The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 2002
Pharmacological properties of nicotinic acetylcholine receptors expressed by guinea pig small intestinal myenteric neurons.
The electrophysiological and pharmacological properties of nicotinic acetylcholine receptors (nAChRs) were studied in guinea pig small intestinal myenteric neurons maintained in culture or in acutely isolated preparations. Acetylcholine and nicotine caused inward currents that desensitized in approximately 4 s. The current-voltage (I-V) relationship rectified inwardly with a reversal potential near 0 mV. ⋯ In neurons in the intact myenteric plexus from newborn and adult guinea pigs, local application of acetylcholine (1 mM) and cytisine (1 mM) caused similar amplitude depolarizations, and these responses were blocked by nAChR antagonists with a rank order potency of mecamylamine > hexamethonium > DHbetaE. These data indicate that myenteric neurons maintained in culture predominantly express nAChRs composed of alpha3, alpha5, beta2, and beta4 subunits. These subunits may be in a homogeneous population of receptors with unique pharmacological properties, or multiple receptors of different subunit composition may be expressed by individual neurons.
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J. Pharmacol. Exp. Ther. · Sep 2002
Chronic muscle pain induced by repeated acid Injection is reversed by spinally administered mu- and delta-, but not kappa-, opioid receptor agonists.
Opioids are commonly used for pain relief clinically and reduce hyperalgesia in most animal models. Two injections of acidic saline into one gastrocnemius muscle 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage. The current study was undertaken to assess the effects of opioid agonists on mechanical hyperalgesia induced by repeated intramuscular injections of acid. ⋯ The reduction in hyperalgesia produced by morphine and DAMGO was prevented by H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) and that of SNC80 was prevented by naltrindole. U50,488 had no effect on the decreased mechanical withdrawal thresholds. Thus, activation of mu- and delta-, but not kappa-, opioid receptors in the spinal cord reduces mechanical hyperalgesia following repeated intramuscular injection of acid, thus validating the use of this new model of chronic muscle pain.
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J. Pharmacol. Exp. Ther. · Sep 2002
Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat.
In human, digestive disorders are often associated with visceral pain. In these pathologies, visceral pain threshold is decreased indicating a visceral hypersensitivity. Pregabalin [CI-1008; S-(+)-3-isobutylgaba] presents antihyperalgesic actions in inflammatory somatic pain models. ⋯ In normal conditions (control animals), morphine (0.3 mg/kg s.c.) significantly increased the colonic pain threshold, whereas pregabalin (200 mg/kg s.c.) did not modify the colonic pain threshold. Pregabalin suppressed the TNBS-induced colonic allodynia but did not modify the colonic threshold in normal conditions. The ability of pregabalin to block the chronic colonic allodynia indicates that it is effective in abnormal colonic hypersensitivity, suggesting a possible effect in chronic pain in irritable bowel syndrome.
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J. Pharmacol. Exp. Ther. · Sep 2002
Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice.
We have investigated the roles of peripheral and central mu, delta, and kappa opioid receptors and their subtypes in opioid-induced hypothermia in mice. Measuring rectal temperature after i.p. injection, opioid agonists [morphine, fentanyl, SNC80 ((+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)3-methoybenzyl]-N,N-diethylbenzamide), U50,488H ((trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide), and loperamide)] were tested alone or with opioid antagonists [naloxone, beta-funaltrexamine, naloxonazine, naltrindole, 7-benzylidenenaltrexone (BNTX), naltriben, nor-binaltorphimine, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA), and methyl-naltrexone] given 15 min after the agonist. All agonists produced dose-related hypothermia, although at low doses, morphine and U50,488H produced hyperthermia. ⋯ In the mediation of delta opioid-induced hypothermia, no clear selectivity between the delta(1) and delta(2) subtypes was defined. The studies provide new evidence that maintenance of the initial effects of agonist/receptor activation vary with the agonist and the receptor. The existence of both central and peripheral components of opioid-induced hypothermia is also emphasized.
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J. Pharmacol. Exp. Ther. · Aug 2002
Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk.
Morphine tolerance in vivo is reduced following blockade of the orphanin FQ/nociceptin (OFQ/N)/opioid receptor-like 1 (ORL1) receptor system, suggesting that OFQ/N contributes to the development of morphine tolerance. We previously reported that a 60-min activation of ORL1 receptors natively expressed in BE(2)-C cells desensitized both mu and ORL1 receptor-mediated inhibition of cAMP. Investigating the mechanism(s) of OFQ/N-mediated mu and ORL1 receptor cross-talk, we found that pretreatment with the protein kinase C inhibitor, chelerythrine chloride (1 microM), blocked OFQ/N-mediated homologous desensitization of ORL1 and heterologous desensitization of mu opioid receptors. ⋯ Reduction of GRK2 and GRK3 levels by antisense, but not sense DNA treatment blocks ORL1 and mu receptor desensitization. This suggests that PKC-alpha is required for GRK2 and GRK3 translocation to the membrane, where GRK can inactivate ORL1 and mu opioid receptors upon rechallenge with the appropriate agonist. Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions.