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OtherGASTROINTESTINAL PHARMACOLOGY

Morphine Tolerance and Dependence in the Rat Intestine In Vivo

Cynthia L. Williams, Cynthia C. Bihm, Gary C. Rosenfeld and Thomas F. Burks
Journal of Pharmacology and Experimental Therapeutics February 1997, 280 (2) 656-663;
Cynthia L. Williams
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Cynthia C. Bihm
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Gary C. Rosenfeld
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Thomas F. Burks
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Abstract

There has been no previous demonstration of opioid tolerance and dependence with respect to the propulsive and contractile activities of the gut in vivo. In the experiments described herein, morphine was administered continuously (1 mg/kg/hr s.c., 72 hr) and/or by bolus injection (2 mg/kg) and intestinal motility and transit were evaluated in unanesthetized rats. Tolerance in intestinal motility (contractions) and propulsion (transit) was measured in two ways,i.e., by measuring the time required for motility and propulsion to return to control values and by measuring the loss of effectiveness of bolus morphine administered to animals receiving continuous infusion of the opiate. The dose of morphine chosen for continuous administration (1 mg/kg/hr s.c. via Alzet minipumps) was based on the dose at which morphine inhibited intestinal propulsion by 50%. Morphine (1 mg/kg/hr) decreased the frequency of contractions in, and propulsion along, the small bowel and colon and produced mild antinociception. The frequency of duodenal and colonic contractions returned to normal within 13 to 16 hr. After 24 hr of morphine treatment, the inhibitory effects of bolus doses of morphine on motility and transit were diminished; the effects were eventually lost (48 hr). Similarly, the antinociceptive effects of bolus doses of morphine were diminished by 18 hr and lost by 24 hr. Naloxone (0.1 mg/kg s.c.) given to morphine-tolerant animals (72 hr) resulted in an increase in the frequency and amplitude of contractions in the colon, an increase in the propulsive activity of the small intestine and colon and diarrhea. These results provide direct demonstration of opioid tolerance and dependence of contractile and propulsive activity in the rat intestine in vivo.

Footnotes

  • Send reprint requests to: Cynthia L. Williams, Department of Pharmacology, The University of Texas Health Science Center, P.O. Box 20708, Houston, TX 77225.

  • ↵1 This work was supported by United States Public Health Service Grant DA02163.

  • Abbreviations:
    CNS
    central nervous system
    D50
    effective dose to inhibit intestinal propulsion by 50%
    ENS
    enteric nervous system
    G.C.
    geometric center
    • Received March 19, 1996.
    • Accepted October 7, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 2
1 Feb 1997
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OtherGASTROINTESTINAL PHARMACOLOGY

Morphine Tolerance and Dependence in the Rat Intestine In Vivo

Cynthia L. Williams, Cynthia C. Bihm, Gary C. Rosenfeld and Thomas F. Burks
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 656-663;

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OtherGASTROINTESTINAL PHARMACOLOGY

Morphine Tolerance and Dependence in the Rat Intestine In Vivo

Cynthia L. Williams, Cynthia C. Bihm, Gary C. Rosenfeld and Thomas F. Burks
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 656-663;
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