臂旁核Penk神经元在机械痛觉敏化中的作用及其机制研究

伤害性刺激在多数情况下能够引起疼痛的感觉，但并非总是如此，例如在激烈的战斗中，某些士兵在严重受伤的当时并未感觉到疼痛；与此同时，非伤害性的刺激，如衣物轻轻地划过皮肤，在炎症或神经损伤后，却可能引起剧烈的疼痛。机械触诱发痛是炎症性和神经病理性疼痛的一个特征性症状。触诱发痛主要分为两种类型，一种是静态（点状）触诱发痛，是由如von Frey毛等对皮肤表面施加稳定的轻触压力引起；另外一种是动态触诱发痛，是由如画笔等轻轻地划过皮肤的表面引起的。触诱发痛对吗啡等阿片类镇痛药相对不敏感，属于顽固性和难治性的异常疼痛，严重影响患者的日常起居和工作生活质量，目前临床上尚缺乏有效的治疗手段，主要原因是其感知的神经机制尚不清楚。Ronald Melzak和Patrick Wall两位伟大的科学家在1965年提出的著名的“痛的闸门控制学说”认为，触诱发痛的发生主要是由于慢性疼痛的情况下，脊髓背角的“闸门控制”失效，从而使正常情况下被“门控”的传递触觉刺激的低阈值机械感受器（low threshold mechanoreceptors, LTMRs）能够激活脊髓背角特异传递痛觉的神经元，从而使慢性疼痛患者在受到非痛的轻触刺激后感知到了痛觉。

痛的“闸门学说”可以很好地解释非痛刺激引起的疼痛现象。然而几十年过去了，研究者们虽然找到了脊髓背角介导机械痛的兴奋性和抑制性神经元类型及其脊髓上行神经环路,但是，关于痛觉机械力感知异常的神经环路机制研究，目前国内外仍然处于起步阶段，诸多核心科学问题尚未回答，是当前研究的热点和前沿领域。例如，临床上存在一些慢性疼痛患者，单侧的局部炎症或神经损伤会导致长时间、全身性的机械痛觉敏化，然而对于大多数患者来说，机械痛只是短暂的，或仅局限于单侧。控制机械痛觉敏化的这些不同时空特征的细胞和神经环路机制，特别是触诱发痛侧性（laterality）的控制机制，目前仍知之甚少。我们近期的一项研究揭示，从脑干lPBN^Oprm1神经元,经由下丘脑dmH^Pdyn神经元，再投射到脊髓背角（spinal dorsal horn,SDH）的脑－脊髓下行神经环路（lPBN^Oprm1→dmH^Pdyn→SDH），通过“下丘脑Dyn－脊髓KOR”轴控制外周炎症和或神经损伤引起的机械痛觉敏化（触诱发痛）的持续时间和扩散范围。进一步，本项目拟在此前期工作基础上，进一步研究痛觉机械力感知异常的脑下行神经环路机制。

在本研究中使用化学遗传学以及条件性敲除等遗传学方法发现，从脑干外侧臂旁核（lateral parabrachial nucleus，lPBN）前脑啡肽（preproenkephalin，Penk）神经元（lPBN^Penk）投射到背腹侧下丘脑（dorsal medial regions of hypothalamus，dmH）的γ-氨基丁酸（Gamma-Aminobutyric Acid，GABA）能神经元（dmH^GABA）环路(lPBN^Penk – dmH^GABA)介导了机械痛觉敏化的诱导。主要实验结果如下：

1. 背侧臂旁核（superior-internal lPBN，slPBN）参与机械痛觉敏化的诱导和或表达。
2. 揭示lPBN Penk神经元介导机械痛觉敏化的诱导和或表达。
3. 激活slPBN中投射到dmH的Penk神经元时可以直接产生机械痛觉敏化，当抑制slPBN中投射到dmH的Penk神经元时，可以阻止由辣椒素引起的机械痛觉敏化的产生。
4. 抑制由下丘脑投射到脊髓背角（spinal dorsal horn，SDH）的γ-氨基丁酸（Gamma-Aminobutyric Acid，GABA）能神经元，正常小鼠出现机械痛觉敏化，而激活下丘脑投射到SDH的GABA能神经元时，可以阻断由辣椒素引起的机械痛觉敏化。

综上所述，本课题找到了一条脑内调控机械痛觉敏化产生的环路，从slPBN的Penk神经元到dmH的GABA能神经元。当兴奋环路中的slPBN^Penk→dmH投射神经元或者抑制dmH^GABA→SDH投射神经元时，都会打开脊髓的门控，促使机械痛觉敏化的产生。相反,当抑制环路中的slPBN^Penk→dmH投射神经元或者兴奋dmH^GABA→SDH投射神经元时，可以抑制由辣椒素诱发的机械痛觉敏化。本研究目标是寻找介导机械痛觉敏化的脑下行神经环路，研究结果希望可以为为治疗机械力感知异常导致的慢性持续性疼痛，如临床上顽固性和难治性的异常机械触诱发痛等，提供基础理论支撑和潜在的新型药物研发和临床治疗靶点和新思路。

