title: 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.
abstract: 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 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.
authors.affiliation: Department of Information Physiology, National Institutes for Physiological Sciences, Okazaki, Japan Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan School of Physiology and Pharmacology, University of Bristol, Bristol, UK School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Funai
authors.forename: Anthony Edward
authors.initials: AE
authors.lastname: Pickering
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uta
authors.forename: Kiyonobu
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Akira
authors.initials: A
authors.lastname: Asada
authors.forename: Keiji
authors.initials: K
authors.lastname: Imoto
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Furue
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects* / Q000502:physiology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage; D000698:Analgesia / Q000379:methods*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000818:Animals; D020927:Dexmedetomidine / Q000008:administration & dosage*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018712:Analgesics, Non-Narcotic; D020927:Dexmedetomidine
keywords: Alpha2 adrenoceptor; Dexmedetomidine; Noradrenaline; Patch-clamp analysis; Spinal cord