European journal of pharmacology
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Many clinical and experimental studies have suggested that diabetes or hyperglycemia alter pain sensitivity, and sensitivity to several drugs. It has been reported that the antinociceptive potency of morphine is decreased in several rodent models of hyperglycemia, including streptozotocin-induced diabetes, an animal models of type I diabetes. The present study was designed to investigate in streptozotocin-induced diabetic mice the effect of the selective micro-opioid agonist [D-Ala(2), NMePhe(4), Gly-ol(5)]enkephalin (DAMGO) on G-protein activation by monitoring guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to pons/medulla membranes, which contain the key areas for opioid antinociception. ⋯ The maximal stimulation of [35S]GTPgammaS binding by DAMGO (10 microM) in streptozotocin-induced diabetic mice (100.55+/-3.12%), was similar to non-diabetic mice. The present results indicated that the antinociceptive effect of DAMGO given supraspinally was less potent in streptozotocin-induced diabetic mice than that in non-diabetic mice, whereas the mu-opioid receptor-mediated G-protein activation in pons/medulla was unaltered in streptozotocin-induced diabetic mice. Thus, the attenuation of DAMGO-induced antinociception in streptozotocin-induced diabetic mice is probably caused by dysfunction in cellular pathways after the activation of G-proteins.
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Using the rat paw pressure test, in which sensitivity is increased by intraplantar injection of prostaglandin E(2) (PGE(2)), we conducted a study using several K(+) channel blockers. The objective was to determine what types of K(+) channels could be involved in the peripheral antinociceptive action of the nitric oxide donor sodium nitroprusside (SNP). SNP elicited a dose-dependent (250 and 500 microgram/paw) peripheral antinociceptive effect, which was considered local, since only higher doses produced an effect in the contralateral paw. ⋯ Charybdotoxin (2 microgram/paw), a selective blocker of high conductance Ca(2+)-activated K(+) channels, and apamin (10 microgram/paw), a selective blocker of low conductance Ca(2+)-activated K(+) channels, did not modify the peripheral antinociception induced by SNP. Tetraethylammonium (2 mg/paw), 4-aminopyridine (200 microgram/paw) and cesium (800 microgram/paw) also had no effect. Based on this experimental evidence, we conclude that the activation of ATP-sensitive K(+) channels could be the mechanism by which nitric oxide, donated by SNP, induces peripheral antinociception, and that Ca(2+)-activated K(+) channels and voltage-dependent K(+) channels appear not to be involved in the process.
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The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. ⋯ In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.
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In the present study, we sought to determine whether administration of caffeine, a non-selective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain. Rats were rendered neuropathic by unilateral tight ligation of the fifth and sixth lumbar spinal nerves, and tested for thermal hyperalgesia using a focused beam of light. Systemic administration of caffeine (1.5-7.5 mg/kg), at the same time as amitriptyline, blocked the thermal antihyperalgesic effect of 10 mg/kg amitriptyline. ⋯ Coadministration of caffeine (1500 nmol) partially antagonized the effects of both doses of amitriptyline. The results of this study suggest that the thermal antihyperalgesic effect of acute amitriptyline in this model may involve enhancement of an endogenous adenosine tone. This involvement is important in light of the widespread consumption of caffeine, which may potentially act to reduce the benefits of amitriptyline in the treatment of neuropathic pain.