Abstract
Short-term morphine stimulates vagal bradycardia. This led us to propose the hypothesis that chronically administered morphine would down-regulate myocardial muscarinic receptor systems. Dogs received morphine continuously for 2 weeks through an s.c. catheter, and cellular aspects of parasympathetic control of the heart were examined. Contrary to expectations, morphine increased muscarinic receptor density in the right atrium and left ventricle by 17 and 34%, respectively, with no change in the apparent affinity of the receptor (KD). Morphine also increased the expression of the G protein Giα by 115 and 233%, respectively, in right atrial and left ventricular sarcolemmal membranes. Morphine increased ventricular and atrial Gsα to a much lesser degree (49 and 25%). Morphine failed to alter basal or maximally stimulated (forskolin plus MnCl2) adenylate cyclase activity. The maximum cyclase activation by isoproterenol and the maximum inhibition by carbachol were similarly unaltered by morphine. Morphine reduced the ventricular but not atrial norepinephrine. Both long- and short-term morphine lowered tissue epinephrine content, suggesting that short-term morphine reduces extraneuronal uptake. Potential systemic and cellular models for myocardial adaptation to morphine are proposed, including sequential sympathetic and parasympathetic compensations.
Footnotes
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Send reprint requests to: James L Caffrey, Ph.D., Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. E-mail:JCaffrey{at}hsc.unt.edu
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↵1 This work was supported by NIDA Grant E1F31-DA05772 (to L.D.N.).
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↵2 Dr. Napier was supported by NIDA grant E1F31DA05772.
- Abbreviations:
- QNB
- quinuclidinyl benzilate
- Received September 9, 1999.
- Accepted July 20, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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