Induction of sensitization to hyperactivity caused by morphine in mice: effects of post-drug environments.

Mice given five repeated administrations of morphine (10 mg/kg sc) at 3 day intervals in a round tilting-type activity cage (20 cm in diameter) or round spaces 15-30 cm in diameter with fixed floor showed almost the same level of ambulatory sensitization to morphine. Whereas, mice given morphine in the same schedule in spaces 4 and 12 cm, but not 6 and 9 cm, in diameter demonstrated a partial increase in the sensitivity to morphine. Furthermore, mice given morphine five times in a transparent cage (20W x 25L x 15H cm) with woodchip bedding, that was the same as the home cage, showed a weak and strong ambulatory sensitization when they were placed in group of ten and singly, respectively, for 3 h after each morphine administration. Repeated administrations of saline to mice in the space 4 cm in diameter resulted in increased sensitivity to morphine. However, the pretreatment with saline in the other environments (activity cage, spaces 6-30 cm in diameter with fixed floor, and home cage-like cage in which mice were placed singly or in group of ten) did not change the sensitivity to morphine. These results suggest that repeated experience of pharmacological effect of morphine and the resultant ambulation is one of the most important factors for induction of strong ambulatory sensitization to morphine in mice. It is estimated that a space 15 cm in diameter, which corresponds to 2-2.5 times as long as the body length without tail is a minimum requirement for induction of strong ambulatory sensitization to morphine. In contrast, even though mice are placed in a sufficient space for ambulation, an interference of ambulation by the other mice acts to inhibit the induction of ambulatory sensitization. It is also suggested that a strong stress caused by restraint is responsible for significant increase in sensitivity to morphine.