![]() ![]() ![]() This was done by measuring locomotor coordination in FNZ-administered mice after chronic pretreatment with N G-nitro- l-arginine methyl ester ( l-NAME)-a nonselective inhibitor of the NOS isoforms, 7-nitroindazole (7-NI)-a preferential inhibitor of nNOS, l-arginine-a substrate for NO formation and sildenafil-a phosphodiesterase type 5 (PDE5) inhibitor that enhances the effects of NO by inhibiting cGMP degradation and is commonly used in erectile dysfunction. The present experiments were undertaken to investigate the effect of compounds which modulate the l-arginine:NO:cGMP pathway on the development of tolerance to flunitrazepam (FNZ)-induced motor impairment in mice. In addition, there are findings suggesting some role of l-arginine:NO:cGMP pathway in the development of diazepam-induced tolerance to its motor-impairing effect in mice (Talarek et al. Moreover, there is behavioural data indicating that inhibition of NOS prolongs the sleeping time induced by BZ (Talarek and Fidecka 2004) and enhances the anticonvulsant (Talarek and Fidecka 2003), antinociceptive (Talarek and Fidecka 2002) and anxiolytic (Quock and Nguyen 1992) effects of BZ. It is also known that NO regulates the GABA release and uptake in the CNS (Guevara-Guzman et al. It has also been reported that NO is released as a result of activation of GABAergic neurotransmission in animal cortex (Guevara-Guzman et al. For example, histochemical mapping of NOS revealed co-localization of NOS-positive neurons with GABA in the cerebral cortex and spinal cord (Valtschanoff et al. There are data pointing to the relationship between l-arginine:NO:cGMP pathway and GABA-mediated transmission in the central nervous system (CNS). NO is supposed to play an important role in several brain functions and/or dysfunctions, including regulation of neuronal excitability, synaptic plasticity, anxiety, seizure activity and drug tolerance. cGMP, in turn, modulates the activity of cGMP-dependent kinases, cGMP-gated ion channels and cGMP-regulated phosphodiesterases (PDE) (Bruckdorfer 2005). ![]() NO allosterically interacts with soluble guanylyl cyclase (sGC) to increase cyclic guanosine 3′,5′-monophosphate (cGMP) expression and cGMP-dependent signaling. nNOS and eNOS are Ca 2+-calmodulin-dependent and are constitutively expressed in mammalian cells. There are four members of the NOS family: neuronal (nNOS), endothelial (eNOS), inducible (iNOS) and mitochondrial NOS (mtNOS). Nitric oxide (NO), an important bioregulatory molecule, is synthesized from l-arginine, by a reaction catalyzed by nitric oxide synthase (NOS) (Bruckdorfer 2005). However, the neurobiological mechanisms underlying tolerance to BZ have not been well characterized yet. All BZ have the capacity to promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABA A receptors (Smith et al. therapeutic) doses and is characterized to many pharmacological effects of these drugs (including their sedative, anxiolytic, muscle relaxant and anticonvulsant effects) (Allison and Pratt 2003). ![]() In the case of BZ, tolerance develops with long-term use, even at low to moderate (i.e. Tolerance is defined as the reduction in certain pharmacological effects of a drug on repeated exposure to a given dose or the need to increase the amount of drug intake to obtain the same effect. This group of agents is widely used in clinics, but the use of these compounds is limited by the development of tolerance to most of their pharmacological actions that occurs after prolonged administration (Bateson 2002 Ferreri et al. Benzodiazepines (BZ) are compounds with sedative, anxiolytic, anticonvulsant and muscle relaxant properties in humans and animals which were introduced to clinical practice over 50 years ago. ![]()
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