Adjacent intact nociceptive neurons drive the acute outburst of pain following peripheral axotomy

Zhiyong Chen,Yun Guan,Xiaodan Song,Xinzhong Dong,Shaoqiu He,Qian Huang,Tao Wang,Yehong Fang,Yikuan Xie,Chao Ma,Huan Cui,Dan Luo,Michael Anderson

doi:10.1038/s41598-019-44172-9

Abstract

Injury of peripheral nerves may quickly induce severe pain, but the mechanism remains obscure. We observed a rapid onset of spontaneous pain and evoked pain hypersensitivity after acute transection of the L5 spinal nerve (SNT) in awake rats. The outburst of pain was associated with a rapid development of spontaneous activities and hyperexcitability of nociceptive neurons in the adjacent uninjured L4 dorsal root ganglion (DRG), as revealed by both in vivo electrophysiological recording and high-throughput calcium imaging in vivo. Transection of the L4 dorsal root or intrathecal infusion of aminobutyrate aminotransferase inhibitor attenuated the spontaneous activity, suggesting that retrograde signals from the spinal cord may contribute to the sensitization of L4 DRG neurons after L5 SNT. Electrical stimulation of low-threshold afferents proximal to the axotomized L5 spinal nerve attenuated the spontaneous activities in L4 DRG and pain behavior. These findings suggest that peripheral axotomy may quickly induce hyperexcitability of uninjured nociceptors in the adjacent DRG that drives an outburst of pain.

Highlights

Denervation from axotomy causes a loss of peripheral sensory inputs
The paw withdrawal threshold (PWT) to mechanical stimulation applied to the ipsilateral hind paw was significantly decreased from 10 min to POD14, as compared to that in sham-operated rats (Fig. 1b)
Severe pain after nerve injury has been reported in patients much earlier than that observed in animal models[2,4,5,17,31,32]

Summary

Introduction

Denervation from axotomy causes a loss of peripheral sensory inputs. Yet, pain can develop rapidly after nerve injury in patients[1,2,3,4]. Owing to inherent limitations from anesthesia and acute postoperative pain associated with common surgical procedures, the earliest time to onset of pain after nerve injury has yet to be demonstrated in animal models Studies in both rodents and non-human primates showed that spontaneous activity (SA) and sensitization of primary nociceptive neurons may contribute to ongoing pain and evoked pain hypersensitivity after injury[5,6,7,8,9]. Our findings unravel a novel neurophysiologic mechanism that may underlie the early onset of pain after axotomy of peripheral nerves, and Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. Suggest the utility of low-intensity electrical nerve stimulation for inhibiting the onset of neuronal sensitization and outburst of pain after peripheral nerve injury

Methods

Results

Conclusion