Pro-opiomelanocortin neurons in the nucleus of the solitary tract mediate endorphinergic endogenous analgesia in mice.
Pro-opiomelanocortin neurons in the nucleus of the solitary tract mediate endorphinergic endogenous analgesia in mice.
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DOI：
10.1097/j.pain.0000000000002802
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发表时间：
2022-10
期刊：
影响因子：
7.4
通讯作者：
P. H. Patra;Becks Tench;T. Hitrec;F. Holmes;R. Drake;S. Cerritelli;D. Spanswick;A. Pickering
中科院分区：
文献类型：
--
作者：
P. H. Patra;Becks Tench;T. Hitrec;F. Holmes;R. Drake;S. Cerritelli;D. Spanswick;A. Pickering
孤束核（NTS）内含有前阿黑皮素（POMC）神经元，是脑内β-内啡肽的两个主要来源之一。这些NTSPOMC神经元在伤害感受和心肺功能中的功能作用是有争议的。我们已经表明，NTSPOMC光遗传激活在工作的心-脑干制备中产生心动过缓和短暂呼吸暂停，并且用工程化离子通道（PSAM）的化学遗传激活在体内产生阿片样镇痛。为了更好地定义NTSPOMC神经元在行为动物中的作用，我们在POMC-Cre小鼠中采用体内光遗传学（ChrimsonR）和兴奋性/抑制性化学遗传学DREADD（hM 3Dq/hM 4Di）策略。我们表明NTSPOMC神经元的光遗传学激活在麻醉小鼠中产生时间锁定的、分级的、短暂的心动过缓和呼吸过缓，所述小鼠是纳洛酮敏感的（1 mg/kg，i. p.），暗示β-内啡肽的作用。NTSPOMC神经元的光遗传学和化学遗传学激活在行为小鼠中产生可被纳洛酮阻断的持续热镇痛。它也产生镇痛炎性疼痛模型（角叉菜胶），但不是在神经性疼痛模型（胫神经横断）。抑制NTSPOMC神经元不会对基础伤害感受产生任何影响，但会抑制应激诱导的镇痛（与弓状POMC神经元的抑制不同）。在清醒小鼠中NTSPOMC神经元群的激活不会引起呼吸抑制、焦虑或运动缺陷（在开放视野中）或情感偏好。这些结果表明，NTSPOMC神经元在产生内啡肽能内源性镇痛中起着关键作用，也可以调节心肺功能。
ABSTRACT The nucleus of the solitary tract (NTS) contains pro-opiomelanocortin (POMC) neurons that are 1 of the 2 major sources of β-endorphin in the brain. The functional role of these NTSPOMC neurons in nociceptive and cardiorespiratory function is debated. We have shown that NTSPOMC optogenetic activation produces bradycardia and transient apnoea in a working heart-brainstem preparation and chemogenetic activation with an engineered ion channel (PSAM) produced opioidergic analgesia in vivo. To better define the role of the NTSPOMC neurons in behaving animals, we adopted in vivo optogenetics (ChrimsonR) and excitatory/inhibitory chemogenetic DREADD (hM3Dq/hM4Di) strategies in POMC-Cre mice. We show that optogenetic activation of NTSPOMC neurons produces time-locked, graded, transient bradycardia and bradypnoea in anaesthetised mice that is naloxone sensitive (1 mg/kg, i.p.), suggesting a role of β-endorphin. Both optogenetic and chemogenetic activation of NTSPOMC neurons produces sustained thermal analgesia in behaving mice that can be blocked by naloxone. It also produced analgesia in an inflammatory pain model (carrageenan) but not in a neuropathic pain model (tibial nerve transection). Inhibiting NTSPOMC neurons does not produce any effect on basal nociception but inhibits stress-induced analgesia (unlike inhibition of arcuate POMC neurons). Activation of NTSPOMC neuronal populations in conscious mice did not cause respiratory depression, anxiety, or locomotor deficit (in open field) or affective preference. These findings indicate that NTSPOMC neurons play a key role in the generation of endorphinergic endogenous analgesia and can also regulate cardiorespiratory function.