The distribution of the immediate-early gene and transcription factor
protein, c-Fos, was examined in the brains of guinea-pigs following tr
eatment with morphine: naloxone or naltrexone, or the induction of mor
phine withdrawal by these opioid antagonists. Guinea-pigs were given s
ubcutaneous injections of morphine sulphate or tartrate three times pe
r 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 administ
ered subcutaneously 1 h after the last dose of morphine or saline, and
the animals killed 1.5 h later by perfusion-fixation under deep sodiu
m pentobarbitone anaesthesia. In the animals that were treated with mo
rphine and withdrawn with either naloxone or naltrexone, c-Fos was exp
ressed in neurons in many brain areas, including the frontal and cingu
late cortices, olfactory tubercles, ventral pallidum, nucleus accumben
s, habenular, paraventricular thalamic nucleus, septal and arcuate nuc
lei, lateral and posterior hypothalamic areas, ventral tegmental area,
central grey, dorsal raphe nucleus, locus coeruleus, raphe magnus, la
teral paragigantocellular nucleus and solitary tract nucleus. In contr
ast, 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 distributio
n of c-Fos induced by morphine withdrawal reflects the complexity of t
he accompanying behavioural and autonomic responses.