Sensitivity to naloxone of the behavioral signs of morphine withdrawal andc-Fos expression in the rat CNS: A quantitative dose-response analysis

Several studies have used c-Fos expression to delineate the neural substrat e underlying naloxone-precipitated morphine withdrawal (MW). However, becau se behavioral manifestations of MW depend on both the degree of dependence and the doses of naloxone (NAL), a comprehensive study would require examin ing c-Fos expression in relation with the degree of MW. Here, changes in be havior and in c-Fos-like immunoreactivity (FLI) were studied in the same ra ts after injection of three doses of NAL to precipitate various degrees of MW. Fifteen established signs of MW were examined for 1 hour after NAL inje ction, and FLI was quantified in 52 regions of the brain and in the lumbosa cral spinal cord. Linear regression analyses were used to examine changes i n numbers of signs and FLI neurons with the doses of NAL, and data were con sidered dose-related for a statistical level of significance of P < 0.05. I n summary, autonomic signs of MW increased in a dose-related manner, wherea s somatomotor signs did not. After MW, 33 central nervous system regions ex hibited significant increases in FLI and were, thus, considered as importan t neural correlates of MW. Twenty of them displayed dose-related increases in c-Fos expression and correspond to regions related to autonomic function s. Low c-Fos expression was detected in some regions involved in motor cont rol or in reward, suggesting either their minor role in MW or a limitation of the technique. This dose-response analysis suggests that the increase in the severity of autonomic manifestations of MW is associated with a gradua l activation of major structures of the autonomic nervous system. J. Comp. Neurol. 433:272-297, 2001. (C) 2001 Wiley-Liss, Inc.