European journal of pharmacology
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Orphanin FQ, also known as nociceptin, is a heptadecapeptide with very high affinity for a novel member of the cloned opioid receptor family which produces hyperalgesia in mice. In addition to hyperalgesia, which is observed soon after administration of orphanin FQ, we now describe a delayed analgesic response. Unlike orphanin FQ-induced hyperalgesia, orphanin FQ-induced analgesia is readily reversed by the opioid antagonist naloxone, implying an opioid mechanism of action. In view of the very poor affinity of orphanin FQ for all the known traditional opioid receptors and the low affinity of opioids for the 125I[Tyr14]orphanin FQ binding site, orphanin FQ-induced analgesia is probably mediated through a novel orphanin FQ receptor subtype.
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Our previous work has suggested that the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) can abolish the protective effect of ischemic preconditioning in the isolated rat heart. Therefore we tested the hypothesis that CGRP- or capsaicin-induced preconditioning protects against ischemia-reperfusion injury in the isolated perfused rat heart. Thirty minutes of global ischemia and 30 min of reperfusion caused a significant cardiac contractile dysfunction, ventricular arrhythmia, and an increased release of creatine phosphate kinase. ⋯ However, the cardioprotection provided by CGRP- or capsaicin-induced preconditioning was abolished by CGRP-(8-37) and ruthenium red, respectively. These findings suggest that CGRP- or capsaicin-induced preconditioning protects against ischemic myocardial injury. The present results also suggest that CGRP may be an endogenous myocardial protective substance in the rat.
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The effects of 2 antimigraine drugs sumatriptan and dihydroergotamine on dilatation of the middle meningeal artery elicited by stimulation of the trigeminal ganglion at the entry point of the first and second divisions was investigated in cats. Carotid and middle meningeal arterial blood flows and resistances were measured in 9 cats anesthetised with chloralose. Electrical stimulation of either trigeminal ganglion produced a frequency-dependent decrease in resistance of the carotid artery ipsilaterally and the middle meningeal artery bilaterally. ⋯ The intravenous injection of dihydroergotamine produced a larger and more prolonged vasoconstriction in these 2 beds than did sumatriptan. Dihydroergotamine, but not sumatriptan, blocked some components of the vascular response induced by stimulation of the trigeminal ganglion. Dihydroergotamine and sumatriptan have a different spectrum of activity on cranial circulatory beds and neither of them is able to reduce trigeminal-induced vasodilatation by blocking antidromic activation of trigeminal nerve fibres in cats at the doses used in these experiments.
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Previous studies in our laboratory have characterized non-conventional opioid binding sites in membrane preparations from both rat and human lung. The studies described in this paper utilized autoradiography to investigate the regional distribution of these [3H]morphine binding sites within rat lungs. Specific binding of [3H]morphine was saturable and Rosenthal analysis of tissue section wipes revealed the presence of both high-affinity and low-affinity opioid binding sites. ⋯ A significantly lower (P < 0.05) density of binding was also observed in the smooth muscle of the trachea and main bronchi (5.5 +/- 2.1 pmol/mg protein). However, no morphine binding sites were evident in the smooth muscle surrounding the smaller airways and pulmonary vasculature within the lobes of the rat lung. It remains to be investigated whether the opioid binding sites located within the trachea and main bronchi of the rat airways are the prejunctional opioid receptors on C-afferent nerve fibres which modulate the release of potent inflammatory neuropeptides.
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Comparative Study
5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon.
The pathways and possible transmitters involved in the contractile response to selective 5-HT3 and 5-HT4 receptor stimulation in the guinea-pig proximal colon were studied. In the presence of methysergide, 5-HT induced contractions, yielding a biphasic concentration-response curve that was changed into a monophasic curve in the presence of the 5-HT3 receptor antagonist, granisetron (1 microM) (low-affinity phase blocked), or the 5-HT4 receptor antagonist, SB 204070 ((1-butyl-4-piperidinyl methyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate) (10 nM) (high-affinity phase blocked) combination of the two antagonists abolished the contraction to 5-HT. The effectiveness and selectivity of both antagonists was confirmed by testing them against contractions in response to the 5-HT3 receptor-selective agonist, 2-methyl-5-HT, and the 5-HT4 receptor-selective agonist, 5-methoxytryptamine. ⋯ The remaining contractions induced by 5-HT3 and 5-HT4 receptor stimulation in the presence of atropine were almost completely inhibited by the tachykinin NK1 receptor antagonist, CP 96345 ((2S,3S)-cis-2-(diphenyl methyl)-N-[(2-methoxy phenyl)-methyl]-1-azabicyclo-[2.2.2]-octan-3-amine) (0.1 microM). CP 96345 also abolished or strongly inhibited contractions in response to substance P (10 nM) and to neurokinin A (30 nM), but neither granisetron nor SB 204070 affected them. Hence, stimulation of either 5-HT3 or 5-HT4 receptors induced contractions that are partially mediated by acetylcholine, and partially by a tachykinin NK1 receptor-stimulating neurotransmitter, probably substance P and/or neurokinin A.