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Involvement of Mrgprd-expressing nociceptors-recruited spinal mechanisms in nerve injury-induced mechanical allodynia.

ABSTRACT: Mechanical allodynia and hyperalgesia are intractable symptoms lacking effective clinical treatments in patients with neuropathic pain. However, whether and how mechanically responsive non-peptidergic nociceptors are involved remains elusive. Here, we showed that von Frey-evoked static allodynia and aversion, along with mechanical hyperalgesia after spared nerve injury (SNI) were reduced by ablation of Mrgprd^CreERT2-marked neurons. Electrophysiological recordings revealed that SNI-opened Aβ-fiber inputs to laminae I-II_o and _vII_i, as well as C-fiber inputs to _vII_i, were all attenuated in Mrgprd-ablated mice. In addition, priming chemogenetic or optogenetic activation of Mrgprd⁺ neurons drove mechanical allodynia and aversion to low-threshold mechanical stimuli, along with mechanical hyperalgesia. Mechanistically, gated Aβ and C inputs to _vII_i were opened, potentially via central sensitization by dampening potassium currents. Altogether, we uncovered the involvement of Mrgprd⁺ nociceptors in nerve injury-induced mechanical pain and dissected the underlying spinal mechanisms, thus providing insights into potential therapeutic targets for pain management.

SUBMITTER: Wang L

PROVIDER: S-EPMC10214713 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Involvement of Mrgprd-expressing nociceptors-recruited spinal mechanisms in nerve injury-induced mechanical allodynia.

Wang Liangbiao L Su Xiaojing X Yan Jinjin J Wu Qiaofeng Q Xu Xiang X Wang Xinyue X Liu Xiaoqing X Song Xiaoyuan X Zhang Zhi Z Hu Wei W Liu Xinfeng X Zhang Yan Y

iScience 20230427 5

Mechanical allodynia and hyperalgesia are intractable symptoms lacking effective clinical treatments in patients with neuropathic pain. However, whether and how mechanically responsive non-peptidergic nociceptors are involved remains elusive. Here, we showed that von Frey-evoked static allodynia and aversion, along with mechanical hyperalgesia after spared nerve injury (SNI) were reduced by ablation of MrgprdCreERT2-marked neurons. Electrophysiological recordings reveale ...[more]

PMID: 37250305

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Project description:Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64-, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.

Dataset Information

Involvement of Mrgprd-expressing nociceptors-recruited spinal mechanisms in nerve injury-induced mechanical allodynia.

Publications

Involvement of Mrgprd-expressing nociceptors-recruited spinal mechanisms in nerve injury-induced mechanical allodynia.

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