Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain

Aubin Moutal, Shizhen Luo, Tally M. Largent-Milnes, Todd W Vanderah, Rajesh Khanna

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.

Original languageEnglish (US)
Article number100022
JournalNeurobiology of Pain
Volume5
DOIs
StatePublished - Jan 1 2019

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Cyclin-Dependent Kinase 5
Neuralgia
Phosphorylation
Hyperalgesia
Wounds and Injuries
Ion Channels
Voltage-Gated Sodium Channels
collapsin response mediator protein-2
Spinal Ganglia
Calcium Channels
Small Interfering RNA
Spinal Cord

Keywords

  • CRMP2
  • Cyclin-dependent kinase 5
  • Neuropathic pain
  • Phosphorylation
  • Spared nerve injury

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Anesthesiology and Pain Medicine
  • Clinical Neurology

Cite this

Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain. / Moutal, Aubin; Luo, Shizhen; Largent-Milnes, Tally M.; Vanderah, Todd W; Khanna, Rajesh.

In: Neurobiology of Pain, Vol. 5, 100022, 01.01.2019.

Research output: Contribution to journalArticle

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AB - Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.

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