Parabrachial nucleus circuit governs neuropathic pain-like behavior

Li Sun,Meng-Yin Wu,Yuan-Yuan Li,Fang Guo,Ceng-Lin Xu,Xin-Jian Li,Zheng-Gang Zhu,Xiao-Lin Ma,Rui Liu,Xiang-Yao Li,Yan-Qin Yu,Zhong Chen,Kai-Yuan Li,Shumin Duan,Hao Sun,Man-Qing Wen

doi:10.1038/s41467-020-19767-w

Abstract

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

Highlights

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses
Immunostaining of c-Fos one week after common peroneal nerve (CPN) ligation showed a dramatic increase in the density of c-Fos-positive cells co-expressing Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα, a marker of glutamatergic neurons) in the LPBN as compared with Sham operation, whereas no significant difference was found between CPN-treated and Sham-treated mice in c-Fospositive cells co-expressing glutamic acid decarboxylase 67 (GAD67, a marker of GABAergic neurons) (Fig. 1a–d)
We found that ~83% of CaMKIIα-positive neurons in the superior LPBN (PBsl) overlapped with vesicular glutamate transporter 2 (VgluT2) and ~82.1% of CaMKIIα-positive neurons in the dorsal LPBN (PBdl) overlapped with VgluT2

Summary

Introduction

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. Using common peroneal nerve (CPN) ligation[39] as a neuropathic pain model combined with Ca2+ signal imaging[40], an optogenetics approach[41], and behavioral testing[20,42,43], we found that glutamatergic neurons in the lateral PBN (LPBN) are responsible for relaying basal nociception, and for the processing of neuropathic pain. Trans-synaptic virus tracing and electrophysiological studies identified direct synaptic innervation of and functional inhibition on glutamatergic LPBN neurons by local GABAergic neurons These results, together with the finding that CPN ligation selectively activated glutamatergic LPBN neurons indicate that GABAergic LPBN neurons gate the sensitization of glutamatergic neurons, which is necessary and sufficient for the development and transmission of neuropathic pain

Methods

Results

Conclusion