Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one’s hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response—such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that—in humans—produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1–3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.In mice, the ablation of spinal neurons that co-express TAC1 and LBX1 leads to the loss of coping responses to sustained pain without affecting reflexive defensive reactions to external threats.

中文翻译：

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确定应对与持续疼痛相关的行为所需的途径

动物和人类对有害刺激表现出两种反应。第一个包括防止或限制伤害的反射性防御反应；这些反应的一个众所周知的例子是在触摸热物体时迅速缩回手。当一线反应未能防止组织损伤（例如，手指被烧伤）时，由此产生的疼痛会引发二线应对反应——例如舔受伤部位以减轻痛苦。然而，驱动这两种行为的潜在神经回路仍然知之甚少。在这里，我们在小鼠中展示了以 TAC1Cre 和 LBX1Flpo 的共表达为标志的脊髓神经元驱动与疼痛相关的应对反应。这些脊髓神经元的消融导致持续舔和由刺激（包括皮肤挤压和烧伤）引起的条件性厌恶的丧失，这些刺激在人类身上产生持续的疼痛，而不影响我们测试的任何反射性防御反应。这种对持续疼痛的选择性冷漠类似于在具有内侧丘脑核损伤的人类中所见的表型1-3。一致地，脊髓 TAC1 谱系神经元通过直接投射和通过上外侧臂旁核的间接途径连接到内侧丘脑核。此外，在脊髓水平观察到的解剖和功能分离也适用于初级感觉神经元。例如，为了响应有害的机械刺激，需要 MRGPRD 和 TRPV1 阳性伤害感受器来引发反射和应对反应，分别。因此，我们的研究揭示了皮肤躯体感觉系统内的一个基本细分，并挑战了使用反射防御反应来测量持续疼痛的有效性。在小鼠中，共表达 TAC1 和 LBX1 的脊髓神经元的消融导致应对反应的丧失持续疼痛而不影响对外部威胁的反射性防御反应。