Corticotropin-releasing factor (CRF) regulates the hypothalamic–pituitary–adrenal axis, coordinates the mammalian stress response, and acting primarily via the CRF₁ receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, the behavioral and autonomic activation that occurs following withdrawal in drug dependent animals resembles the mammalian stress response. Concordant with this view is evidence of enhanced CRF transcription, release and activity following withdrawal from several drugs of abuse. Conversely, CRF receptor antagonists have been demonstrated to reduce the severity of many drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed during withdrawal. To extend these findings, we investigated whether pretreatment with a selective CRF₁ receptor antagonist, R121919, is capable of similarly decreasing the autonomic, behavioral and neuroendocrine activation observed following precipitation of morphine withdrawal in dependent rats. The results indicate that pretreatment with R121919 attenuates the global severity of the precipitated morphine withdrawal syndrome as measured by the Gellert–Holtzman scale. In addition, rats pretreated with R121919 prior to precipitation of morphine withdrawal demonstrated decreased hypothalamic–pituitary–adrenal axis activation, as measured by plasma ACTH concentrations, and decreased early expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA. These findings suggest that activation of CRF neuronal systems via the CRF₁ receptor may be one element of the neurobiological mechanisms activated during drug withdrawal and that CRF₁ receptor antagonists may have a potential therapeutic role in the treatment of human drug withdrawal syndromes.