The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Oct 1998
Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig.
We studied the actions of Sch 50971, a novel histamine H3 receptor agonist, in an experimental neurogenic model of migraine and characterized its sedative and respiratory actions. Sch 50971 (i.v. and p.o) inhibited plasma protein extravasation in the dura mater of guinea pigs after electrical stimulation of the trigeminal ganglia. The minimum effective doses of Sch 50971 were 3.0 mg/kg i.v. and 10 mg/kg p.o., which produced a 40% and 42% decrease in plasma protein extravasation, respectively. ⋯ In contrast, triazolam (1.0 mg/kg p. o.) depressed delta and theta wave activity and produced large increases in alpha and beta wave activity. In conclusion, Sch 50971 is an orally active, potent and selective agonist of histamine H3 receptors that may act to ameliorate the sequelae of migraine headaches, where activation of histamine H3 receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity consistent with physiological sleep.
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J. Pharmacol. Exp. Ther. · Oct 1998
Substituted 3beta-phenylethynyl derivatives of 3alpha-hydroxy-5alpha-pregnan-20-one: remarkably potent neuroactive steroid modulators of gamma-aminobutyric acidA receptors.
Neuroactive steroids are positive allosteric modulators of gamma-aminobutyric acidA (GABAA) receptor complexes. Synthetic modification generally does not increase neuroactive steroid potency beyond that of the naturally occurring progesterone metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P). Recently, it has been shown that introduction of appropriately para-substituted phenylethynyl groups at the 3beta-position of 5beta steroids increases receptor potency. ⋯ Moreover, Co 152791 was orally active (ED50 1.1 mg/kg) and exhibited a therapeutic index of 7 relative to rotorod impairment. The remarkable potency of Co 152791 as a positive allosteric modulator of GABAA receptors may be explained by its interaction with an auxiliary binding pocket in the neuroactive steroid binding site. In addition, modification at the 3beta-position probably hinders metabolism of the 3alpha-hydroxy group contributing to the exceptional anticonvulsant potency of this compound relative to other neuroactive steroids.
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J. Pharmacol. Exp. Ther. · Oct 1998
Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation.
High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. ⋯ In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.
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J. Pharmacol. Exp. Ther. · Sep 1998
Randomized Controlled Trial Comparative Study Clinical TrialComparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.
The purposes of this study were to characterize the subjective, psychomotor and physiological effects of pentazocine in non-drug-abusing volunteers and to compare and contrast the effects of pentazocine with those of morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 7.5, 15 or 30 mg/70 kg pentazocine or 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. Pentazocine increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "sweating" and "turning of stomach" and increased visual analog scale ratings of "difficulty concentrating," "drunk" and "having unpleasant bodily sensations." Pentazocine (30 mg) had a greater propensity to increase ratings associated with dysphoria than did 10 mg of morphine. ⋯ Both pentazocine and morphine induced miosis, but 10 mg of morphine had a greater magnitude of effect than 30 mg of pentazocine. The results of the present study demonstrate that 7.5 to 30 mg of pentazocine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of pentazocine, 30 mg, produced a greater magnitude of dysphoric subjective effects than did 10 mg of morphine, which is consistent with the literature reporting that pentazocine has a greater likelihood of inducing psychotomimesis than do other opioids.
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J. Pharmacol. Exp. Ther. · Sep 1998
Purification of two rat hepatic proteins with A-esterase activity toward chlorpyrifos-oxon and paraoxon.
A-esterases are calcium-dependent hydrolases that can detoxify the active metabolites (oxons) of organophosphorus insecticides such as chlorpyrifos and parathion. A-esterases from rat liver have previously been shown to hydrolyze chlorpyrifos-oxon but not paraoxon at low substrate concentrations. Two A-esterases were extracted by ammonium sulfate fractionation from solubilized rat liver microsomes followed by gel filtration chromatography and preparative scale isoelectric focusing. ⋯ The protein hydrolyzed phenyl acetate, chlorpyrifos-oxon and paraoxon, suggesting that arylesterase and A-esterase activities are attributable to the same liver protein(s). Assays of purified protein and kinetic studies of microsomes suggested that the activity toward high (320 microM) and low (