Pharmacol Rep
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Many sedative-hypnotic agents are thought to act by positively modulating γ-aminobutyric acid type A (GABAA) receptors. However, for many agents, the location(s) of the binding site(s) responsible for such receptor modulation is uncertain. We previously developed a low efficacy ligand (naphthalene-etomidate) that binds within a homologous set of hydrophobic cavities located at GABAA receptor subunit interfaces in the transmembrane domain, and thus acts as a competitive antagonist for higher efficacy sedative-hypnotics that also bind to these sites. In this report, we describe studies using this compound as a pharmacological screening tool to test whether sedative-hypnotics representing a range of chemical classes can modulate GABAA receptors by binding within these receptor cavities. ⋯ Our results suggest that many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities.
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Xylazine is an α2 adrenoceptor agonist that is extensively used in veterinary medicine and animal experimentation procedures to produce analgesia, sedation and muscle relaxation without causing general anesthesia. Considering the lack of knowledge of the mechanisms involved in peripheral antinociception induced by xylazine and the potential interactions between the adrenergic and endocannabinoid systems, the present study investigated the contribution of the latter system in the mechanism of xylazine. ⋯ The present results provides evidence that the peripheral antinociceptive effect of the α2 adrenoceptor agonist xylazine probably results from anandamide release and subsequent CB1 cannabinoid receptor activation.