Assessment in the Guinea‐pig Ileum and Mouse Vas Deferens of Benzomorphans Which Have Strong Antinociceptive Activity but Do Not Substitute for Morphine in the Dependent Monkey

Hutchinson, Mark R.; Kosterlitz, H. W.; Leslie, Frances M.; Waterfield, Angela A.; Terenius, Lars

doi:10.1111/j.1476-5381.1975.tb07430.x

Cited by 180 publications

(53 citation statements)

References 11 publications

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“…Four receptor subtypes have been suggested, these being ,, K, (, and 6. In the guinea pig ileum myenteric plexus/smooth muscle preparation, the modulation of acetylcholine release by opioids appears to be mediated mainly by ,u receptors (and possibly K receptors) (22,23 (22,24,25). Thus, in the mouse vas deferens, which is thought to be relatively rich in 3 receptors, the relative potencies of these agents are 29.0/0.32/0.03 (22).…”

Section: Resultsmentioning

confidence: 99%

Control of guinea pig intestinal electrolyte secretion by a delta-opiate receptor.

Kachur

Miller

Field

1980

Proc. Natl. Acad. Sci. U.S.A.

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The effects of opioids on transepithelial potential difference and short-circuit current across guinea pig ileum stripped of one muscle layer were measured in vitro in Ussing chambers. Opioid peptides such as [DA6a2, DMet5Jenkephalin, which are primarily agonists at -opiate receptors, were able to reduce transepithelial potential difference and short-circuit current at concentrations as low as 1 nM. The narcotic drug etorphine was also very potent in reducing short-circuit current, but fentanyl and morphine, which are primarily agonists at -opiate receptors, were almost complete y ineffective. Ketocyclazocine was relatively ineffective, and P-endorphin had intermediate potency.All opioid effects could be reversed by the opiate antagonist naloxone. Somatostatin also reduced short-circuit current, but its effect was not reduced by naloxone. Chloride flux measurements indicated that the effect of etorphine on short-Circuit current is associated with an enhancement of active Cl-absorption. The relative effects of opioids in this system suggest that their actions are being mediated by a specific 5-opiate receptor. In contrast, opioid effects on guinea pig intestinal smooth muscle seem to be primarily mediated by a i-opiate receptor.Opiates and opiate-like drugs such as diphenoxylate and loperamide are widely used in the treatment of diarrhea (1-4). Opiates are generally believed to produce their antidiarrheal action by stimulating intestinal circular muscle, thereby impeding the progress of material through the gut (5-7). In addition, in the guinea pig myenteric plexus, opioids also decrease the stimulated release of acetylcholine from cholinergic neurons. This action is the basis for a well established pharmacological assay for opiates (8). The recent discovery of the endogenous opioid peptides, the enkephalins, has provided a neuroanatomical basis for much of the classical pharmacology of the opiates (9). In particular, both [Met5]enkephalin and [Leu5]enkephalin have been found in intestinal enteric ganglia and in endocrine cells of the gut mucosa, suggesting a physiological role for the enkephalins in the gastrointestinal tract (10-12). One possibility is that they act as neurotransmitters and influence intestinal motility. Another possibility is that the enkephalins may have "paracrine" effects on the intestinal mucosa. Enkephalin released locally from endocrine cells or neuronal elements might act upon the intestinal mucosa to regulate the release of other bioactive substances or, more directly, the transport of ions across the mucosa. We have recently demonstrated that somatostatin may modulate electrolyte transport across rabbit ileal mucosa (13). The present paper demonstrates that opioids have an antisecretory effect on guinea pig mucosa. At the present time there is considerable discussion as to the possible existence of multiple opiate receptors. This would be analogous to the situation with acetylcholine, for example, where both nicotinic and muscarinic types of receptors The publication costs ...

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Section: Resultsmentioning

confidence: 99%

Control of guinea pig intestinal electrolyte secretion by a delta-opiate receptor.

Kachur

Miller

Field

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…That is, they do not substitute for morphine in the dependent monkey (Villarreal & Seevers, 1972;Swain & Seevers 1974;; in the chronic spinal dog they have a profile of action that differs from that of the p-agonists and in the mouse isolated vas deferens they are more potent than in the guinea-pig ileum relative to morphine; in both preparations more naloxone is required to antagonize their effects than those of the p-agonists (Hutchinson et al, 1975).…”

Section: Discussionmentioning

confidence: 99%

A Classification of Opiate Receptors That Mediate Antinociception in Animals

Tyers

1980

British J Pharmacology

331

139

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1To investigate the opiate receptors that mediate antinociception, the activity profiles of opioid analgesic drugs have been determined against different nociceptive stimuli in the mouse and rat.2 In tests that employ heat as the nociceptive stimulus, p-opiate receptor agonists, such as morphine, pethidine and dextropropoxyphene, had steep and parallel dose-response curves and were capable of achieving maximum effects. In addition, the antinociceptive potency ratios of these drugs in heat tests were similar to those for analgesia in man. 3 The K-agonists, such as ethylketazocine, nalorphine, Mr2034 and pentazocine, were essentially inactive against heat nociception except at doses that caused sedation and motor incapacitation. 4 In the writhing and paw pressure tests both j-and a--agonists produced steep and parallel dose-response curves. 5 It is concluded that both t-and K-opiate receptors mediate antinociception in animals and that the interactions of analgesic drugs with these receptors may be classified in terms of their antinociceptive activities against qualitatively different nociceptive stimuli.

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“…The assays were the guinea-pig myenteric plexus-longitudinal muscle preparation which has both IA-and K-receptors (Hutchinson et al, 1975;Chavkin & Goldstein, 1981) and the vasa deferentia of the hamster having only 6-receptors (McKnight et al, 1984a), the rabbit having only K-receptors (Oka et al, 1981), the mouse having all three receptors (Lord et al, 1977) and the rat having pt-and possibly 8-receptors (Wfister et al, 1979;Gillan et al, 1981). In addition to the bioassays, the effects of P-funaltrex-…”

Section: Introductionmentioning

confidence: 99%

Pre‐incubation of guinea‐pig myenteric plexus with β‐funaltrexamine: discrepancy between binding assays and bioassays

Corbett

Kosterlitz

McKnight

et al. 1985

British J Pharmacology

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1 The acute effects of P-funaltrexamine and the effects of pre-incubation with this compound were examined in five in vitro assay tissues and in selective binding assays in homogenates of guinea-pig brain and myenteric plexus. 4 These findings indicate that the effects of pre-incubation with P-funaltrexamine on agonist potency of the IA-receptor ligand are due to an interference with the coupling mechanism between the n-binding site and the effector system.

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Assessment in the Guinea‐pig Ileum and Mouse Vas Deferens of Benzomorphans Which Have Strong Antinociceptive Activity but Do Not Substitute for Morphine in the Dependent Monkey

Cited by 180 publications

References 11 publications

Control of guinea pig intestinal electrolyte secretion by a delta-opiate receptor.

Control of guinea pig intestinal electrolyte secretion by a delta-opiate receptor.

A Classification of Opiate Receptors That Mediate Antinociception in Animals

Pre‐incubation of guinea‐pig myenteric plexus with β‐funaltrexamine: discrepancy between binding assays and bioassays

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