The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 1997
Role of spinal gamma-aminobutyric acidA receptors in formalin-induced nociception in the rat.
This study investigated the role of gamma-aminobutyric acid (GABA) and GABA(A) receptors in the spinal cord in the expression of pain behaviors evoked by injection of formalin in concentrations ranging from 0.25 to 2.5% in the hindpaw of the rat. Two approaches were used. The first approach compared the effect of drug treatment to saline at each concentration of formalin. ⋯ Pretreatment with the GABA(A) receptor agonists, muscimol (0.3 microg) or isoguvacine (10 or 30 microg i.t.), significantly decreased the number of flinches in phase 1 and phase 2, but produced only a marginal decrease in the weighted pain score at the highest doses. These findings suggest that there is little tonic activation of GABA(A) receptors by GABA in the spinal cord before or immediately after the injection of formalin. However, approximately 10 min after the induction of injury by formalin, there is a release of GABA and activation of GABA(A) receptors in the spinal cord that 1) contributes to the period of quiescence between phase 1 and phase 2 and 2) coincidentally diminishes the magnitude of pain behaviors in phase 2, possibly by limiting the development of central sensitization in the spinal cord.
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J. Pharmacol. Exp. Ther. · Aug 1997
Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands.
Activation of kappa receptors inhibits adenylate cyclase, enhances K+ conductance and reduces Ca++ conductance via pertussis toxin-sensitive G proteins. We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined. ⋯ Nalbuphine and buprenorphine had low levels of agonist activities. Norbinaltorphimine and naloxone were antagonists devoid of activities. Enhancement of [35S]GTPgammaS binding by kappa agonists provides a simple functional measure for receptor activation and can be used for determination of potencies and efficacies of opioid ligands at the kappa receptor.
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J. Pharmacol. Exp. Ther. · Aug 1997
Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord.
Our study was designed to determine involvement of nitric oxide (NO) in the antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. The effect of intrathecally (i.t.) injected NO synthase inhibitors and opioid receptor agonists was evaluated in acute pain using a tail-flick and a paw pressure tests, and in prolonged pain by quantification the pain-related behavior after peripheral formalin injection. It was found that the neuronal NO synthase inhibitor 7-nitroindazole (50-400 microg), used in inactive doses, dose-dependently enhanced antinociception induced by morphine (0.5 microg) in the tail-flick and paw pressure. ⋯ Additionally, N(G)-nitro-L-arginine methyl ester (100 microg) profoundly potentiated the antinociception induced by [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (0.5, 15 ng) and [D-Pen(2,5)]enkephalin (2, 10 microg) in the dose-related manner in the formalin test. N(G)-nitro-L-arginine methyl ester (100 microg) also enhanced the antinociception induced by 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamid e (10-100 microg) but only at the last two time points of the second phase of the formalin test. These data show that inhibition of the spinal NO synthase potentiates the mu-, delta- and to a lesser extent, kappa-mediated spinal antinociception in both acute and prolonged pain.
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J. Pharmacol. Exp. Ther. · Aug 1997
Susceptibility to lidocaine of impulses in different somatosensory afferent fibers of rat sciatic nerve.
Mechanosensitive A beta-fibers (n = 29) and nociceptive A delta- (n = 6) and C-fibers (n = 10) of the rat sciatic nerve were superfused with lidocaine (LID, 0.1-1.4 mM) in vivo. The [LID] to abolish single electrically stimulated impulses (tonic blockade) in axons was 0.2 to 0.8 mM for A beta-, 0.1 to 0.6 mM for A delta- and 0.1 to 1.4 mM for C-fibers. Within each of the fiber groups there was no dependence of blocking [LID] on conduction velocity; slower fibers were no more susceptible than faster ones. ⋯ Stimulation of nociceptive A delta-fibers (n = 4) and C-fibers (n = 5) at 5 or 10 Hz for 10 pulses produced no phasic block at [LID]s (0.1-0.5 mM) below those required for tonic blockade. Uptake of 14C-lidocaine by the nerve, measured in vivo under conditions identical with those for electrophysiology, showed that: a) little drug was in the segments of nerve beyond the superfusion chamber, b) lidocaine was uniformly distributed in the nerve within the chamber, c) the intraneural lidocaine content was identical with that in nerves equilibrated in vitro. The results show a lack of monotonic dependence of sensitivity to local anesthetic on fiber diameter, but do suggest that mean susceptibility to nerve block by lidocaine differs for fibers grouped by, and perhaps according to, function.
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J. Pharmacol. Exp. Ther. · Aug 1997
Influence of renal failure on the disposition of morphine, morphine-3-glucuronide and morphine-6-glucuronide in sheep during intravenous infusion with morphine.
The influence of experimentally induced renal failure on the disposition of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was examined in seven sheep infused intravenously with morphine for 6 hr. Between 5 and 6 hr, blood was collected from the aorta, pulmonary artery, hepatic, hepatic portal and renal veins and posterior vena cava. Additional samples from the aorta and urine were collected up to 144 hr. ⋯ The renal extraction of M3G and M6G and urinary recovery of the dose as summed morphine, M3G and M6G were reduced by renal failure. The kidney metabolized morphine to M3G. The data suggest that nonrenal elimination of M3G becomes more important during renal failure.