Summary
Guinea-pigs were treated with morphine for 6–8 days by subcutaneous implantation of pellets, each containing a mixture of morphine base (120 mg) and morphine hydrochloride (35 mg). Each guinea-pig received a single pellet. Mechanical activity of the circular muscle was recorded in vitro in preparations comprising the circular muscle and myenteric plexus. Exposure to morphine was maintained by addition of 1 μM morphine to the organ baths. After 90 min, morphine was withdrawn, either by repeatedly washing tissues in morphine-free Krebs' solution , or by addition of naloxone to reduce the occupancy of the opioid receptors by morphine. Withdrawal of morphine resulted in markedly enhanced contractile activity compared with that in circular muscle-myenteric plexus preparations from untreated control guinea-pigs. The withdrawal contractions were abolished by tetrodotoxin (600 nM) and greatly reduced by hyoscine (1 μM), indicating that they resulted from action potential discharge in myenteric neurons that release acetylcholine onto the circular muscle. Activation of the cholinergic excitatory motor neurons was not secondary to synaptic activation by cholinergic interneurons, because hexamethonium (100 μM) did not affect withdrawal contractions. The withdrawal response may therefore arise in the cholinergic excitatory motor neurons themselves, or in neurons that activate them via noncholinergic mechanisms.
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References
Collier HO (1980) Cellular site of opiate dependence. Nature 283:625–629
Collier HO, Cuthbert NJ, Francis DL (1981) Model of opiate dependence in the guinea-pig isolated ileum. Br J Pharmacol 73:921–932
Collier HO, Tucker JF (1984) Sites and mechanisms of dependence in the myenteric plexus of guinea pig ileum. Natl Inst Drug Abuse Res Monogr Ser 54:81–94
Cox (1979) Characteristics of the increased response to electrical stimulation of ileum preparations from morphine pretreated guinea pigs. Life Sci 24:1503–1510
Ehrenpreis S, Light I, Schonbuch GH (1972) Use of the electrically stimulated guinea-pig ileum to study potent analgesics. In: Singh JM, Miller LH, Lal H (eds) Drug addiction: experimental pharmacology. Futura Publishing Co., New York, pp 319–341
Frederickson RCA, Hewes CR, Aiken JW (1976) Correlation between the in vivo and in vitro expression of opiate withdrawal precipitated by naloxone; their antagonism by 1-(−)-tetrahydrocannabinol. J Pharmacol Exp Ther 199:375–384
Goldstein A, Schulz R (1973) Morphine-tolerant longitudinal muscle strip from guinea-pig ileum. Brit J Pharmacol 48:655–666
Ito Y, Tajima K (1980) Action of morphine on the neuro-effector transmission in the guinea-pig ileum and in the mouse vas deferens. J Physiol (Lond) 307:367–383
Johnson SM, Westfall DP, Howard SA, Fleming WW (1978) Sensitivities of the isolated ileal longitudinal smooth musclemyenteric plexus and hypogastric nerve-vas deferens of the guinea pig after chronic morphine pellet implantation. J Pharmacol Exp Ther 204:54–66
Johnson SM, Katayama Y, Morita K, North RA (1981) Mediators of slow synaptic potentials in the myenteric plexus of the guinea-pig ileum. J Physiol 320:175–186
Johnson SM, Humphreys CMS, Costa M (1987a) Sustained nervemediated contractions of guinea-pig ileum during morphine withdrawal by washout. Eur J Pharmacol 141:41–50
Johnson SM, Costa M, Humphreys CMS, Shearman R (1987b) Inhibitory effects of opioids in a circular muscle-myenteric plexus preparation of guinea-pig ileum. Naunyn-Schmiedeberg's Arch Pharmacol 336:419–424
Johnson SM, Williams JT, Costa M, Furness JB (1987c) Naloxone-induced depolarization and synaptic activation of myenteric neurons in morphine-dependent guinea pig ileum. Neuroscience 21:595–602
Kosterlitz HW, Lees GM (1964) Pharmacological analysis of intrinsic intestinal reflexes. Pharmacol Rev 16:301–339
Kromer W, Woinoff R (1980) Peristalsis in the isolated guinea-pig ileum during opiate withdrawal. Naunyn-Schmiedeberg's Arch Pharmacol 314:191–3
Lujan M, Rodriguez R (1981) Pharmacological characterization of opiate physical dependence in the isolated ileum of the guinea-pig. Brit J Pharmacol 73:859–866
Rezvani A, Way EL (1983) Hypersensitivity of the opioid-tolerant guinea-pig ileum to electrical stimulation after abrupt agonist removal. Life Sci 33:349–52
Schulz R, Goldstein A (1973) Morphine tolerance and super-sensitivity to 5-hydroxytryptamine in the myenteric plexus of the guinea-pig. Nature 244:168–169
Schulz R, Herz A (1976) Aspects of opiate dependence in the myenteric plexus of the guinea-pig. Life Sci 19:1117–1128
Takagi K, Takayanagi I, Irikura T, Nishino K, Ichinoseki N, Shishido K (1965) Responses of the isolated ileum of the morphine-tolerant guinea-pig. Arch Int Pharmacodyn Ther 158:39–44
Trendelenburg P (1917) Physiologische und pharmakologische Versuche über die Dünndarmperistaltik. Arch Exp Pathol Pharmakol 81:55–129
Van Nueten JM, Lal H (1974) Naloxone-induced facilitation of contractions, spontaneous activity and tolerance to morphine in ileum of morphine-dependent guinea-pigs. Arch Int Pharmacodyn 208:378–382
Wilson AJ, Llewellyn-Smith IJ, Furness JB, Costa M (1987) The source of the nerve fibres forming the deep muscular and circular muscle plexuses in the small intestine of the guinea-pig. Cell Tissue Res 247:497–504
Winer BJ (1971) Second edn, Statistical principles in experimental design. McGraw-Hill, New York, p 24
Wood JD, Mayer CJ (1979) Serotonergic activation of tonic-type enteric neurons in guinea-pig small bowel. J Neurophys 42: 582–593
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Johnson, S.M., Costa, M. & Humphreys, C.M.S. Opioid dependence in myenteric neurons innervating the circular muscle of guinea-pig ileum. Naunyn-Schmiedeberg's Arch Pharmacol 339, 166–172 (1989). https://doi.org/10.1007/BF00165139
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DOI: https://doi.org/10.1007/BF00165139