European journal of pharmacology
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Comparative Study
Adenosine A1 receptors modulate the anxiolytic-like effect of ethanol in the elevated plus-maze in mice.
The anxiolytic property of ethanol is generally accepted to be an important motivational factor for its consumption and the development of alcohol dependence. Recent studies suggest that adenosine receptors mediate important actions of ethanol, such as motor incoordination and hypnotic effects. In addition, several lines of evidence support the involvement of adenosine in anxiety. ⋯ The prior administration of "non-anxiogenic" doses of caffeine (10.0 mg/kg, i.p.) and DPCPX (3.0 mg/kg, i.p.), but not ZM241385 (1.0 mg/kg, i.p.), significantly reduced the anxiolytic-like effect of ethanol (1.2 g/kg, i.p.). Moreover, anxiolytic-like response was observed by the co-administration of "non-anxiolytic" doses of CCPA (0.125 mg/kg) and ethanol (0.6 g/kg). These results reinforce the involvement of adenosine in anxiety and suggest that the activation of adenosine A1 receptors, but not adenosine A(2A) receptors, mediate the anxiolytic-like effect induced by ethanol in mice.
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Comparative Study
Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist.
The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. ⋯ These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.
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Comparative Study
Inhibition of interleukin-1beta reduces mouse lung inflammation induced by exposure to cigarette smoke.
We examined nuclear factor kappaB activation, release of inflammatory mediators and cellular infiltration in acute cigarette smoke inflammation models. One hour after exposure to one puff of cigarette smoke, alveolar macrophages from bronchoalveolar lavage (BAL) fluid of C57BL/6J mice showed an increased activity of nuclear factor kappaB-DNA binding but similar numbers as compared to that of BAL fluid from mice exposed to ambient air. Exposure to 1 cigarette/day for 1, 4 or 7 days led to an increase in interleukin-1beta and monocyte chemoattractant protein-1 levels and to a progressive influx of nuclear factor kappaB-activated alveolar macrophages into the BAL fluid and lung tissue. ⋯ Tumor necrosis factor-alpha levels and subsequent neutrophil influx were only detected after exposure to 4 or 8 cigarettes/day for 7 days. Treatment of mice with an antibody anti-interleukin-1beta during cigarette smoke exposure for 7 days significantly reduced both interleukin-1beta levels and alveolar macrophage influx. These data show that a single exposure to cigarette smoke rapidly activates alveolar macrophages, inducing the production of interleukin-1beta, which may play an important role in triggering chronic cigarette smoke-mediated lung inflammation.
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Comparative Study
Upregulation of Rho-kinase (ROCK-2) expression and enhanced contraction to endothelin-1 in the mesenteric artery from lipopolysaccharide-treated rats.
Effects of bacterial lipopolysaccharide (Escherichia coli serotype, 055:B5, 20 mg kg(-1), i.p., for 6 h) and a Rho-kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate, Y-27632 (10(-9)-10(-5) M) were investigated on the contractile responses of the rat mesenteric artery to phenylephrine (10(-9)-3 x 10(-5) M), angiotensin-2 (10(-10)-10(-6) M) and endothelin-1 (10(-10)-10(-7) M). Moreover, alteration in the level of Rho-kinase (ROCK-2) expression was examined in the superior mesenteric artery obtained from saline- and lipopolysaccharide-treated rats by Western blotting. Endotoxemic rat mesenteric rings exhibited no different contractions to phenylephrine and angiotensin-2 but augmented contractile activity to endothelin-1. ⋯ Western blot analysis revealed that Rho-kinase was upregulated significantly in the mesenteric artery obtained from the rats treated with LPS for 6 h. In addition, serum NO2-/NO3- level, which was detected by Griess method, was 10.0+/-1.4 microM in endotoxemic rats; however, it was 6.6+/-0.5 microM in control (P<0.05). Taken together, these results show that the expression of the contractile protein Rho-kinase could be upregulated in endotoxemic mesenteric artery and this upregulation may be coincided with an enhanced contraction to endothelin-1 but not phenylephrine and angiotensin-2.
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Somatostatin released from capsaicin-sensitive sensory nerves exerts systemic anti-inflammatory and antinociceptive actions. TT-232 is a stable, peripherally acting heptapeptide (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) somatostatin analogue with highest binding affinity for somatostatin sst4 receptors. It has been shown to inhibit acute and chronic inflammatory responses and sensory neuropeptide release from capsaicin-sensitive nociceptors. ⋯ Five weeks after streptozotocin administration (50 mg/kg i.v.) the diabetes-induced decrease in the mechanonociceptive threshold was inhibited by 10-100 microg/kg i.p. TT-232. These findings show that TT-232 potently inhibits acute chemical somatic/visceral and thermal nociception and diminishes chronic mechanical allodynia associated with diabetic neuropathy, thereby it could open new perspectives in the treatment of various pain syndromes.