An Inhibitor of Neuronal Exocytosis (DD04107) Displays Long-Lasting In Vivo Activity against Chronic Inflammatory and Neuropathic Pain

Abstract

Small peptides patterned after the N terminus of the synaptosomal protein of 25 kDa, a member of the protein complex implicated in Ca 2ϩ -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 (palmitoyl-EEMQRR-NH 2 ), a 6-mer palmitoylated peptide that blocks the inflammatory recruitment of ion channels to the plasma membrane of nociceptors and the release of calcitonin gene-related peptide from primary sensory neurons, displays potent and long-lasting in vivo antihyperalgesia and antiallodynia 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 antihyperalgesic and antiallodynic activity that lasted Ն24 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 caused by locomotor impairment. Therefore, DD04107 is a potent and long-lasting antinociceptive 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.

αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors

“…Cumulative evidence suggests that algesic agents regulate TRPV1 activity by a complex mechanism that involves the fast mobilization of new channels to the neuronal membrane through a regulated exocytotic pathway and the channel posttranslational modification (10,11,30). Notably, blockers of regulated exocytosis such as BoNTA or compound DD04107 reduce the algesic-induced surface expression of TRPV1 and exhibit long-lasting in vivo antinociceptive activity (31,32). This finding indicates that mobilization of channels by algogens is a key mechanism contributing to nociceptor sensitization under pathological conditions.…”

Secretagogin is Expressed in Sensory CGRP Neurons and in Spinal Cord of Mouse and Complements other Calcium-Binding Proteins, with a Note on Rat and Human

“…This finding suggests a role in the control of neurotransmitter release since N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs)-associated proteins are part of the exocytotic machinery [18]. Interestingly, inhibition of exocytosis causes long-lasting attenuation of pain [75]. …”

Whirlin increases TRPV1 channel expression and cellular stability

“…Analysis of the TRPV1 channelosome or singalplex has identified thus far protein partners mainly involved in receptor trafficking, delivery and clustering into the plasma membrane, as well as proteins that modulate its channel activity (16,29,36). Furthermore, interfering with receptor membrane delivery has resulted in a useful pharmacological approach to understand the contribution of TRPV1 pathological recruitment to pain transduction (7), and a therapeutic strategy to reduce pain signaling (37). Therefore, unveiling the components of the TRPV1 signalplex is important for understanding the intricacies of the receptor pathophysiological regulation.…”