Involvement of the cyclic AMP system in the switch from tolerance into supersensitivity to the antinociceptive effect of the opioid sufentanil

We have previously demonstrated that chronic and simultaneous treatment of rats with the μ‐opioid receptor agonist sufentanil and the Ca 2+ channel blocker nimodipine, not only prevented tolerance development, but the animals became supersensitive to the antinociceptive effect of the opioid. The focus of the present work was to determine the possible involvement of cross interactions between the adenylyl cyclase pathway and L‐type voltage‐sensitive Ca 2+ ‐channels, in modulating the switch from opioid tolerance into supersensitivity. The modulatory effect of sufentanil on adenylyl cyclase activity was determined by measuring cyclic AMP production in slices from the cortex of rats rendered tolerant or supersensitive to the antinociceptive effect of the opioid. Tolerance was induced by chronic infusion of sufentanil, at a rate of 2 μg h −1 , for 7 days. Supersensitivity was induced by concurrent infusion of sufentanil (2 μg h −1 ) and nimodipine (1 μg h −1 ) for 7 days. Antinociception was evaluated by the tail‐flick test. Tolerance to the analgesic effect of sufentanil was associated with a significant reduction in the response of adenylyl cyclase to forskolin. Furthermore, the effect of the opioid on forskolin‐induced cyclic AMP accumulation was abolished. On the other hand, supersensitivity to the analgesic effect of the opioid was associated with an increase in both, the adenylyl cyclase response to forskolin, and the opioid inhibition of cyclic AMP production. We suggest that sustained L‐type Ca 2+ channel blockade may result in changes in the adenylyl cyclase effector system triggered by μ‐opioid receptor activation, leading to the switch from opioid tolerance into supersensitivity.British Journal of Pharmacology (2000) 130 , 174–180; doi: 10.1038/sj.bjp.0703304