title: Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia.
abstract: The neuropeptide bradykinin (BK) sensitizes nociceptor activation following its release in response to inflammatory injury. Thereafter, the bioactivity of bradykinin is controlled by the enzymatic activities of circulating peptidases. One such enzyme, the metalloendopeptidase EC3.4.24.15 (EP24.15), is co-expressed with bradykinin receptors in primary afferent neurons. In this study, using approaches encompassing pharmacology, biochemistry, cell biology, and behavioral animal models, we identified a crucial role for EP24.15 and the closely related EP24.16 in modulating bradykinin-mediated hyperalgesia. Pharmacological analyses indicated that EP24.15 and EP24.16 inhibition significantly enhances bradykinin type-2 receptor activation by bradykinin in primary trigeminal ganglia cultures. In addition, bradykinin-induced sensitization of TRPV1 activation was increased in the presence of the EP24.15/16 inhibitor JA-2. Furthermore, behavioral analyses illustrated a significant dose-response relationship between JA-2 and bradykinin-mediated thermal hyperalgesia. These results indicate an important physiological role for the metallopeptidases EP24.15 and EP24.16 in regulating bradykinin-mediated sensitization of primary afferent nociceptors.
authors: Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center of San Antonio, TX, USA Department of Pharmacology, University of Texas Health Science Center of San Antonio, TX, USA Center for Biomedical Neuroscience, University of Texas Health Science Center of San Antonio, TX, USA Department of Biochemistry and Molecular Biology and Midwest Proteome Center, Rosalind Franklin University of Medicine and Science/Chicago Medical School, North Chicago, IL, USA.
authors: Ruben
authors: R
authors: Gomez
authors: Elaine D
authors: ED
authors: Por
authors: Kelly A
authors: KA
authors: Berg
authors: William P
authors: WP
authors: Clarke
authors: Marc J
authors: MJ
authors: Glucksman
authors: Nathaniel A
authors: NA
authors: Jeske
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000009:adverse effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000201:enzymology*; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology; D050916:TRPV Cation Channels / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; C404521:JA 2 compound; D009842:Oligopeptides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D045726:Metalloproteases; D001920:Bradykinin; D002118:Calcium