Morphine tolerance and nonspecific subsensitivity of the longitudinal muscle myenteric plexus preparation of the guinea-pig to inhibitory agonists
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The sensitivity of the longitudinal smooth muscle/myenteric plexus (LM/MP) to agonists which reduce the amplitude of neurogenic contractions was studied in preparations obtained from animals implanted with either placebo or morphine (75 mg/pellet) pellets 7 days prior.
Tolerance or subsensitivity to morphine was observed following chronic treatment with morphine and was revealed as a rightward shift of the concentration-response curve to morphine. The degree of tolerance decayed modestly with time after removal from a morphine containing environment suggesting a time dependence for the loss of subsensitivity to morphine.
LM/MP preparations from animals pretreated with morphine also developed subsensitivity to the inhibitory effects of the purine analogue, 2-chloroadenosine. Subsensitivity to 2-chloroadenosine was seen as a parallel rightward shift of the concentration-response curve in morphine-tolerant preparations. The magnitude of the loss in sensitivity was comparable to that observed to morphine.
A reduction in sensitivity of the LM/MP following chronic treatment with morphine was also observed to the inhibitory effects of the alpha2 adrenoceptor agonists, clonidine and xylazine. In contrast to the results obtained with morphine and 2-chloroadenosine, the development of subsensitivity to alpha2 adrenoceptor agonists was characterized by a marked reduction in slope and a depression of the maximum response.
These data suggest that myenteric neurons possess spare receptors for morphine and 2-chloroadenosine but not for clonidine and xylazine. Furthermore, the studies support the idea that tolerance is associated with a general cellular change or adaptation which impacts on all of these inhibitory substances in such a way as to reduce their efficacy.
Key wordsOpioid tolerance Subsensitivity Myenteric plexus Guinea-pig ileum Spare receptors
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- Collier HOJ (1966) Tolerance, physical dependence and receptors. Adv Drug Res 3:171–188Google Scholar
- Fleming WW (1976) The variable sensitivity of excitable cells: possible mechanisms and biological significance. Rev Neurosci 2:43–90Google Scholar
- Fleming WW, McPhillips JJ, Westfall DP (1973) Postjunctional supersensitivity and subsensitivity of excitable tissues to drugs. Rev Physiol Biochem Exp Pharmacol 68:56–119Google Scholar
- Furness JB, Costa M (1987) The enteric nervous system. Churchill Livingstone, Edinburgh, London, Melbourne New YorkGoogle Scholar
- Jaffe JA, Sharpless SK (1968) Pharmacological denervation supersensitivity in the CNS. A theory of physical dependence. Res Publ Ass Nerv Ment Dis 46:226–247Google Scholar
- Kosterlitz HW, Lord JAH, Watt AJ (1972) Morphine receptor in the myenteric plexus of the guinea pig ileum. In: Kosterlitz HW, Collier HOJ, Villarreal JE (eds) Agonist and antagonist actions of narcotic analgesic drugs. Macmillan Press, London, pp 45–61Google Scholar
- Leedham JA, Fleming WW, Taylor DA (1988) Morphine tolerance is associated with electrophysiological changes in S-type neurons. FASEB J 2:A1808, 1988Google Scholar
- Paton WDM (1957) The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum. Br J Pharmacol 12:119–127Google Scholar
- Rang HP (1964) Stimulant actions of volatile anesthetics on smooth muscle. Br J Pharmacol 22:356–365Google Scholar
- Robson LE, Gillan MGC, Watertield AA, Kosterlitz HW (1978) The inhibitory effects of presynaptic α-adrenoceptor agonists on the contractions of the guinea-pig and mouse vas deferens in the morphine-dependent and withdrawn states. In: Van Ree JM, Terenius L (eds) Characteristics and function of opioids. Elsevier, North Holland, pp 67–68Google Scholar