The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2001
ReviewPharmacology of opioid and nonopioid analgesics in chronic pain states.
Chronic pain represents a mixture of pathophysiologic mechanisms, a complex assortment of spontaneous and elicited pain states, and a somewhat unpredictable response to analgesics. Opioids remain the mainstay of treatment of moderate to severe chronic pain, although there is little systematic examination to guide drug selection. Cyclooxygenase inhibitors play primarily an adjunctive role in chronic pain treatment. ⋯ A number of arthritic states have also been produced by means of chronic joint inflammation in rats. The pharmacology of these neuropathic and arthritic pain models generally resembles that found in the respective human conditions. Additional models of chronic pain, particularly visceral pain, have been developed; however, the pharmacology of these models is not well established at this time.
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J. Pharmacol. Exp. Ther. · Nov 2001
Protein kinase C-epsilon is a trigger of delayed cardioprotection against myocardial ischemia of kappa-opioid receptor stimulation in rat ventricular myocytes.
Kappa-opioid receptor (OR) stimulation with a selective agonist, U50,488H (U50), known to mediate the delayed cardioprotection of metabolic inhibition preconditioning (MIP) against cell injury/death in rat ventricular myocytes, has been shown to act via protein kinase C (PKC). We attempted to identify the PKC isoform(s) that is activated, thus triggering delayed cardioprotection of MIP and pretreatment with 10 microM U50 (U50 pretreatment, UP). Release of lactate dehydrogenase and exclusion of trypan blue by isolated rat ventricular myocytes were used as indices of cell injury and death, respectively. ⋯ More importantly, 0.1 microM epsilonV1-2, a selective PKC-epsilon inhibitor administered before and during MIP/UP, also attenuated the effects of both treatments on cell injury/death and translocation of PKC-epsilon. On the other hand, 5 microM rottlerin, a selective PKC-delta inhibitor, did not alter the effects of either treatment on injury/death. The results indicate that both MIP and UP activate PKC-epsilon, leading to delayed cardioprotection in rat ventricular myocytes.
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J. Pharmacol. Exp. Ther. · Nov 2001
Lithium increases potency of lidocaine-induced block of voltage-gated Na+ currents in rat sensory neurons in vitro.
We and others have obtained data both in vivo and in isolated nerve preparations suggesting that Li+ increases the potency of local anesthetics in the block of conduction. In the present study we have tested the hypothesis that Li+ increases the potency of local anesthetic-induced block of conduction via a shift in the potency of local anesthetic-induced block of voltage-gated Na+ channels. To test this hypothesis we have used whole cell patch-clamp electrophysiological techniques on isolated adult rat sensory neurons. ⋯ These results support the suggestion that the influence of Li+ on lidocaine-induced conduction block reflects an increase in potency of lidocaine-induced block of voltage-gated Na+ channels. This increase in potency appears to reflect an increase in the affinity of the low-affinity binding site for local anesthetics. Including Li+ in lidocaine preparations may be an effective way to increase the safety factor associated with the use of this anesthetic clinically.
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J. Pharmacol. Exp. Ther. · Sep 2001
Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys.
In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive gamma-aminobutyric acid(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ(1)-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABA(A) modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABA(A) modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. ⋯ The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABA(A) receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABA(A) receptor complex. Thus, interactions among GABA(A) modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABA(A) receptor complex.
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J. Pharmacol. Exp. Ther. · Aug 2001
Comparative StudyDifferential antinociception induced by spinally administered endomorphin-1 and endomorphin-2 in the mouse.
We have previously demonstrated that the antinociception induced by either endomorphin-1 or endomorphin-2 given supraspinally is mediated by the stimulation of mu-opioid receptors. However, the antinociception induced by endomorphin-2 given supraspinally contains additional components, which are mediated by the spinal release of dynorphin A (1-17) acting on kappa-opioid receptors and the spinal release of [Met5]enkephalin acting on delta2-opioid receptors in the spinal cord. The present studies were performed to determine whether there are any differential effects on the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given intrathecally (i.t.) in mice. ⋯ It is concluded that the tail-flick inhibition induced by endomorphin-1 and endomorphin-2 given spinally is mediated by the stimulation of mu-opioid receptors. However, the tail-flick inhibition induced by spinally injected endomorphin-2 contains an additional component, which is mediated by the spinal release of dynorphin A (1-17) acting on kappa-opioid receptors in the spinal cord. We propose that there are at least two different subtypes of micro-opioid receptors for endomorphin-1 and endomorphin-2 to produce antinociception in the spinal cord.