The central extended amygdala, a forebrain macrostructure, may represent a common substrate for acute drug reward and the dysphoric effects of drug withdrawal. To test its involvement during opiate withdrawal, we studied the distribution of c-Fos immunoreactive neurons, in relation to their neuropeptide content, in brain sections from morphine-dependent or naive rats, killed 90 min after naloxone or saline intraperitoneal injection. Naloxone treatment in naive rats induced a slight increase in c-Fos immunoreactivity in the central amygdaloid nucleus, the lateral bed nucleus of the stria terminalis and the interstitial nucleus of the posterior limb of the anterior commissure. In morphine-dependent rats, naloxone injection significantly increased the number of c-Fos-positive neurons in these structures as well as in the majority of the other central extended amygdala components. Double immunocytochemistry was used to determine the neurochemical nature of c-Fos-positive neurons in the central extended amygdala. Corticotropin-releasing factor- and methionine-enkephakin-immunoreactive neurons displayed c-Fos immunoreactivity in naive rats after naloxone injection, whereas only enkephalinergic neurons were found to be c-Fos positive in morphine-dependent rats after naloxone injection. The possible involvement of the corticotropin-releasing factor system during withdrawal is discussed. These results suggest that the whole central extended amygdala is activated during opiate withdrawal, with a lateral to medial decreasing gradient, and emphasize the role of peptidergic systems in this morphofunctional continuum.