The aim of this study was to determine whether sensitization occurred to morphine withdrawal. Guinea-pigs were treated twice daily with increasing doses of morphine (10-100 mg/kg s.c.) for 3 days followed by injection of morphine 100 mg/kg on the fourth day. Sixty min after the last morphine injection, animals were withdrawn from morphine with naltrexone, 15 mg/kg s.c., and locomotor activity and all other behaviours scored over 90 min. Animals were then rested for 3 days. This procedure was repeated twice over the next 2 weeks. Control animals were treated with saline for the first two treatment cycles. Guinea-pigs subjected to three cycles of morphine withdrawal showed a significant increase in the total number of withdrawal behaviour counts over the 90-min observation period following the third cycle of withdrawal compared with the first and second withdrawal cycles. However, locomotor activity, a major sign of morphine withdrawal in guinea-pigs, was not significantly increased. Fos-LI was markedly increased in the repeatedly withdrawn animals in several brain regions, including amygdala, dorsal striatum, thalamus, ventral tegmental area, and ventrolateral periaqueductal gray area. It is concluded that sensitization to morphine withdrawal occurs in guinea-pigs.
European Journal of Pharmacology Vol. 509, no. 2-3, p. 135-143