Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine <i>in vitro</i>

Coynel, David; Davis, Nancy D.; Mason, Rob; Wilson, V.G.

doi:10.1111/j.1476-5381.1993.tb13995.x

Cited by 8 publications

(8 citation statements)

References 17 publications

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“…Since the early work of Paton (Paton, 1957), the guinea-pig longitudinal muscle-myenteric plexus (LMPP) preparation has been the tissue preparation of choice to study the in vitro effects of morphine and related opioids in the gastrointestinal tract. Both tolerance and dependence have been demonstrated in this preparation (Rezvani et al, 1983; Leedham et al, 1989; Leedham et al, 1992; David et al, 1993) and in other species (Weisbrodt et al, 1977). This contrasts with the clinical findings of the lack of tolerance to constipation and raises the question of whether similar tolerance occurs within the colon, an important site for the induction of constipation.…”

Section: Introductionsupporting

confidence: 54%

Morphine Tolerance in the Mouse Ileum and Colon

Ross¹,

Gabra²,

Dewey³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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Repeated administration of morphine is associated with tolerance to its antinociceptive properties. However, constipation remains the major side effect of chronic exposure to morphine. In contrast, previous studies suggest that tolerance to opioids develops in the ileum of several species. In this study, we provide evidence that constipation may arise due to a lack of tolerance development to morphine in the colon. Mice received implants with either placebo or 75 mg of morphine pellets, and they were examined for morphine tolerance to antinociception, defecation, and intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon, and contractile responses were measured from longitudinal and circular muscle preparations. In morphine-pelleted mice, a 5.5-fold tolerance developed to antinociception after 72 h, and a 53.2-fold tolerance developed in mice that received an additional daily morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscles, electrical field stimulation-induced cholinergic contractions were dose-dependently inhibited by morphine in both the ileum and colon of placebo pelleted with a pD 2 of 7.1 Ϯ 0.4 and 7.8 Ϯ 0.4, respectively. However, the dose response to morphine inhibition was shifted to the right for the ileum from morphine-pelleted mice (pD 2 ϭ 5.1 Ϯ 0.4) but not the colon (pD 2 ϭ 6.9 Ϯ 0.4). In circular muscle preparations, morphine induced atropine-insensitive contractions in both tissue segments. Tolerance to morphine developed in the ileum but not the colon upon repeated administration of morphine. These findings indicate that a lack of tolerance development in the colon is the basis for opioid bowel dysfunction.

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Section: Introductionsupporting

confidence: 54%

Morphine Tolerance in the Mouse Ileum and Colon

Ross¹,

Gabra²,

Dewey³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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“…Secondly, neither the sensitivity of the electricallyevoked contractions to inhibition by morphine nor the maximum eect produced were in¯uenced by the experimental manipulation. These observations also provide evidence against the development of tolerance in the myenteric plexus to the eect of morphine (see David et al, 1993). Thirdly, and perhaps most revealing, is that while naloxone-induced contractions in the presence of morphine were associated with a reversal of the action of the agonist on electrically-evoked contractions, this was not the case in preparations previously exposed overnight to morphine (see Figure 1).…”

Section: Discussionmentioning

confidence: 79%

“…We have con®rmed our earlier observation that overnight exposure of the guinea-pig isolated ileum to morphine (at 48C), followed by extensive washing to remove the agonist, induces à state' of m-opioid receptors that renders naloxone capable of producing neurogenic contractions (David et al, 1993). Qualitatively, this ®nding is similar to that reported for naloxone on both adenylyl cyclase activity and cyclic AMP formation in SH-SY5Y cells previously exposed (48 h at 378C) to morphine (Wang et al, 1994), and raises the possibility that a common mechanism may account for antagonist-induced responses in both systems.…”

