title: 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(2+)-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 ≥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 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.
authors.affiliation: BCN Peptides, Sant Quintí de Mediona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Ponsati
authors.forename: Cristina
authors.initials: C
authors.lastname: Carreño
authors.forename: Verdad
authors.initials: V
authors.lastname: Curto-Reyes
authors.forename: Belen
authors.initials: B
authors.lastname: Valenzuela
authors.forename: María José
authors.initials: MJ
authors.lastname: Duart
authors.forename: Wim
authors.initials: W
authors.lastname: Van den Nest
authors.forename: Omar
authors.initials: O
authors.lastname: Cauli
authors.forename: Beatriz
authors.initials: B
authors.lastname: Beltran
authors.forename: Jimena
authors.initials: J
authors.lastname: Fernandez
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.forename: Antonio
authors.initials: A
authors.lastname: Caprioli
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Serio
authors.forename: Mario
authors.initials: M
authors.lastname: Veretchy
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
authors.forename: Luis
authors.initials: L
authors.lastname: Menendez
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
authors.forename: Pilar
authors.initials: P
authors.lastname: de la Pena
authors.forename: Ricardo
authors.initials: R
authors.lastname: Borges
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002351:Carrageenan / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects*; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D055666:Lipopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000473:pathology; D009437:Neuralgia / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000700:Analgesics; D055666:Lipopeptides; C545102:palmitoyl-glutamyl-glutamyl-methionyl-glutaminyl-arginyl-argininamide; D002351:Carrageenan; D015740:Calcitonin Gene-Related Peptide