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Equipotent antinociceptive doses, as determined by a tail-flick response, for centrally administered (periaqueductal gray) morphine (M) and d-Ala2, d-Leu5 enkephalin (DADLE) were established as 5 μg and 19 μg, respectively. Chronic (28 day) subcutaneous infusion of clomipramine (CMI) via an Alzet minipump attenuated both central M-and DADLE-induced analgesia by day 15; attenuation persisted for the duration of the infusion (day 29). Within 7 days following removal of the pump, antinociceptive responses to M and DADLE returned to near pre-CMI Ievels.Our results indicate a similarity between M and DADLE with regard to attenuation of their antinociceptive action by chronic CMI. This attenuation may be due to decreased mu opioid receptor sensitivity or density resulting from chronic tricyclic antidepressant administration.