Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: An in vivo patch-clamp analysis of analgesic mechanisms

A novel analgesic mechanism of systemic dexmedetomidine (α2-agonist) revealed by in vivo patch-clamp analysis: paradoxical activation of descending noradrenergic system enhances spinal inhibitory synaptic transmission. α2-Adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of α2-agonists such as dexmedetomidine produces clinically useful, centrally mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie, unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of α2-agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine. We found that dexmedetomidine at doses that produce analgesia (10μg/kg) induced outward currents by a direct postsynaptic action. The dexmedetomidine-mediated inhibitory postsynaptic current facilitation was not mimicked by spinal application of dexmedetomidine and was absent in spinalized rats, suggesting that it acts at a supraspinal site. Furthermore, it was inhibited by spinal application of the α1-antagonist prazosin. In the brainstem, low doses of systemic dexmedetomidine produced an excitation of locus coeruleus neurons. These results suggest that systemic α2-adrenoceptor stimulation may facilitate inhibitory synaptic responses in the superficial dorsal horn to produce analgesia mediated by activation of the pontospinal noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention, perhaps allowing analgesic actions to be dissociated from excessive sedation.