Effects of Pavlovian conditioning and MIF-I on the development of morphine tolerance in rats.

Thirty male Sprague-Dawley-derived rats were given daily IP injections of morphine (5.0 mg/kg) in the presence of a specific set of environmental cues for eleven consecutive days. Twelve hours after each morphine session, a control injection was given in a different environment. On Day 12 through 14 the environmental cues associated with each session were reversed. On Day 15 environmental cues associated with each session were the same as on Days 1-11. Analgesia was assessed by the tail-flick method 30 minutes after each morphine and control injection. Four independent groups (n=6) received either a lower (0.1 mg/kg) or a higher (5.0 mg/kg) dose of MIF-I either 10 minutes before or immediately after each morphine and control session. A control group received an injection of a diluent vehicle both before and after each session. None of these peptide-treatments significantly affected either acute action of morphine or the development of tolerance across days. Tail-flick latencies from both morphine and control sessions significantly decreased across days. On Day 12, when morphine was administered in the presence of cues not previously associated with its administration, tail-flick latencies were significantly longer than on the previous day. Tail-flick latencies did not change from Day 11 to Day 15 during control sessions. Morphine-session latencies did not change from Day 14 to Day 15, although they did decrease from Day 12 to Day 14. The significant morphine-induced analgesia on Day 15 of the experiment increases a remarkable resistance to the development of tolerance to morphine. The results partially support the hypothesis proposed by Siegel [115-18] that principles of Pavlovian conditioning exert an important influence on the development of tolerance to morphine.