Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine

Morphine (Mor) tolerance has been attributed to a reduction of opioid-adren ergic antinociceptive synergy at the spinal level. The present experiments tested the interaction of intrathecally (i.t.) administered Mor-clonidine ( Clon) combinations in mice made acutely or chronically tolerant to Mor. ICR mice were pretreated with Mor either acutely (40 nmol i.t., 8 h; 100 mg/kg s.c., 4 h) or chronically (3 mg/kg s.c. every 6 h days 1 and 2; 5 mg/kg s. c. every 6 h days 3 and 4). Antinociception was detected via the hot water (52.5 degrees C) tail-flick test. After the tail-flick latencies returned t o baseline levels, dose-response curves were generated to Mor, Cion, and Mo r-Clon combinations in tolerant and control mice. Development of tolerance was confirmed by significant rightward shifts of the Mor dose-response curv es in tolerant mice compared with controls. Isobolographic analysis was con ducted; the experimental combined ED50 values were compared statistically a gainst their respective theoretical additive ED50 values. In all Mor-pretre ated groups, the combination of Mor and Cion resulted in significant leftwa rd shifts in the dose response curves compared with those of each agonist a dministered separately. In all tolerant and control groups, the combination of Mor and Cion produced an ED50 value significantly less than the corresp onding theoretical additive ED50 value. Mor and Cion synergized in Mor-tole rant as well as in control mice. Spinally administered adrenergic/opioid sy nergistic combinations may be effective therapeutic strategies to manage pa in in patients apparently tolerant to the analgesic effects of Mor.