An investigation of the mechanisms by which opiates affect the motility of the gut

Laniyonu, Adebayo Adeyinka (1985) An investigation of the mechanisms by which opiates affect the motility of the gut. PhD thesis, University of Glasgow.

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(1) The object of this study was to investigate the effect and mechanisms by which morphine and the opioid peptides affect gut motility. Emphasis was placed on the examination of the neuronal basis of these effects, particularly the involvement of a tonic non-adrenergic, non-cholinergic inhibitory mechanism postulated to be responsible for the suppression of myogenic activity and the release of 5-hydroxytryptamine (5-HT) and acetylcholine (ACh) by these drugs. Alternative explanations of these effects were also sought. (2) The preparation chosen for this study was the rat isolated colon, which permits demonstration of the responses to opioids and other drugs in vitro. (3) The isolated colon of the rat contracts rhythmically to morphine and other opioid peptides. These rhythmic contractions could be divided into the initial contraction and the subsequent waves of contractions. The 5-HT antagonist, methysergide, non-competitively antagonised the initial response but had no effect on the waves of rhythmic contractions. In contrast, the specific opioid antagonist, naloxone, competitively antagonised the initial contraction and abolished the rhythmic contractile activity. (4) The rhythmic waves of contractions were unaffected by pretreatment with parachlorophenylalanine (PCPA) which depleted the intestinal 5-HT as measured spectrofluorometrically. Contractions were still produced in tissues made subsensitive to 5-HT by a process of autodesensitisation and were not abolished by atropine, casting doubt on the 5-HT/ACh hypothesis. The ineffectiveness of reserpine in depleting the 5-HT content of the colon was also confirmed in the study. (5) Several other drugs having in common the ability to block conductance in neural pathways or neuro-effector transmission, i. e. tetrodotoxin (TTX), apamin, tolazoline, phentolamine, oxprenolol and clonidine, produced similar patterns of rhythmic contractile activity in the rat colon. This suggested that the inherent myogenic activity of the colonic muscle might normally be suppressed by nervous influence. (6) Electrical field stimulation of the colon provided evidence about the innervation of this tissue. It was demonstrated that there is a motor cholinergic response to nerve stimulation which was reduced or abolished by atropine or morphine and potentiated by 6-hydroxydopamine pretreatment or apamin. Indirect evidence for the presence of an inhibitory adrenergic influence was provided. The inability of adrenergic and cholinergic antagonists to block inhibitory responses of the colon to nerve stimulation provided evidence for the existence of non-adrenergic, non-cholinergic (NANC) inhibitory nerves in the colon. In addition, the optimum frequency of stimulation of the inhibitory response was less than that characteristic of either an adrenergic or cholinergic mechanism. (7) The observation that this NANC inhibitory, nerve-mediated response to electrical field stimulation could still be elicited in the presence of drugs producing rhythmic waves of contractions, made it unlikely that the removal of a non-adrenergic, non-cholinergic inhibitory mechanism was responsible for producing the. rhythmic contractile activity in the colon. (8) The similarity between the effects of the opioids, the adrenergic neurone blocker and adrenoceptor antagonists, clonidine and apamin, raised the possibility that the actions of these drugs might be mediated through adrenergic neurones. This possibility was examined using the techniques of High Performance Liquid Chromatography (HPLC) with electrochemical detection and also in tritium efflux studies. (9) Preliminary experiments with the HPLC were concerned with the optimisation of the conditions necessary for chromatographic separation. It was demonstrated that changes in the electrode potential voltage, mobile phase composition and flow rate affected the detection and separation of catecholamines. The catecholamine content of the rat colon, mouse, guinea-pig and rat vasa deferentia were also measured. Transmitter overflow from the mouse and guinea-pig vasa deferentia occurring spontaneously and in response to electrical field stimulation were measured. No spontaneous release of noradrenaline or its metabolites was demonstrated in the rat colon. (10) Morphine, clonidine and TTX did not affect tritium efflux at concentrations at which they produce rhythmic waves of contractions in the colon. (11) The implications of these results for the hypothesis previously postulated and the one suggested in this study to explain the rhythmic contractions are discussed.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Medicine, Pharmacology
Date of Award: 1985
Depositing User: Enlighten Team
Unique ID: glathesis:1985-76596
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 14:05
Last Modified: 19 Nov 2019 14:05

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