We studied the effects of sildenafil, a selective inhibitor of PDE5, on the development and the expression of tolerance to diazepam (DZ)-induced motor impairment and sedation in mice. DZ-induced motor incoordination was assessed by the rotarod and chimney tests, and DZ-induced sedation was examined using a photocell apparatus. Sildenafil treatment enhanced the development of tolerance to the motor impairing effects, but not to the sedative effects, of DZ. Sildenafil treatment did not affect the expression of tolerance to DZ-induced motor impairment and sedation in mice. Our results suggest that sildenafil treatment, at least in part, affects the development of DZ tolerance.
The non-peptidergic opioid receptor-like 1 (ORL1, OP4) receptor ligand, Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one], is a full agonist of the OP4 receptor. The aim of this study was to evaluate whether this compound influences morphine antinociception and dependence in mice. Ro 64-6198 inhibits the acute analgesic effect of morphine in the tail-immersion test, however, when given chronically during the acquisition of morphine dependence, development of this dependence is not prevented. The acute injection of Ro 64-6198 suppresses withdrawal escape jumps in morphine dependent mice, though this effect may be a result of the loss of locomotor activity induced by this compound and/or its myorelaxant action. The study provides evidence that stimulation of the OP4 receptor suppresses acute morphine antinociception, but is not sufficient to inhibit the development of morphine dependence in mice.
This study was undertaken to evaluate the effect of nitric oxide (NO) synthase inhibitors on benzodiazepine withdrawal syndrome in mice and rats. Diazepam withdrawal in mice was read out as intensification of the seizures induced by a subthreshold dose of pentetrazole. In rats, the withdrawal syndrome resulting from chronic administration of diazepam, chlordiazepoxide, clonazepam and temazepam was characterized by audiogenic seizures, hypermotility and weight loss. Administration of the non-selective NO synthase inhibitors N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) significantly attenuated the withdrawal syndrome (i.e., pentetrazole-induced seizures) in diazepam-dependent mice. L-NOARG significantly suppressed hypermotility in clonazepam-dependent rats and inhibited the decrease in body weight observed after 12 h of withdrawal in chlordiazepoxide- and clonazepam-dependent rats. Moreover, a clear propensity of L-NOARG to protect benzodiazepine-dependent rats against audiogenic seizures was observed. These findings suggest that the cGMP/NO system may participate in causing the signs of benzodiazepine withdrawal.
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