The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1998
Differential effects of intrathecally administered delta and mu opioid receptor agonists on formalin-evoked nociception and on the expression of Fos-like immunoreactivity in the spinal cord of the rat.
This study examined the effects of intrathecally (i.t.) administered mu and delta opioid receptor agonists on the flinching behavior and the expression of Fos-like immunoreactivity (Fos-LI) in the spinal cord elicited by s.c. injection of 5% formalin in one hindpaw of the rat. Intrathecal pretreatment with either the delta-1 opioid receptor agonist [D-Pen2,5]enkephalin (DPDPE) or the delta-2 opioid receptor agonist [D-Ala2,Glu4]deltorphin (DELT) produced a dose-dependent inhibition of flinching behavior in phase 1 and phase 2 that was antagonized by coadministration of the delta-1 opioid receptor antagonist 7-benzylidinenaltrexone or the delta-2 opioid receptor antagonist Naltriben, respectively. Although i.t. pretreatment with 60 micrograms of DPDPE produced a small decrease in the numbers of Fos-LI neurons in laminae I, IIi and IIo, as well as laminae V and VI and laminae VII-X, i.t. pretreatment with 30 micrograms of DELT did not decrease the number of Fos-LI neurons in any region of the spinal cord. ⋯ The relative lack of effect of DPDPE or DELT suggests that delta opioid receptors do not modulate the early-immediate gene c-fos. Alternatively, because delta opioid receptor agonists inhibit synaptic transmission in the spinal cord by predominantly presynaptic mechanisms and do not hyperpolarize dorsal horn neurons, the excitatory inputs that persist in the presence of these agonists may be sufficient to activate the c-fos gene. Taken together, these results provide new evidence, at the level of a "third messenger," that the antinociception produced by i.t. administration of delta and mu opioid receptor agonists is mediated by different mechanisms.
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J. Pharmacol. Exp. Ther. · Jan 1998
Comparative StudyOpioid-induced analgesia in neonatal dogs: pharmacodynamic differences between morphine and fentanyl.
Whether the analgesic effects of opioids change as a neonate matures is not well understood. To address this issue, we determined the pharmacokinetics and pharmacodynamics of analgesic effects of morphine and fentanyl in 35 dogs aged 1 to 34 days. Opioids were infused to produce analgesia, response times to a noxious thermal stimulus were measured and plasma opioid concentrations were determined. ⋯ For both opioids, values for Keo did not vary with age. Values for delta decreased with age (i.e., decreasing sensitivity with increasing age), and the magnitude of the change during the first month of life was similar for the two opioids. In the context of our previous study concerning ventilatory depressant effects of these opioids (that sensitivity to morphine, but not to fentanyl, decreased markedly during the first month of life), these results in dogs suggest that fentanyl has greater utility than morphine in neonates during spontaneous ventilation.
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J. Pharmacol. Exp. Ther. · Jan 1998
Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion.
Topotecan is primarily eliminated by the kidneys, with 60 to 70% of the dose recovered as topotecan total in the urine. To elucidate the mechanisms of topotecan renal clearance, we evaluated the effect of probenecid on topotecan renal and systemic disposition in mice. Topotecan lactone or hydroxy acid (1.25 mg/kg i.v.) was administered alone or in combination with probenecid (600 or 1,200 mg/kg) given by oral gavage 30 min before and 3 hr after topotecan. ⋯ By inhibiting renal tubular secretion, probenecid decreased renal and systemic clearance which led to an increase in topotecan systemic exposure. These data suggest that probenecid primarily inhibited secretion of the anionic hydroxy acid form, and by direct or indirect mechanisms increased topotecan lactone systemic exposure. Topotecan elimination through renal tubular secretion may have clinical relevance for the use of topotecan in patients with altered renal function.
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J. Pharmacol. Exp. Ther. · Dec 1997
Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists.
The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. ⋯ The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors.
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J. Pharmacol. Exp. Ther. · Oct 1997
The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells.
Levosimendan, a new Ca++-sensitizing and positive inotropic agent, was reported to act as a coronary vasodilator and protect ischemic myocardium. To elucidate the mechanisms of these actions, the possible electrophysiological effects of levosimendan on isolated rat ventricular cells were examined by the patch-clamp technique with whole-cell and single-channel recordings. Levosimendan (3 and 10 microM) markedly shortened action potential duration and activated an outward current at potentials positive to -70 mV. ⋯ Levosimendan stimulates cardiac K[ATP] channels that are suppressed by intracellular ATP. It appears that levosimendan acts synergistically with nucleotide diphosphates. These properties of levosimendan may help protect ischemic myocardium because activation of K[ATP] channels by levosimendan would likely occur in ischemic regions in which intracellular ADP concentration is increased and intracellular ATP concentration is decreased.