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Vol. 288, Issue 3, 1107-1116, March 1999
Department of Pharmacology (C.A.F., G.L.W.),
Graduate Program in
Neuroscience (G.L.W.), University of Minnesota, Minneapolis, Minnesota
Morphine (Mor) tolerance has been attributed to a reduction of
opioid-adrenergic 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°C) tail-flick
test. After the tail-flick latencies returned to baseline levels,
dose-response curves were generated to Mor, Clon, and Mor-Clon
combinations in tolerant and control mice. Development of tolerance was
confirmed by significant rightward shifts of the Mor dose-response
curves in tolerant mice compared with controls. Isobolographic analysis
was conducted; the experimental combined ED50 values were
compared statistically against their respective theoretical additive
ED50 values. In all Mor-pretreated groups, the combination
of Mor and Clon resulted in significant leftward shifts in the
dose-response curves compared with those of each agonist administered
separately. In all tolerant and control groups, the combination of Mor
and Clon produced an ED50 value significantly less than the
corresponding theoretical additive ED50 value. Mor and Clon
synergized in Mor-tolerant as well as in control mice. Spinally
administered adrenergic/opioid synergistic combinations may be
effective therapeutic strategies to manage pain in patients apparently
tolerant to the analgesic effects of Mor.
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