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

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. [ABSTRACT FROM AUTHOR]