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

Liangbiao Wang; Xiaojing Su; Jinjin Yan; Qiaofeng Wu; Xiang Xu; Xinyue Wang; Xiaoqing Liu; Xiaoyuan Song; Zhi Zhang; Wei Hu; Xinfeng Liu; Yan Zhang

doi:10.1016/j.isci.2023.106764

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

iScience. 2023 Apr 27;26(5):106764. doi: 10.1016/j.isci.2023.106764. eCollection 2023 May 19.

Authors

Affiliations

¹ Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
² School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China.
³ Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China.

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.

Keywords: Cell biology; Cellular neuroscience; Neuroscience.