Abstract

Small peptides patterned after the N-terminus of the synaptosomal protein of 25 kDa (SNAP-25), a member of the protein complex implicated in Ca²⁺-dependent neuronal exocytosis, inhibit in vitro the release of neuromodulators involved in pain signaling, suggesting an in vivo analgesic activity. Here, we report that compound DD04107, a 6-mer palmitoylated peptide that blocks the inflammatory recruitment the inflammatory recruitment of ion channels to the plasma membrane of nociceptors, and the release of calcitonin gen-related peptide (CGRP) from primary sensory neurons, displays potent and long-lasting in vivo anti-hyperalgesia and anti-allodynia in chronic models of inflammatory and neuropathic pain, such as the complete Freund's Adjuvant, osteosarcoma, chemotherapy and diabetic neuropathic models. Subcutaneous administration of the peptide produced a dose-dependent anti-hyperalgesic and anti-allodynic activity that lasted ≥24 h. The compound showed a systemic distribution, characterized by a bicompartmental pharmacokinetic profile. Safety pharmacology studies indicated that the peptide is largely devoid of side effects, and substantiated that the in vivo activity is not due to locomotor impairment. Therefore, DD04107 is a potent and long-lasting anti-nociceptive compound that displays a safe pharmacological profile. These findings support the notion that neuronal exocytosis of receptors and neuronal algogens pivotally contribute to chronic inflammatory and neuropathic pain, and imply a central role of peptidergic nociceptor sensitization to the pathogenesis of pain.