Section: Discussionmentioning

confidence: 99%

“…It is well documented that while naloxone per se exerts little eect on electrically-evoked contractions in this preparation, the reversal of morphineinduced inhibition of these responses is associated with the appearance of a`withdrawal' contraction due to the release of myenteric neurotransmitters (Collier et al, 1981;Johnson et al, 1987;David et al, 1993;Mundey et al, 1998). Furthermore, we have reported that following 20 h incubation of the guinea-pig ileum in morphine at 48C, and subsequent washout to remove the agonist, naloxone was still capable of eliciting a withdrawal contraction (David et al, 1993), prima facie evidence for the induction of an activated state of mopioid receptors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

Mundey

Ali

Mason

et al. 2000

British J Pharmacology

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1 We have assessed the potential of several m-opioid receptor antagonists to elicit a response in the guinea-pig isolated ileum in the presence of, and following overnight exposure to, morphine. 2 Naloxone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), (7)-5,9a-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan (MR2266), but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), produced a transient inhibition of electrically-evoked contractions of the guinea-pig ileum. The eect of 1 mM CTOP, but not that to MR2266, was inhibited by 1 mM somatostatin. 3 Naloxone (0.3 mM), CTOP (3 mM), CTAP (3 mM) and MR2266 (0.3 mM) antagonized the inhibitory eect of morphine on electrically-evoked contractions of the guinea-pig to a similar degree and, following 60 min exposure to morphine, produced non-sustained contractions. The response to 3 mM CTOP was signi®cantly smaller than that to 3 mM CTAP. None of the antagonists produced a response in the absence of morphine. 4 Following overnight exposure of the ileum to 0.3 mM morphine (48C), and repeated washing to remove the agonist, all four antagonists elicited non-sustained contractions. However, the responses to 3 mM CTOP and 0.3 mM MR2266 were signi®cantly smaller than those elicited by 0.3 mM naloxone and 3 mM CTAP. Somatostatin (1 mM) signi®cantly reduced naloxone-induced contractions, but not those to CTAP. 5 While all four m-opioid antagonists elicited contractions in the presence of, and following prolonged exposure to, morphine, dierences between them were noted which may be a consequence of non-opioid actions.

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“…Recent evidence, however, has suggested that dependence may occur independently. A temperature-dependent functional dissociation of tolerance and dependence on morphine has been demonstrated in guinea-pig in vitro (David et al, 1993). Our results demonstrate that in the model of peripheral antinociception, tolerance and dependence can be dissociated.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

Aley

Levine

1997

J. Neurosci.

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-ol] enkephalin (DAMGO) produces acute tolerance and dependence on its peripheral antinociceptive effect against prostaglandin E 2 (PGE 2 )-induced mechanical hyperalgesia. In this study we evaluated the roles of protein kinase C (PKC) and nitric oxide (NO) in the development of this tolerance and dependence. Repeated administration of PKC inhibitors chelerythrine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride with DAMGO did not alter the tolerance to DAMGO; however, dependence (defined as naloxone-induced withdrawal hyperalgesia) was blocked. Repeated administration of N-(n-heptyl)-5-chloro-1-naphthalenesulfonamide, a PKC activator, which alone did not produce tolerance, mimicked the dependence produced by DAMGO. Repeated administration of the NO synthase inhibitor N G -methyl-L-arginine with DAMGO blocked the development of tolerance to DAMGO but had no effect on the development of dependence. Repeated administration of L-arginine, a NO precursor, mimicked tolerance produced by repeated administration of DAMGO (i.e., the antinociceptive effect of DAMGO was lost); however, L-arginine did not mimic dependence. These findings suggest that the development of acute tolerance and dependence on the peripheral antinociceptive effects of DAMGO have different, dissociable mechanisms. Specifically, PKC is involved in development of -opioid dependence, whereas the NO signaling system is involved in the development of -opioid tolerance.

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Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine in vitro

Cited by 8 publications

References 17 publications

Morphine Tolerance in the Mouse Ileum and Colon

Morphine Tolerance in the Mouse Ileum and Colon

Pharmacological examination of contractile responses of the guinea‐pig isolated ileum produced by μ‐opioid receptor antagonists in the presence of, and following exposure to, morphine

Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

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