UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.
Department of Psychology, Rutgers University, New Brunswick, NJ, USA.
Nat Commun. 2022 Feb 9;13(1):764. doi: 10.1038/s41467-022-28332-6.
Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.
μ 阿片受体（MOR）激动剂是强效的镇痛药，但也会引起镇静、呼吸抑制和成瘾风险。丘脑外侧缰核（LHb）传递包括疼痛在内的厌恶状态信号，而我们在此发现，它是大鼠中 MOR 激动剂类镇痛反应的有效部位。重要的是，LHb MOR 的激活在没有有害输入的情况下并不具有强化作用。LHb 接收来自多个部位的兴奋性输入，包括腹侧被盖区、外侧下丘脑、脚间核和下丘脑外侧视前区（LPO）。在这里，我们报告说，LHb 投射谷氨酸能 LPO 神经元受到有害刺激的兴奋，并优先被 MOR 选择性激动剂抑制。关键的是，LHb 投射 LPO 神经元的光遗传学刺激会产生一种厌恶状态，而 LHb MOR 的激活可以缓解这种状态，而 LHb 投射 LPO 神经元的光遗传学抑制则可以缓解持续疼痛的厌恶感。
