Funai Yusuke, Pickering Anthony Edward, Uta Daisuke, Nishikawa Kiyonobu, Mori Takashi, Asada Akira, Imoto Keiji, Furue Hidemasa
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.
Pain. 2014 Mar;155(3):617-628. doi: 10.1016/j.pain.2013.12.018. Epub 2013 Dec 16.
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.
α2肾上腺素能受体广泛分布于中枢神经系统（CNS），全身给予右美托咪定等α2激动剂可产生临床上有用的、由中枢介导的镇静和镇痛作用；然而，这些相同的作用也限制了这些药物的应用（即不必要的镇静作用）。尽管在体外有大量关于α2激动剂的细胞和突触作用的数据，但尚不清楚体内哪些神经回路被调节以产生镇痛效果。为了解决这个问题，我们对脊髓背角浅层神经元的膜电流和突触活动进行了体内记录，并研究了它们对全身给予右美托咪定的反应。我们发现，产生镇痛作用的右美托咪定剂量（<10μg/kg）可增强脊髓背角浅层的抑制性突触传递，而不改变兴奋性突触传递或诱发直接的突触后膜电流。相比之下，更高剂量的右美托咪定（>10μg/kg）通过直接的突触后作用诱导外向电流。右美托咪定介导的抑制性突触后电流增强不能被脊髓局部应用右美托咪定所模拟，并且在脊髓横断的大鼠中不存在，这表明它作用于脊髓以上部位。此外，它可被脊髓局部应用α1拮抗剂哌唑嗪所抑制。在脑干，低剂量的全身右美托咪定可引起蓝斑神经元兴奋。这些结果表明，全身α2肾上腺素能受体刺激可能促进脊髓背角浅层的抑制性突触反应，以产生由脑桥脊髓去甲肾上腺素能抑制系统激活介导的镇痛作用。这种新机制可能为干预提供新的靶点，也许能使镇痛作用与过度镇静分离。
