The Journal of pharmacology and experimental therapeutics
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(+)Pentazocine antagonizes morphine analgesia as potently as its (-)-isomer, ruling out an opioid receptor mechanism of action and suggesting, which suggests a role for sigma 1 receptors. Systemic (+) pentazocine also reverses supraspinal or spinal morphine analgesia. 1,3-Di(2-tolyl)guanidine, a sigma ligand with no appreciable opioid receptor affinity, antagonizes morphine analgesia. The actions of both (+)pentazocine and 1,3-di(2-tolyl)guanidine are reversed by haloperidol, which has high affinity for both sigma and D2 receptors, but not by the D2-selective antagonist (-)sulpiride, which lacks activity at sigma sites. ⋯ Blockade of the sigma system with haloperidol eliminates these strain differences. In conclusion, sigma 1 systems functionally antagonize opioid analgesia without affecting morphine's effects on gastrointestinal transit or lethality. The antiopioid sigma system is tonically active and is more active against kappa analgesia than mu.(ABSTRACT TRUNCATED AT 250 WORDS)
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J. Pharmacol. Exp. Ther. · Dec 1994
Antinociceptive actions of dexmedetomidine and the kappa-opioid agonist U-50,488H against noxious thermal, mechanical and inflammatory stimuli.
The antinociceptive efficacies of both intrathecally (i.t.) and systemically administered dexmedetomidine (a selective alpha-2 adrenoceptor agonist) and U-50,488H [trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzene-acetamide] (a kappa-opioid receptor agonist) were studied during peripheral inflammation induced by carrageenan. The antinociceptive tests were the hot plate (HP), the tail flick (TF) and the paw pressure tests (PP). The motor incoordination, if any, produced by both i.t. and s.c. dexmedetomidine were evaluated with the rotarod. ⋯ The i.t. dexmedetomidine (0.15, 0.45, 1.35, 4.05) micrograms) resulted in dose-dependent increases in the PP thresholds and TF latencies in both the control rats and the rats with unilateral inflammation, without causing changes in motor coordination, whereas on s.c. administration of dexmedetomidine (3-100 micrograms/kg), antinociception was produced in PP only at doses (30 micrograms/kg) that already interfered with rotarod performance. U-50,488H was ineffective i.t. (5-200 micrograms) but, on s.c. administration (2.5-22.5 mg/kg), dose-dependent increases were found in the PP thresholds and TF latencies of the rats with unilateral inflammation. Atipamezole, in a dose (3 mg/kg) that has been shown to block the antinociceptive effects of dexmedetomidine, did not modify the antinociceptive effects of U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)
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J. Pharmacol. Exp. Ther. · Dec 1994
Role of endogenous cholecystokinin in the facilitation of mu-mediated antinociception by delta-opioid agonists.
Published results suggest that delta-opioid agonists can modulate the mu-mediated analgesia. In this work, the antinociceptive effects produced by the mu agonist [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin or the mixed inhibitor of enkephalin-degrading enzymes RB 101 (N- [(R,S)-2-benzyl-3[(S)(2-amino-4-methyl- thio)butyldithio]-1-oxopropyl]-L-phenylalanine benzyl ester) were studied after administration of the systemically active and selective delta agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu- Thr(O-tert-butyl). In the hot-plate test in mice, Tyr-D-Ser(O-tert-butyl)-Gly- Phe-Leu-Thr(O-tert-butyl) (i.v.) potentiated the antinociceptive responses elicited by [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin (i.v.) or RB 101 (i.v.). ⋯ In addition, the CCK analog [Boc- Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2] (a mixed CCK-A/CCK-B agonist) increased the jump latency and this effect was blocked by MK-329 (20 micrograms/kg i.p.) and by naloxone, but not by the selective CCK-B antagonist L-365,260 (5 mg/kg i.p.). In contrast, the selective CCK-B agonist BC 264 (62 micrograms/kg i.v.) produced a hyperalgesic effect that was antagonized by L-365,260 (5 mg/kg i.p.). Taken together, these findings suggest that the potentiating effects of delta agonists on mu-mediated analgesia are due to an increase in the release of endogenous CCK interacting with CCK-A and CCK-B receptors and resulting in positive and negative regulation of the endogenous opioid system.(ABSTRACT TRUNCATED AT 250 WORDS)