Differential expression of Cdk5-phosphorylated CRMP2 following a spared nerve injury

Aubin Moutal,Rajesh Khanna,Yingshi Ji,Shreya Sai Bellampalli

doi:10.1186/s13041-020-00633-1

Abstract

Effective treatment of high-impact pain patients is one of the major stated goals of the National Pain Strategy in the United States. Identification of new targets and mechanisms underlying neuropathic pain will be critical in developing new target-specific medications for better neuropathic pain management. We recently discovered that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. In our previous studies, we found that interfering with the phosphorylation status of CRMP2 is sufficient to confer protection from chronic pain. Here we examined the expression of CRMP2 and CRMP2 phosphorylated by cyclin-dependent kinase 5 (Cdk5, on serine residue 522 (S522)) in sciatic nerve, nerve terminals of the glabrous skin, and in select subpopulations of DRG neurons in the SNI model of neuropathic pain. By enhancing our understanding of the phosphoregulatory status of CRMP2 within DRG subpopulations, we may be in a better position to design novel pharmacological interventions for chronic pain.

Highlights

Chronic neuropathic pain can be characterized by allodynia, hyperalgesia or spontaneous pain
Inspired by the idiopathic pain reported by patients with Neurofibromatosis type 1 (NF1), we found that deleting the Nf1 gene using clustered regularly interspaced short palindromic repeats and CRISPRassociated (Cas9) (CRISPR/Cas9) in dorsal root ganglia (DRG) could elicit hyperalgesic behaviors [4,5,6]
Here we aimed to study the populations of DRGs that express both collapsin response mediator protein 2 (CRMP2) and phosphorylated CRMP2 under naïve conditions as well conditions of a neuropathic pain model; the spared nerve injury model (SNI) model was chosen because we previously reported in this model of chronic neuropathic pain that CRMP2 phosphorylation by cyclin dependent kinase 5 (Cdk5) was increased in DRGs and in spinal cord [8]

Summary

Introduction

Chronic neuropathic pain can be characterized by allodynia (painful response to a non-painful stimulus), hyperalgesia (increase sensitivity to pain) or spontaneous pain. These symptoms may be alleviated by pharmacological inactivation of the damaged nerve [1, 2]. In clinically defined genetic pain syndromes where patients experience uncontrollable pain during their lifetimes, activating mutations of voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9), restricted to the DRGs, have been reported [3]. Together, these findings highlight that dysregulation of DRG function may be sufficient for expression of chronic pain. A function of neurofibromin is to bind to the cytosolic collapsin

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