Lançon Kevin, Tian Jiakang, Bach Haleigh, Drapeau Pierre, Poulin Jean-Francois, Séguéla Philippe
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, QC, Canada.
Alan Edwards Centre for Research on Pain, McGill University, Montreal H3A 2B4, QC, Canada.
Proc Natl Acad Sci U S A. 2025 Jul;122(26):e2502558122. doi: 10.1073/pnas.2502558122. Epub 2025 Jun 26.
Chronic pain arises from maladaptive changes in both peripheral and central nervous systems, including the anterior cingulate cortex (ACC), a key region implicated in descending pain modulation. Chronic pain increases the excitability of pyramidal neurons in the ACC. Although a reduction in inhibitory inputs onto pyramidal neurons has been observed in neuropathic conditions, the identity of the specific interneurons responsible remains unclear. We show that chronic pain selectively impairs parvalbumin (PV), but not somatostatin, interneurons in the rostral ACC. This is characterized by a decrease in the density of PV interneuron processes, a reduction in their surrounding perineuronal net, and a lower expression of PV. Functionally, PV interneurons display diminished inhibitory efficacy in vitro and reduced phasic activation in response to aversive stimuli in vivo. Dopamine (DA) fibers preferentially contact PV interneurons and excite them via D1 dopamine receptor activation, increasing their excitability and enhancing the frequency of inhibitory postsynaptic currents on pyramidal neurons in healthy, but not neuropathic, conditions. Furthermore, we show that this pathway is involved in hunger-induced analgesia: Food deprivation increases DA release in the ACC and consequently decreases pain thresholds in neuropathic mice. Conversely, when mice are not food deprived, neuropathic pain significantly reduces DA release in the ACC. We conclude that the loss of PV interneuron inhibitory efficacy, alongside convergent hypodopaminergic signaling, synergistically contributes to pathological ACC dysfunction and associated symptoms of chronic pain.
慢性疼痛源于外周和中枢神经系统的适应性改变，包括前扣带回皮质（ACC），这是一个与下行性疼痛调节相关的关键区域。慢性疼痛会增加ACC中锥体神经元的兴奋性。尽管在神经性疾病中已观察到锥体神经元上抑制性输入的减少，但具体负责的中间神经元的身份仍不清楚。我们发现，慢性疼痛会选择性地损害喙部ACC中的小白蛋白（PV）中间神经元，而不是生长抑素中间神经元。其特征是PV中间神经元突起的密度降低、其周围神经周网减少以及PV的表达降低。在功能上，PV中间神经元在体外显示出抑制效能降低，在体内对厌恶性刺激的相位激活减少。多巴胺（DA）纤维优先接触PV中间神经元并通过D1多巴胺受体激活来兴奋它们，在健康而非神经性条件下增加其兴奋性并提高锥体神经元上抑制性突触后电流的频率。此外，我们表明该途径参与饥饿诱导的镇痛：食物剥夺会增加ACC中的DA释放，从而降低神经性小鼠的疼痛阈值。相反，当小鼠没有食物剥夺时，神经性疼痛会显著降低ACC中的DA释放。我们得出结论，PV中间神经元抑制效能的丧失，与多巴胺能信号减弱共同作用，协同导致病理性ACC功能障碍和慢性疼痛的相关症状。
