European journal of pharmacology
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A variety of G-protein-coupled receptors regulate membrane excitability via M-type K(+) current (M-current) modulation. Muscarinic m1 and m3 acetylcholine receptors have both been implicated in the modulation of M-current. The muscarinic m5 receptor, like muscarinic m1 and m3 receptors, couples to phospholipase C via a pertussis toxin-insensitive G protein. ⋯ Muscarinic m1, m3, or m5 receptor stimulation decreased the deactivation time constants of M-current at -50 mV. The inhibition of M-current by stimulation of muscarinic m1, m3, or m5 receptors was insensitive to overnight treatment with pertussis toxin or cholera toxin, which interfere with G(i/o) and G(s) G-protein signaling. These data suggest that muscarinic m1, m3, and m5 receptors inhibit M-channels via the activation of a common G protein.
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The ability of allergens to induce hyperalgesia in immunoglobulin E (IgE)-sensitized rats was investigated. The left hind paws of Wistar rats were sensitized with intraplantar injections of IgE anti-dinitrophenylated bovine serum albumin monoclonal antibody, and challenged with dinitrophenylated bovine serum albumin 24 h later. Allergen challenge yielded rapid thermal hyperalgesia and oedema formation in the ipsilateral paws, both reaching a plateau from 15 min to 3 h, and both diminishing thereafter. ⋯ Anaphylactic hyperalgesia was mimicked by the combined administration of histamine, 5-hydroxytryptamine and bradykinin at doses which were ineffective when injected alone. This synergistic effect was abolished by treatment with either meclizine, methysergide, Hoe 140 or des-Arg(9)-[Leu(8)]-bradykinin. Our findings show that local thermal hyperalgesia is a feature of allergen-evoked inflammation, and that a synergistic interaction among bradykinin, 5-hydroxytryptamine and histamine plays a critical role in this phenomenon.
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This study focused on the antinociceptive action of morphine in the formalin test in rats. Formalin-induced behaviour is characterised by two phases relevant to acute and tonic pain. Morphine (1-6 mg/kg) was administered systemically before or after the early phase, and its ability to affect the late phase was investigated. ⋯ Furthermore, manipulation of stimulation intensity (2% vs. 5% formaldehyde) significantly affected the ability of morphine (3 mg/kg) to suppress early (55+/-7% and 76+/-10%, respectively) but not late phase of formalin-induced behaviours. These results agree with the previous demonstrations on the effects of acute nociceptive stimulation intensity on analgesic potency of opiate drugs. Thus, the present study revealed two factors that affect the potency of morphine in formalin test: administration regimen and formalin concentration.
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Comparative Study
Blockade of mu-opioid receptor-mediated G-protein activation and antinociception by TRK-820 in mice.
The effects of kappa-opioid receptor agonists trans-3,4-dichloro-N-(2-(1-pyrollidinyl)-cyclohexyl) benzeneacetamide ((-)-U50,488H) and 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) on the G-protein activation and antinociception induced by the selective mu-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO), were determined in mice. G-protein activation was measured by monitoring the guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding in the mouse pons/medulla. DAMGO (10 microM) produced a marked increase of [35S]GTPgammaS binding to the mouse pons/medulla membrane. ⋯ In the tail-flick test, DAMGO (16 ng) given intracerebroventricularly (i.c.v.), produced a marked antinociception. The antinociception induced by DAMGO was dose-dependently blocked by co-treatment with TRK-820, but not (-)-U50,488H, in mice pretreated with norbinaltorphimine (5 microg, i.c.v.). The present results provide direct evidence for the antagonistic property of TRK-820 for mu-opioid receptors, in addition to the full agonistic property for kappa-opioid receptors.