Interval-dependent inhibition of morphine sensitization of ambulation in mice by post-morphine treatment with naloxone or restraint.

The ambulation-increasing effect of morphine (10 mg/kg SC) persisted for approximately 3 h with a peak effect at around 1 h after the administration. This was examined on four occasions at 3-day intervals. Thus, treatment regimen-induced sensitization and the 3-h overall activity in the fourth administration was about 1.7 times higher than that in the first administration. Post-morphine treatments with naloxone (1 mg/kg SC) at 0 (i.e., simultaneously with) to 30 min after each morphine administration almost completely inhibited the induction of morphine sensitization. However, post-morphine treatments with naloxone at 1 h and later had no such inhibitory effect. Similarly, physical restriction of the ambulation of mice for 3 h (restraint), by putting them in a jar (6 cm in diameter, and 15 cm in height) inhibited the induction of morphine sensitization when restrain was started 0-30 min after each administration of morphine. Restraint starting 1 h and later did not alter the morphine sensitization. Post-morphine treatment with saline at any times did not change morphine sensitization. Furthermore, repeated administration of saline alone, naloxone alone, and saline with naloxone post-treatment or restraint did not change the sensitivity to morphine. These results clearly indicate that free ambulation for at least 1 h after the administration of morphine, i.e., the latency to reach the peak effect, is required completely to induce sensitization to morphine in terms of ambulation in mice.