Sensitivity to naloxone of the behavioral signs of morphine withdrawal and c-Fos expression in the rat CNS: a quantitative dose-response analysis.

Several studies have used c-Fos expression to delineate the neural substrate underlying naloxone-precipitated morphine withdrawal (MW). However, because behavioral manifestations of MW depend on both the degree of dependence and the doses of naloxone (NAL), a comprehensive study would require examining c-Fos expression in relation with the degree of MW. Here, changes in behavior and in c-Fos-like immunoreactivity (FLI) were studied in the same rats 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 injection, and FLI was quantified in 52 regions of the brain and in the lumbosacral spinal cord. Linear regression analyses were used to examine changes in numbers of signs and FLI neurons with the doses of NAL, and data were considered dose-related for a statistical level of significance of P < 0.05. In summary, autonomic signs of MW increased in a dose-related manner, whereas somatomotor signs did not. After MW, 33 central nervous system regions exhibited significant increases in FLI and were, thus, considered as important neural correlates of MW. Twenty of them displayed dose-related increases in c-Fos expression and correspond to regions related to autonomic functions. Low c-Fos expression was detected in some regions involved in motor control 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 gradual activation of major structures of the autonomic nervous system. Copyright 2001 Wiley-Liss, Inc.