Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex

Sarah M. Wilson, Joel M. Brittain, Andrew D. Piekarz, Carrie J. Ballard, Matthew S. Ripsch, Theodore R. Cummins, Joyce H. Hurley, May Khanna, Nathan M. Hammes, Brian C. Samuels, Fletcher A. White, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The N-type voltage-gated calcium channel (Ca v2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Ca v2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Ca v2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphatidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Ca v2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.

Original languageEnglish (US)
JournalChannels
Volume5
Issue number5
DOIs
StatePublished - 2011

Keywords

  • Chronic pain
  • CRMP-2
  • Migraine
  • N-type voltage-gated calcium channel/Ca 2.2
  • Pain therapeutics
  • Peptide

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

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