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Background <p>Recent evidence determined that acupoints frequently overlap with regions of referred somatic hypersensitivity induced by visceral disease, a phenomenon known as acupoint sensitization. This state is typically characterized by sensory hypersensitivity and functional enhancement, often accompanied by superior therapeutic outcomes following acupuncture. However, the neurobiological mechanisms that prime acupoints for enhanced responsiveness remain poorly understood.</p> Methods <p>Using a rat model of TNBS intracolonic injection-induced colitis and relative acupoint sensitization, we investigated the role of CHRNA3⁺ mechanoinsensitive nociceptors (MINs), a subclass of silent C-fiber neurons, in modulating the acupoint sensory interface and electroacupuncture (EA) responsiveness. Behavior tests, neuroanatomical tracing, <i>in situ</i> hybridization, pharmacological blockade, and chemogenetic silencing were employed to assess the involvement of CHRNA3⁺ MINs in the onset of acupoint sensitization. Colonic distension-evoked visceral motor reflex and spinal local field potential recording were utilized to evaluate the contribution of CHRNA3⁺ MINs in the acupuncture-induced analgesic effect.</p> Results <p>We found that CHRNA3⁺ MINs are primarily C nociceptors co-expressing TrkA, pERK, and PIEZO2, innervating both the colon and lumbar skin (BL25 acupoint region) via axonal bifurcation. Colitis significantly activated CHRNA3⁺ nociceptors via the NGF–TrkA/pERK/PIEZO2 pathway, converting them from mechanoinsensitive to mechanosensitive. This activation correlated with increased plasma extravasation and mechanical allodynia at BL25. Pharmacological inhibition of CHRNA3⁺ MINs via pERK blockade or chemogenetic silencing alleviated mechanical hypersensitivity of BL25 and attenuated the analgesic effect of EA on both visceral pain and spinal sensitization.</p> Conclusion <p>Our findings reveal that CHRNA3⁺ silent nociceptors dynamically prime and reshape the sensory interface of the colitis-induced sensitized acupoint BL25, subsequently facilitating both pathological hypersensitivity and therapeutic responsiveness by heightening mechano-responsiveness of the acupoint. This study establishes a mechanistic link between visceral dysfunction, acupoint functional plasticity, and EA-induced therapeutic neuromodulation.</p>

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CHRNA3⁺ nociceptors prime the cutaneous sensory interface to enhance electroacupuncture analgesia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Wenjie Xu,
  • Dingdan Zhang,
  • Yuanwei Tang,
  • Ying Wang,
  • Zijie Wang,
  • Hanqing Xi,
  • Xinyan Gao,
  • Bing Zhu,
  • Xiang Cui

摘要

Background

Recent evidence determined that acupoints frequently overlap with regions of referred somatic hypersensitivity induced by visceral disease, a phenomenon known as acupoint sensitization. This state is typically characterized by sensory hypersensitivity and functional enhancement, often accompanied by superior therapeutic outcomes following acupuncture. However, the neurobiological mechanisms that prime acupoints for enhanced responsiveness remain poorly understood.

Methods

Using a rat model of TNBS intracolonic injection-induced colitis and relative acupoint sensitization, we investigated the role of CHRNA3⁺ mechanoinsensitive nociceptors (MINs), a subclass of silent C-fiber neurons, in modulating the acupoint sensory interface and electroacupuncture (EA) responsiveness. Behavior tests, neuroanatomical tracing, in situ hybridization, pharmacological blockade, and chemogenetic silencing were employed to assess the involvement of CHRNA3⁺ MINs in the onset of acupoint sensitization. Colonic distension-evoked visceral motor reflex and spinal local field potential recording were utilized to evaluate the contribution of CHRNA3⁺ MINs in the acupuncture-induced analgesic effect.

Results

We found that CHRNA3⁺ MINs are primarily C nociceptors co-expressing TrkA, pERK, and PIEZO2, innervating both the colon and lumbar skin (BL25 acupoint region) via axonal bifurcation. Colitis significantly activated CHRNA3⁺ nociceptors via the NGF–TrkA/pERK/PIEZO2 pathway, converting them from mechanoinsensitive to mechanosensitive. This activation correlated with increased plasma extravasation and mechanical allodynia at BL25. Pharmacological inhibition of CHRNA3⁺ MINs via pERK blockade or chemogenetic silencing alleviated mechanical hypersensitivity of BL25 and attenuated the analgesic effect of EA on both visceral pain and spinal sensitization.

Conclusion

Our findings reveal that CHRNA3⁺ silent nociceptors dynamically prime and reshape the sensory interface of the colitis-induced sensitized acupoint BL25, subsequently facilitating both pathological hypersensitivity and therapeutic responsiveness by heightening mechano-responsiveness of the acupoint. This study establishes a mechanistic link between visceral dysfunction, acupoint functional plasticity, and EA-induced therapeutic neuromodulation.