Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide

Authors

  • Weina Ju,

    1. Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    2. Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
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    • The first two authors contributed equally to this work.
  • Qi Li,

    1. Department of Pharmacology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin Province, China
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    • The first two authors contributed equally to this work.
  • Yohance M. Allette,

    1. Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
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  • Matthew S. Ripsch,

    1. Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
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  • Fletcher A. White,

    1. Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    2. Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    3. Department of Anatomy and Cell Biology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    4. Department of Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
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  • Rajesh Khanna

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    2. Department of Anatomy and Cell Biology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    3. Department of Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
    4. Sophia Therapeutics LLC, Indianapolis, Indiana, USA
    • Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, Indiana, USA
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Address correspondence and reprint requests to Dr Rajesh Khanna, 950 West Walnut Street, R2-Room 478, Indianapolis, IN 46202, USA. E-mail: khanna5@iu.edu

Abstract

The N-type voltage-gated calcium channel (CaV2.2) is a clinically endorsed target in chronic pain treatments. As directly targeting the channel can lead to multiple adverse side effects, targeting modulators of CaV2.2 may prove better. We previously identified ST1-104, a short peptide from the collapsin response mediator protein 2 (CRMP2), which disrupted the CaV2.2–CRMP2 interaction and suppressed a model of HIV-related neuropathy induced by anti-retroviral therapy but not traumatic neuropathy. Here, we report ST2-104 –a peptide wherein the cell-penetrating TAT motif has been supplanted with a homopolyarginine motif, which dose-dependently inhibits the CaV2.2–CRMP2 interaction and inhibits depolarization-evoked Ca2+ influx in sensory neurons. Ca2+ influx via activation of vanilloid receptors is not affected by either peptide. Systemic administration of ST2-104 does not affect thermal or tactile nociceptive behavioral changes. Importantly, ST2-104 transiently reduces persistent mechanical hypersensitivity induced by systemic administration of the anti-retroviral drug 2′,3′-dideoxycytidine (ddC) and following tibial nerve injury (TNI). Possible mechanistic explanations for the broader efficacy of ST2-104 are discussed.

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