Distribution of c-Fos in guinea-pig brain following morphine withdrawal

The distribution of the immediate-early gene and transcription factor protein, c-Fos, was examined in the brains of guinea-pigs following treatment with morphine, naloxone or naltrexone, or the induction of morphine withdrawal by these opioid antagonists. Guinea-pigs were given subcutaneous injections of morphine sulphate or tartrate three times per day in increasing doses for three days (total dose 690 mg/kg as base). Control animals received saline injections. Naloxone hydrochloride (30 mg/kg), naltrexone hydrochloride (15 mg/kg) or saline was administered subcutaneously 1 h after the last dose of morphine or saline, and the animals killed 1.5 h later by perfusion-fixation under deep sodium pentobarbitone anaesthesia. In the animals that were treated with morphine and withdrawn with either naloxone or naltrexone, c-Fos was expressed in neurons in many brain areas, including the frontal and cingulate cortices, olfactory tubercles, ventral pallidum, nucleus accumbens, habenular, paraventricular thalamic nucleus, septal and arcuate nuclei, lateral and posterior hypothalamic areas, ventral tegmental area, central grey, dorsal raphe nucleus, locus coeruleus, raphe magnus, lateral paragigantocellular nucleus and solitary tract nucleus. In contrast, only low levels of c-Fos were found in brains of animals that had been treated for three days with morphine followed by saline, or with saline followed by naltrexone or naloxone. The widespread distribution of c-Fos induced by morphine withdrawal reflects the complexity of the accompanying behavioural and autonomic responses.