Furue, H. (2014). 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

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 (<10 μg/kg) enhanced inhibitory postsynaptic transmission within the superficial dorsal horn without altering excitatory synaptic transmission or evoking direct postsynaptic membrane currents. In contrast, higher doses of dexmedetomidine (>10 μg/kg) induced outward currents by a direct postsynaptic action. The dexmedetomidine-mediated inhibitory postsynaptic current (IPSC) facilitation was not mimicked by spinal application of dexmedetomidine and was absent in spinalized rats, suggesting it acts at a supraspinal site. Further it was inhibited by spinal application of the α1-antagonist prazosin. In the brain stem, 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 Correspondence should be addressed to: Hidemasa Furue, Department of Information Physiology, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan. furue@nips.ac.jp; Tel, +81-564-59-5887; Fax, +81-564-59-5891. Conflict of interest statement: There are no financial or other relationships that may cause a conflict of interest. Europe PMC Funders Group Author Manuscript Pain. Author manuscript; available in PMC 2014 November 20. Published in final edited form as: Pain. 2014 March ; 155(3): 617–628. doi:10.1016/j.pain.2013.12.018. E uope PM C Fuders A uhor M ancripts E uope PM C Fuders A uhor M ancripts noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention perhaps allowing analgesic actions to be dissociated from excessive sedation.