The role of contextual cues on counterirritation in the development process of analgesic tolerance to morphine.

Tolerance to morphine analgesia was determined by daily exposing rats either to the same box or different boxes during repeated administration of formalin (2.5%, 0.4 mL/body, sc) and morphine (5 mg/kg, sc). The analgesic effect was determined daily for four consecutive days by exposing rats to either the same box or different boxes, and the process of tolerance development was assessed by a hot plate test (52.5 degrees C). The rats were divided into four groups: one group received formalin and morphine in the same context (Group FM-Same), one group in the different context (Group FM-Diff), one group received saline and morphine in the same context (Group SM-Same), two groups received formalin in the same or different contexts (Groups FS-Same or FS-Diff), and one group received saline in the same context (Group SS-Same). The response latency of Group SM-Same was decreased from Day 2 to a level similar to that of Group SS-Same on Day 4, while that of FM-Same decreased more slowly. The latency of Group FM-Diff maintained the level of Day 2 until Day 4, being significantly longer than that of FM-Same. In the Extinction Phase, all rats received formalin and saline injections in the same box they had been exposed to on Day 1. On the first day, hyperalgesia was evident in Group SM-Same alone. In the Re-test Phase, the rats underwent a second morphine injection, and showed recovery from tolerance. These results indicate that formalin-induced chronic stress pain reduces tolerance development to morphine, and the mutual influence of pain, counterirritation, between formalin and hot-plate, facilitates the effect of contextual cues by inhibiting an associative learning.