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.
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This work is supported by grants from the US National Institutes of Health: Dental and Craniofacial Research (DE14318-06 to J.C.F. and DE017794 to R.-R.J.), Drug Abuse (DA026040 to F.A.W.), Neurological Disorders and Stroke (NS051668 to C.M.H. and NS050131 to N.B.) and Environmental Health Sciences (ES017430 to G.S.O. and J.H.H.); the Indiana State Department of Health−Spinal Cord and Brain Injury Fund (A70-0-079212 to N.B. and A70-9-079138 to R.K.) and the Indiana University Biomedical Committee–Research Support Funds (2286501 to R.K.); a National Scientist Development Grant from the American Heart Association (SDG5280023 to R.K.); and the Elwert Award in Medicine to R.K. J.M.B. is the recipient of a Larry Kays Medical Neuroscience fellowship. S.M.W. is a Stark Scholar. We thank A. Molosh and members of the Pain and Sensory Group for discussions, S.K. Ahuja for assistance with behavioral experiments and C. Kohn for comments on the manuscript.
The authors declare no competing financial interests.
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Brittain, J., Duarte, D., Wilson, S. et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nat Med 17, 822–829 (2011). https://doi.org/10.1038/nm.2345
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