POTENTIATION OF ACUTE OPIOID-INDUCED RESPIRATORY DEPRESSION AND REVERSAL OF TOLERANCE BY THE CALCIUM-ANTAGONIST NIMODIPINE IN AWAKE RATS

The interaction between sufentanil, a mu-opioid agonist, and the Ca2antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstra ted that chronic treatment with nimodipine together with sufentanil in creases the analgesic potency of the opioid 50 fold. Therefore, we hav e investigated whether the opioid-induced respiratory depression is po tentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10- 80 mug/kg) consistently induced a dose-dependent respiratory depressio n. Pretreatment with nimodipine (200 mug/kg) potentiated this effect b ut to a lesser extent than it potentiated analgesia. After chronic adm inistration of the opioid (2 mug/h, 7 days) tolerance was manifested a s a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 mug/h) administered concurrently with su fentanil for 7 days counteracted the tolerance to respiratory depressi on but no additional potentiation was observed. These results demonstr ate that the interaction between nimodipine and sufentanil is not limi ted to antinociception but also exends to respiratory depression. Howe ver, compared with analgesia, the clinical relevance of a potential in crease in opioid-induced respiratory depression by nimodipine may be n egligible.