The possible effects on the morphine withdrawal signs of the nonspecific corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, the selective CRF receptor subtype 1 antagonist CP-154,526 and the selective CRF receptor subtype 2 antagonist antisauvagine-30 (AS-30) were investigated in rats. The most withdrawal signs, including jumping, teeth chatter, writhing, shakes, lacrimation, piloerection, irritability and diarrhoea, were attenuated by pretreatment with α-helical CRF (10 µg i.c.v.) and CP-154,526 (30 mg/kg i.p.). However, no morphine withdrawal signs except for diarrhea were significantly affected by pretreatment with AS-30 (10 µg, i.c.v.). To investigate the possible role of different CRFR antagonists (α-helical CRF, CP-154,526 and AS-30) in relapse to opiate dependence, the 28-day extinction of morphine-conditioned place preference (CPP) was used. The morphine-CPP disappeared following a 28-day extinction and then was reactivated by a single injection of 10 mg/kg morphine. Pretreatment with α-helical CRF (10 µg, i.c.v.) and CP-154,526 (30 mg/kg, i.p.) could significantly block this reactivation of morphine-CPP. In contrast, pretreatment with AS-30 (1 or 10 µg i.c.v.) did not affect this reactivation of morphine-CPP. The present study demonstrated that activation of the CRF receptor is involved in morphine withdrawal signs and relapse to morphine dependence, and that the role of CRF receptor subtypes 1 and 2 in withdrawal and reactivation of morphine dependence is not identical. CRF receptor subtype 1, but not subtype 2, is largely responsible for the action of the CRF system on opiate dependence. These results suggest that the CRF receptor antagonists, particularly the CRF receptor subtype 1 antagonist, might be of some value in the treatment and prevention of drug dependence.