In most cases, noxious stimuli can produce pain perception, but not always. For instance, in the battle field, soldiers were severly injured, but did not feel pain. In contrast, non-painful stimuli, such as gentle moving of clothes across cutaneous skin, could induce intense pain following inflammation or nerve injury. Mechanical allodynia is a hallmark symptom of inflammatory and neuropathic pain. Mechanical allodynia is mainly divided into two types: static (punctate) allodynia, caused by applying steady light pressure across the skin such as with von Frey filaments; and dynamic allodynia, caused by lightly brushing objects such as a brush across the skin's surface. Mechanical allodynia is relatively resistant to opioids such as morphine and represents a type of refractory and intractable abnormal pain. It severely affects the quality of patients life, and effective treatment methods are still lacking in clinical practice. The main reason is that the neural mechanism of its perception is not yet clear. In 1965, two great scientists, Ronald Melzak and Patrick Wall, proposed the famous "Gate Control Theory of Pain", which suggests that the occurrence of mechanically induced pain is mainly due to the failure of "gate control" in the dorsal horn of the spinal cord under chronic pain conditions. This allows low-threshold mechanoreceptors (LTMRs), which are normally "gated" and transmit tactile stimuli, to activate specific neurons in the dorsal horn of the spinal cord that transmit pain, thus causing chronic pain patients to perceive pain after receiving non-painful light touch stimuli.

The "Gate Theory of Pain" can well explain the phenomenon of pain caused by non-painful stimuli. However, decades have passed, and although researchers have identified the excitatory and inhibitory neuron types in the dorsal horn of the spinal cord that mediate mechanical pain and their spinal ascending neural circuits, research on the neural circuit mechanisms of abnormal mechanical pain perception is still in its infancy both domestically and internationally. Many core scientific questions remain unanswered, making this a current research hotspot and frontier field. For example, in clinical settings, there are chronic pain patients where unilateral local inflammation or nerve damage can lead to prolonged, systemic mechanical allodynia. However, for most patients, mechanical pain is only transient or confined to one side. The cellular and neural circuit mechanisms that control these different spatial and temporal characteristics of mechanical allodynia, especially the control mechanisms of mechanical allodynia laterality, are still largely unknown. Our recent study reveals that a brain-spinal descending neural circuit (lPBN^Oprm1→dmH^Pdyn→SDH) from the lPBN^Oprm1neurons in the brainstem, via dmH^Pdyn neurons in the dorsal medial regions of hypothalamus, projecting to the spinal dorsal horn (SDH), controls the duration and spread of mechanical allodynia caused by peripheral inflammation and/or nerve injury through the "Hypothalamic Dyn-Spinal KOR" axis. Furthermore, this project intends to further study the neural circuit mechanisms of abnormal mechanical pain perception in the descending neural circuits of the brain, based on the preliminary work.

In this study, using chemogenetics and conditional knockout genetic methods, we discovered that the circuit from the preproenkephalin (Penk) neurons in the lateral parabrachial nucleus (lPBN) projecting to the gamma-aminobutyric acid (GABA) neurons in the dorsal medial regions of the dorsal medial regions of hypothalamus (dmH) (lPBN^Penk – dmH^GABA) mediates the induction of mechanical allodynia. The main experimental results are as follows:

The superior-internal lPBN (slPBN) is involved in the induction and/or expression of mechanical allodynia.

Revealed that lPBN Penk neurons mediate the induction and/or expression of mechanical allodynia.

Activation of Penk neurons in the slPBN projecting to the dmH can directly produce mechanical allodynia. In contrast, inhibiting Penk neurons in the slPBN projecting to the dmH can prevent the occurrence of mechanical allodynia caused by capsaicin.

Inhibiting GABA neurons from the dorsal medial regions of hypothalamus projecting to the spinal dorsal horn (SDH) causes mechanical allodynia in normal mice. In contrast, activating GABA neurons from the dorsal medial regions of hypothalamus projecting to the SDH can block the mechanical allodynia caused by capsaicin.

In summary, this study found a brain circuit that regulates the induction of mechanical allodynia, from Penk neurons in the slPBN to GABA neurons in the dmH. Exciting neurons in the slPBN^Penk→dmH projection or inhibiting dmH^GABA→SDH projection neurons both open the spinal gate, leading to the generation of mechanical allodynia. Conversely, inhibiting neurons in the slPBN^Penk→dmH projection or exciting dmH^GABA→SDH projection neurons can suppress mechanical allodynia induced by capsaicin. The goal of this study is to find the brain descending neural circuit that mediates mechanical allodynia. The research results hope to provide theoretical support and potential new drug development and clinical treatment targets and new ideas for treating chronic persistent pain caused by abnormal mechanical force perception, such as refractory and intractable abnormal mechanical allodynia in clinical settings.

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