The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1990
Respiratory and locomotor stimulation by low doses of dermorphin, a mu1 receptor-mediated effect.
The selective opioid mu receptor agonist dermorphin increased the locomotor activity of rats dose dependently at 10 to 100 pmol/kg i.c.v. Respiratory rate, relative tidal volume and respiratory minute volume also increased unrelated to changes in locomotor activity. ⋯ The selective benzodiazepine antagonist flumazenil (5 mg/kg), which has been shown previously to antagonize catalepsy and respiratory depression produced by relatively high doses of dermorphin, did not antagonize the respiratory or locomotor stimulant effect of dermorphin. The data suggest that mu1-opioid receptors are responsible for the low dose stimulant effects of dermorphin on locomotor activity and respiration whereas mu2 receptors mediate the respiratory depressant effect of dermorphin.
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J. Pharmacol. Exp. Ther. · Nov 1989
Reinforcing effect of alfentanil is mediated by mu opioid receptors: apparent pA2 analysis.
Apparent pA2 analysis was used to determine whether the short-duration opioid agonist, alfentanil, acts at mu receptors in the positive reinforcement of operant behavior in the rhesus monkey. In test sessions a red light signaled the availability of alfentanil injections. If a monkey pressed a response lever 30 times, a specific dose of alfentanil was injected i.v., and the red light was extinguished for 10 min. ⋯ In Schild Plot analysis the regression line fit to the antagonism data had a slope of -1.1; the apparent pA2 value for quadazocine was 7.6. This value was close to apparent pA2 values obtained with mu agonists in studies of other behavioral effects of opioids, but distinct from values obtained with kappa agonists in those studies. Thus, it is likely that mu receptors mediate the positive reinforcing effect of alfentanil.
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J. Pharmacol. Exp. Ther. · Oct 1989
Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine.
The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. ⋯ After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.
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J. Pharmacol. Exp. Ther. · Oct 1989
Kappa-opioid receptor-mediated antinociception in the rat. II. Supraspinal in addition to spinal sites of action.
This study examines whether there is a supraspinal, in addition to spinal, component to the antinociceptive actions against heat and pressure stimuli of kappa-opioid receptor agonists (U-69,593, U50,488H, bremazocine and tifluadom) as compared to mu-opioid receptor agonists (Tyr-D-Ala-Gly-NMe-Gly-ol, fentanyl and morphine) in the rat. The antinociception induced by kappa- and mu-opioids (applied s.c.) was unaffected by systemic quaternary naltrexone (50 mg/kg) revealing that it is mediated in the central nervous system. All kappa- and mu-opioids produced dose-dependent antinociception upon intrathecal application, in each case reversible by naloxone (5 mg/kg s.c.). ⋯ Naltrexone was 10-fold more potent in blocking morphine as compared to U50,488H whereas nor-binaltorphimine, a preferential kappa-antagonist, was 6-fold more potent against U50,488H than morphine. Indeed, whereas a dose of 0.2 mg/kg of naltrexone reversed mu-agonist actions, this dose was inactive against all kappa-agonists: the actions of these could be antagonized only by 2.0 mg/kg. These data indicate that in addition to kappa-receptors in the spinal cord, kappa-receptors in the brain can mediate antinociception against noxious heat and pressure.
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J. Pharmacol. Exp. Ther. · Jul 1989
Quantitative histologic analysis of local anesthetic-induced injury to rat sciatic nerve.
Quantitative measurements of endoneurial edema, cytoplasmic lipid droplets, nerve fiber injury and Schwann cell damage were used to elucidate the pathogenesis of local anesthetic-induced injury to sciatic nerve in the rat. All histopathologic measurements were conducted on rat sciatic nerves removed at 48 hr after the extraneural injection of one of three concentrations of the local anesthetic 2-chloroprocaine, procaine, etidocaine or lidocaine. ⋯ Quantitative electron microscopic evaluation of Schwann cell injury indicated that the Schwann cells of unmyelinated fibers were more likely to undergo lysis after exposure to local anesthetics, whereas those of myelinated fibers were more likely to accumulate cytoplasmic lipid droplets. These quantitative data on the specificity of the regional distribution of nerve injury and of Schwann cell effects are consistent with a direct cellular toxicity of the local anesthetics; however, these results do not preclude a role for toxicity mediated indirectly by changes in the endoneurial environment.