Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 338, Issue 5, pp 553–559 | Cite as

Morphine tolerance and nonspecific subsensitivity of the longitudinal muscle myenteric plexus preparation of the guinea-pig to inhibitory agonists

  • David A. Taylor
  • Judith A. Leedham
  • Nancy Doak
  • William W. Fleming


  1. 1.

    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.

  2. 2.

    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.

  3. 3.

    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.

  4. 4.

    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.

  5. 5.

    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 words

Opioid tolerance Subsensitivity Myenteric plexus Guinea-pig ileum Spare receptors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abel PW, Urquilla PR, Goto K, Westfall DP, Robinson RL, Fleming WW (1981) Chronic reserpine treatment alters sensitivity and membrane potential of the rabbit saphenous artery. J Pharmacol Exp Ther 217:430–439PubMedGoogle Scholar
  2. Bauer V, Kuriyama H (1982) Homogenous and non-homogenous distribution of inhibitory and excitatory adrenoceptors in the longitudinal muscle of the guinea-pig ileum. Br J Pharmacol 76:603–611CrossRefGoogle Scholar
  3. Chavkin C, Goldstein A (1984) Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus. Proc Natl Acad Sci 81:7253–7257CrossRefGoogle Scholar
  4. Collier HOJ (1965) A general theory of the genesis of drug dependence by induction of receptors. Nature 205:181–182CrossRefGoogle Scholar
  5. Collier HOJ (1966) Tolerance, physical dependence and receptors. Adv Drug Res 3:171–188Google Scholar
  6. Collier HOJ, Plant NT, Tucker JF (1983) Pertussis vaccine inhibits the chronic but not acute action of normorphine on the myenteric plexus of guinea-pig ileum. Eur J Pharmacol 91:325–326CrossRefGoogle Scholar
  7. Collier HOJ, Tucker JF (1983) Novel form of drug dependence on adenosine in guinea-pig ileum. Nature 302:618–621CrossRefGoogle Scholar
  8. Cox BM, Padhya R (1977) Opiate binding and effect in ileum preparations from normal and morphine pretreated guinea-pigs. Br J Pharmacol 61:271–278CrossRefGoogle Scholar
  9. Dingledine R, Goldstein A (1976) Effect of synaptic transmission blockade on morphine action in the guinea-pig myenteric plexus. J Pharmacol Exp Ther 196:97–106PubMedGoogle Scholar
  10. Ehrenpreis S, Greenberg J, Comaty JE (1975) Mechanism of development of tolerance to injected morphine by guinea-pig ileum. Life Sci 17:49–54CrossRefGoogle Scholar
  11. Fleming WW (1976) The variable sensitivity of excitable cells: possible mechanisms and biological significance. Rev Neurosci 2:43–90Google Scholar
  12. Fleming WW (1980) The electrogenic Na+,K+-pump in smooth muscle: physiologic and pharmacologic significance. Ann Rev Pharmacol 20:129–149CrossRefGoogle Scholar
  13. 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
  14. Fleming WW, Westfall UP (1988) Adaptive supersensitivity. In: Trendelenburg U, Weiner N (eds) Catecholamines, Handbook of Pharmacology. Springer, Berlin Heidelberg New York Tokyo, pp 509–559CrossRefGoogle Scholar
  15. Furness JB, Costa M (1987) The enteric nervous system. Churchill Livingstone, Edinburgh, London, Melbourne New YorkGoogle Scholar
  16. Gerthoffer WT, Fedan JS, Westfall DP, Goto K, Fleming WW (1979) Involvement of the sodium-potassium pump in the mechanism of postjunctional supersensitivity of the vas deferens of the guinea-pig. J Pharmacol Exp Ther 210:27–36PubMedGoogle Scholar
  17. Gillan MGC, Kosterlitz HW, Robson LE, Waterfield AA (1979) The inhibitory effects of presynaptic-adrenoceptor agonists on contractions of guinea-pig ileum and mouse vas deferens in the morphine-dependent and withdrawn states produced in vitro. Br J Pharmacol 66:601–608CrossRefGoogle Scholar
  18. Goldstein A, Schulz R (1973) Morphine-tolerant longitudinal muscle strip from guinea-pig ileum. Br J Pharmacol 48:655–666CrossRefGoogle Scholar
  19. Hawthorn MH, Taylor DA, Fleming WW (1987) Characteristics of adaptive supersensitivity in the left atrium of the guinea pig. J Pharmacol Exp Ther 241:453–457PubMedGoogle Scholar
  20. 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
  21. Johnson SM, Westfall DP, Howard SA, Fleming WW (1978) Sensitivities of the isolated ileal longitudinal smooth muscle-myenteric plexus and hypogastric nerve-vas deferens of the guinea pig after chronic morphine pellet implantation. J Pharmacol Exp Ther 204:54–66PubMedGoogle Scholar
  22. Johnson SM, Williams JT, Costa M, Furness JB (1987) Naloxone-induced depolarization and synaptic activation of myenteric neurons in morphine-dependent guinea pig ileum. Neuroscience 21:595–602CrossRefGoogle Scholar
  23. 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
  24. Leedham JA, Fleming WW, Taylor DA (1988) Morphine tolerance is associated with electrophysiological changes in S-type neurons. FASEB J 2:A1808, 1988Google Scholar
  25. Leedham JA, Pennefather JN (1986) Selectivities of some agonists acting at α1- and α2-adrenoreceptors in the rat vas deferens. J Auton Pharmacol 6:39–46CrossRefGoogle Scholar
  26. Morita K, North RA (1982) Opiate activation of potassium conductance in myenteric neurons: inhibition by calcium ion. Brain Res 242:145–150CrossRefGoogle Scholar
  27. North RA, Katayama Y, Williams JT (1979) On the mechanism and site of action of enkephalin on single myenteric neurons. Brain Res 165:67–77CrossRefGoogle Scholar
  28. North RA, Tonini M (1977) The mechanism of action of narcotic analgesics in the guinea-pig ileum. Br J Pharmacol 61:541–549CrossRefGoogle Scholar
  29. Paton DM (1981) Structure-activity relations for presynaptic inhibition of noradrenergic and cholinergic transmission by adenosine: evidence for action on A1 receptors. J Auton Pharmacol 1:287–290CrossRefGoogle Scholar
  30. 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
  31. Rang HP (1964) Stimulant actions of volatile anesthetics on smooth muscle. Br J Pharmacol 22:356–365Google Scholar
  32. 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
  33. Ruffolo RR (1982) Important concepts of receptor theory. J Auton Pharmacol 2:277–295CrossRefGoogle Scholar
  34. Schulz R, Goldstein A (1973) Morphine tolerance and supersensitivity to 5-hydroxytryptamine in the myenteric plexus of the guinea pig. Nature 251:329–331CrossRefGoogle Scholar
  35. Starke K (1981) α-Adrenoceptor sub-classification. Rev Physiol Biochem Pharmacol 88:199–228CrossRefGoogle Scholar
  36. Wikberg JES (1978) Pharmacological classification of adrenergic α-receptors in the guinea-pig. Nature 273:164–166CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • David A. Taylor
    • 1
  • Judith A. Leedham
    • 1
  • Nancy Doak
    • 1
  • William W. Fleming
    • 1
  1. 1.Department of Pharmacology and ToxicologyWest Virginia University Health Sciences CenterMorgantownUSA

Personalised recommendations