title: Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide.
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 Ca(2+) influx in sensory neurons. Ca(2+) 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.
authors.affiliation: Department of Pharmacology and Toxicology, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, IN 46202, USA.
authors.forename: Weina
authors.initials: W
authors.lastname: Ju
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Yohance M
authors.initials: YM
authors.lastname: Allette
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D059408:Pain Management / Q000379:methods; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C095114:collapsin response mediator protein-2; C015462:polyarginine