N-type voltage-gated calcium channels (CaV2.2) are critical mediators of neurotransmitter release and are thought to be involved with transmission of nociception. The use of conventional CaV2.2 blockers in pain therapeutics is limited by side effects. Reported herein is a means to suppress both inflammatory and neuropathic pain without directly blocking CaV2.2, but rather by inhibiting the binding of the axonal collapsin response mediator protein 2 (CRMP-2), a protein known to enhance CaV2.2 function. A 15 amino acid peptide of CRMP-2 fused to the protein transduction domain of the HIV tat protein (TAT CBD3) reduced meningeal blood flow induced by activation of the trigeminovascular system, prevented inflammation-induced tactile hypernociception induced by intraplantar formalin and nocifensive behavior following corneal capsaicin application, and reversed neuropathic hypernociception produced by the antiretroviral drug 2′,3′-dideoxycytidine. Preventing CRMP-2—mediated enhancement of CaV2.2 function suppressed inflammatory and neuropathic nociception, providing a method for treating pain and inflammation.
