U-50,488H, the cannabinoid agonist WIN 55,212-2 increased the opioid-induced inhibition of the tissue response to CCK-8 and decreased the NL-induced responses. These results show that opioid exposure may also activate the cannabinoid CB1 system, which leads to an inhibition of the opioid acute withdrawal response. This phenomenon and the antagonistic effect of SR on the opioid-induced inhibition of the response to CCK-8 suggest that reciprocal interaction between opioid and cannabinoid systems are operating in the enteric nervous system.