Neuron. 2022 Jan 19;110(2):209-220.e6. doi: 10.1016/j.neuron.2021.10.019. | PubMed

Qin Zheng¹, Wenrui Xie², Debora D Lückemeyer², Mark Lay¹, Xue-Wei Wang³, Xintong Dong¹, Nathachit Limjunyawong¹, Yaqing Ye¹, Feng-Quan Zhou³, Judith A Strong², Jun-Ming Zhang⁴, Xinzhong Dong⁵

1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA.
2. Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
3. Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA.
4. Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: jun-ming.zhang@uc.edu.
5. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA. Electronic address: xdong2@jhmi.edu.

Abstract

Spontaneous pain refers to pain occurring without external stimuli. It is a primary complaint in chronic pain conditions and remains difficult to treat. Moreover, the mechanisms underlying spontaneous pain remain poorly understood. Here we employed in vivo imaging of dorsal root ganglion (DRG) neurons and discovered a distinct form of abnormal spontaneous activity following peripheral nerve injury: clusters of adjacent DRG neurons firing synchronously and sporadically. The level of cluster firing correlated directly with nerve injury-induced spontaneous pain behaviors. Furthermore, we demonstrated that cluster firing is triggered by activity of sympathetic nerves, which sprout into DRGs after injury, and identified norepinephrine as a key neurotransmitter mediating this unique firing. Chemogenetic and pharmacological manipulations of sympathetic activity and norepinephrine receptors suggest that they are necessary and sufficient for DRG cluster firing and spontaneous pain behavior. Therefore, blocking sympathetically mediated cluster firing may be a new paradigm for treating spontaneous pain.

Presented By Qin Zheng