Evidence that negative regulation of wakefulness in neonatal rats is an intrinsic function of the brain alpha2A-adrenergic receptors

Previously, it was proposed that sedative and anesthetic effects of alpha2-adrenergic receptor (alpha2-AR) agonists may be exerted via neuronal networks normally implicated in the regulation of wakefulness. The aim of this study was to evaluate the role of A subtype of alpha2-ARs in the development of drug-independent anesthetic state induced by hypothermia in newborn rats. Using short interfering RNA (siRNA) gene-targeting strategy, we found that down-regulation of the brainstem alpha2A-AR expression resulted in a delay in the onset of hypothermia-induced anesthesia assessed by loss of righting reflex. Involvement of the brain alpha2A-ARs in this delay was confirmed by inability of clonidine, a subtype-nonselective alpha2-AR agonist, to prolong duration of hypothermia-induced anesthesia in siRNA-treated animals, while significant prolongation of this anesthetic state by the alpha2A-AR agonist was observed in control pups. The data suggest that negative regulation of the animal's waking state is an intrinsic function of the brainstem alpha2A-ARs activated by exogenous agonists, as well as by endogenous noradrenaline, also.

Research highlights▶ siRNA decreases alpha2A-adrenoceptor expression in the brainstem of neonatal rat. ▶ Decreased alpha2A-AR expression delays onset of hypothermia-induced anesthesia. ▶ Clonidine is unable to prolong the anesthesia in alpha2A-AR-siRNA-treated animals. ▶ Negative regulation of waking state is intrinsic function of the brain alpha2A-AR.