Abstract
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 madeacutely 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.
Footnotes
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Send reprint requests to: Dr. George L. Wilcox, Department of Pharmacology, University of Minnesota, 3-249 Millard Hall, 435 Delaware St. SE, Minneapolis, MN 55455. E-mail:george{at}med.umn.edu
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↵1 This research was supported by National Institute on Drug Abuse Grants R01-DA-01933 and R01-DA-04274. Alcohol, Drug Abuse, and Mental Health Administration Training Grant T32A07234, awarded by the National Institute on Drug Abuse, supported C.A.F.
- Abbreviations:
- Clon
- Clonidine
- i.t.
- intrathecal
- %MPE
- percentage of maximum possible effect
- Mor
- morphine
- i.c.v.
- intracerebroventricular
- Received June 10, 1998.
- Accepted October 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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