The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 1994
Randomized Controlled Trial Clinical TrialAcute effects of pentazocine, naloxone and morphine in opioid-dependent volunteers.
The purpose of this study was to evaluate the agonist and antagonist properties of pentazocine, an opioid mixed agonist-antagonist analgesic, in relation to prototypic opioid agonist and antagonist drugs in opioid-dependent human subjects. Pentazocine (45 and 60 mg), naloxone (0.1 and 0.2 mg), morphine (20, 40 and 60 mg) and saline placebo were administered intramuscularly to six male volunteers maintained on methadone (30 mg/24 hr p.o.), following a double-blind, randomized block order design. Drugs were administered 20 hr after the last dose of methadone. ⋯ Pentazocine precipitated a withdrawal syndrome, but the effects were not dose-dependent, and produced symptoms of confusion and dysphoric changes that were not observed after naloxone administration. Pentazocine was classified as an antagonist by some individuals, and as alcohol or hallucinogen by others. The results of the present study indicate that pentazocine acts in humans as a partial mu agonist with a non-mu component of activity.
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J. Pharmacol. Exp. Ther. · Mar 1994
The heroin metabolite, 6-monoacetylmorphine, activates delta opioid receptors to produce antinociception in Swiss-Webster mice.
Heroin activates delta receptors, whereas morphine activates mu receptors, in the brain of Swiss-Webster mice, to produce antinociception. The present study determined the type of opioid receptor activated by 6-monoacetylmorphine (MAM), a metabolite of heroin. Intracerebroventricular MAM-induced inhibition of the tail-flick response was reduced by coadministration of naltrindole (a delta opioid receptor antagonist), suggesting that i.c.v. ⋯ MAM acted on spinal mu receptors because i.t. administration of naloxone, but not naltrindole, produced inhibition. In conclusion, the ability to ascribe delta receptor selectivity to the action of heroin and MAM in Swiss-Webster mice served to reinforce the concept that heroin and MAM act primarily on their own and not through formation of morphine. Further elucidation of the difference in heroin and MAM receptor selectivities between Swiss-Webster and ICR mice might contribute to a better understanding of opioid receptor mechanisms.
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J. Pharmacol. Exp. Ther. · Feb 1994
Antinociception produced by oral, subcutaneous or intrathecal administration of SC-39566, an opioid dipeptide arylalkylamide, in the rodent.
This study characterized the prototypic "minimum structure" enkephalin SC-39566 [2,6-dimethyl-L-tyrosinyl-D-alanine-(3-phenyl-1-propyl)-amide hydrochloride]. SC-39566 bound with highest affinity to mu opioid receptors (Ki, 0.13 nM), as well as to delta (Ki, 4.0 nM) opioid receptors in the rat brain, and with much lower affinity to kappa opioid receptors (Ki, 83.8 nM) in the guinea pig brain. In the mouse, SC-39566 inhibited phenylbenzoquinone-induced writhing and increased tail-flick and hot-plate latencies in a dose-dependent manner after either s.c. or p.o. (i.g.; intragastrical) administration. ⋯ In addition, the increase in tail-flick latency produced by i.t. SC-39566 was not antagonized by i.t. administration of naltrindole or nor-binaltorphimine, a kappa receptor antagonist. These data suggest that the antinociceptive activity of SC-39566 is mediated predominantly by mu opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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J. Pharmacol. Exp. Ther. · Jan 1994
Randomized Controlled Trial Clinical TrialA dose-response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers.
The purpose of this study was to characterize the subjective, psychomotor and physiological effects of morphine in healthy volunteers. Subjects (10 males and 2 females) without histories of opiate dependence were injected in an antecubetal vein with 0, 2.5, 5.0 or 10 mg/70 kg of morphine, by using a randomized, double-blind, cross-over design. Subjective effects, psychomotor performance and physiological measures were assessed immediately before the injection and for up to 5 hr afterward. ⋯ Miosis was induced by morphine. Most effects of morphine were dose-related, some effects peaked soon after morphine injection (e.g., increased stimulated and high ratings) and dissipated gradually, whereas other effects did not peak until later into the session (sedation or exophoria). Our results are fairly consistent with other studies examining morphine effects in healthy volunteers, and also indicate that the profile of morphine effects differ between healthy volunteers and those with a history of opiate dependence.
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J. Pharmacol. Exp. Ther. · Oct 1993
Systemic excitatory amino acid receptor antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and of the N-methyl-D-aspartate (NMDA) receptor relieve mechanical hypersensitivity after transient spinal cord ischemia in rats.
We have previously reported that transient spinal cord ischemia induced a behavioral hypersensitivity (allodynia) to innocuous cutaneous mechanical stimulation in rats. The spinal ischemia-induced allodynia was not relieved by morphine, but it was relieved by the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, indicating that the allodynia may be related to dysfunction of the spinal GABA-ergic inhibitory system. In the present study we report that systemic application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor for excitatory amino acids, dose-dependently relieved allodynia after spinal cord ischemia. ⋯ On the other hand, the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) only partially alleviated allodynia, even at doses that produced severe motor deficits. It is suggested that the abnormal, possibly painful, sensations elicited by innocuous mechanical stimulation observed after spinal cord ischemia may be mediated by excitatory amino acids, acting mainly on the AMPA receptor. Antagonists of excitatory amino acid receptors, especially at the AMPA site, may be effective in treating pain conditions where input from low threshold afferents triggers painful sensations.