Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca²⁺ channel complex.

Abstract

The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.

• Authors: Joel M Brittain, Djane B Duarte, Sarah M Wilson, Weiguo Zhu, Carrie Ballard, Philip L Johnson, Naikui Liu, Wenhui Xiong, Matthew S Ripsch, Yuying Wang, Jill C Fehrenbacher, Stephanie D Fitz, May Khanna, Chul-Kyu Park, Brian S Schmutzler, Bo Myung Cheon, Michael R Due, Tatiana Brustovetsky, Nicole M Ashpole, Andy Hudmon, Samy O Meroueh, Cynthia M Hingtgen, Nickolay Brustovetsky, Ru-Rong Ji, Joyce H Hurley, Xiaoming Jin, Anantha Shekhar, Xiao-Ming Xu, Gerry S Oxford, Michael R Vasko, Fletcher A White, Rajesh Khanna
• Journal: Nature medicine (Nat Med) Vol. 17 Issue 7 Pg. 822-9 (Jun 05 2011) ISSN: 1546-170X [Electronic] United States
• PMID: 21642979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CBD3 peptide
• Cacna1b protein, rat
• Calcium Channels, N-Type
• Intercellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Peptide Fragments
• collapsin response mediator protein-2

Topics

• Animals
• Calcium Channels, N-Type (drug effects, metabolism, physiology)
• Dose-Response Relationship, Drug
• Dura Mater (drug effects, physiology)
• Intercellular Signaling Peptides and Proteins (physiology)
• Maze Learning (drug effects)
• Mice
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Nerve Tissue Proteins (drug effects, physiology)
• Pain (drug therapy, metabolism, physiopathology)
• Peptide Fragments (drug effects, physiology)
• Posterior Horn Cells (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (drug effects, metabolism, physiology)
• Synaptic Transmission (drug effects, physiology)
• Vasodilation (drug effects)