The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 2001
Differences between peptide and nonpeptide B(2) bradykinin receptor antagonists in blocking bronchoconstriction and hypotension induced by bradykinin in anesthetized Guinea pigs.
We have compared the in vivo activity of the bradykinin B(2) receptor peptide antagonists MEN 11270 and Icatibant versus the nonpeptide antagonist FR 173657, after intravenous (i.v.) and intratracheal (i.t.) administration, on the bradykinin (BK)-induced bronchoconstriction and hypotension in anesthetized guinea pigs. We have also assessed the affinity of these antagonists for B(2) receptors in guinea pig lung membranes by radioligand binding and the metabolic stability of peptide antagonists in guinea pig plasma and tissue homogenates. The i.v. administration of MEN 11270, Icatibant, or FR 173657 induced a dose-dependent (10-100 nmol/kg) inhibition of both hypotension and bronchoconstriction induced by bradykinin (10 nmol/kg i.v.). ⋯ The antibronchoconstrictor effect of MEN 11270 was more prolonged than that of Icatibant and FR 173657, whereas no differences were found between the peptide antagonists in inhibiting hypotension. These findings indicated that, in vivo, the peptide antagonists are more potent and longer lasting than FR 173657 acting on bradykinin B(2) receptors in guinea pig airways and in the vascular system. The greater efficacy of the antagonists in blocking airway compared with vascular B(2) receptors after topical administration suggests that they can block airway B(2) receptors with little systemic effects.
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J. Pharmacol. Exp. Ther. · Mar 2001
Antinociceptive effects of delta-opioid agonists in Rhesus monkeys: effects on chemically induced thermal hypersensitivity.
The effects of SNC80 and other structurally related delta-opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degrees C), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. ⋯ In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta-agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs.
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J. Pharmacol. Exp. Ther. · Feb 2001
Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection.
The effects of systemic and local injections of gabapentin, a novel anticonvulsant agent, were tested on nociceptive behaviors in mice with acute herpetic pain. Transdermal infection with herpes simplex virus type-1 (HSV-1) produced nociceptive hypersensitivity of the infected hind paw to innocuous (allodynia) and noxious mechanical stimulation (hyperalgesia) with von Frey filaments. Systemic administration of gabapentin (10-100 mg/kg, peroral) produced a dose-dependent inhibition of both allodynia and hyperalgesia; gabapentin (30-300 mg/kg) did not affect locomotor activity. ⋯ Pretreatment with naltrexone (1 mg/kg) inhibited antinociceptive effect of morphine (5 mg/kg), but not gabapentin (100 mg/kg). Repeated administration of morphine (5 mg/kg, four times) led to tolerance of antinociceptive action, whereas gabapentin (100 mg/kg, four times) had antinociceptive effect even after the forth administration. The present results suggest that gabapentin is effective in the treatment of acute herpetic pain without apparent adverse effects, and analgesic action of gabapentin is mainly mediated by actions on the spinal cord.
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J. Pharmacol. Exp. Ther. · Feb 2001
Evidence of a functional alpha7-neuronal nicotinic receptor subtype located on motoneurons of the dorsal motor nucleus of the vagus.
In vitro autoradiography using 125I-alpha-bungarotoxin (alpha-BGTx) and anti-alpha7 immunohistochemistry were performed on the dorsal motor nucleus of the vagus (DMV) of sham and chronically vagotomized rats to determine whether the alpha7-nicotinic acetylcholine receptor (nAChR) is located postsynaptically on DMV neurons whose axons contribute to the vagus nerve. Intense bilateral 125I-alpha-BGTx binding and anti-alpha7 immunostaining were observed in coronal brain sections containing the DMV of sham-vagotomized animals. Unilateral cervical vagotomy resulted in ipsilateral losses of 125I-alpha-BGTx binding and anti-alpha7 immunostaining from the DMV. ⋯ To test whether the alpha7-nAChR is similar to the alpha7-homomeric nAChR, experiments were performed in anesthetized rats, and compounds were microinjected into the DMV while monitoring intragastric pressure (IGP). alpha-BGTx and strychnine antagonized nicotine-induced increases in IGP; no antagonism was observed with methyllycaconitine, a compound known to block the homomeric alpha7-nAChR subtype. Recovery from alpha-BGTx-induced antagonism of the nicotine response was observed. We conclude that there is a nAChR containing the alpha7-subunit in the DMV that is different from the homomeric alpha7-nAChR subtype.
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J. Pharmacol. Exp. Ther. · Feb 2001
Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action.
The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) relative contributions of supraspinal, spinal, and peripheral sites to the actions of A-134974. Systemic A-134974 (i.p.) dose dependently reduced hyperalgesia (ED(50) = 1 micromol/kg) and at higher doses, reduced locomotor activity (ED(50) = 16 micromol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50) = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED(50) = 100 nmol, i.c.v.) or intraplantar (ED(50) >300 nmol) routes. ⋯ In the locomotor assay, i.t.-injected THEO did not antagonize hypomobility caused by systemic or i.t. administration of A-134974. However, i.c.v. infusion of THEO did block the hypomotive actions of i.c.v.-, i.t.-, and i.p.-administered A-134974. These data demonstrate that the novel AK inhibitor A-134974 potently reduces thermal hyperalgesia primarily through interactions with spinal sites, whereas its ability to depress locomotor activity is predominantly mediated by supraspinal sites.