title: Central activation of TRPV1 and TRPA1 by novel endogenous agonists contributes to mechanical allodynia and thermal hyperalgesia after burn injury.
abstract: The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of mechanical and thermal allodynia. The transient receptor potential channels, TRPV1 and TRPA1, are expressed by a subset of nociceptive sensory neurons and contribute to inflammatory hypersensitivity. Although their function in the periphery is well known, a role for these TRP channels in central pain mechanisms is less well defined. Lipid agonists of TRPV1 are released from peripheral tissues via enzymatic oxidation after burn injury; however, it is not known if burn injury triggers the release of oxidized lipids in the spinal cord. Accordingly, we evaluated whether burn injury evoked the central release of oxidized lipids . Analysis of lipid extracts of spinal cord tissue with HPLC-MS revealed a significant increase in levels of the epoxide and diol metabolites of linoleic acid: 9,10-DiHOME, 12,13-DiHOME, 9(10)-EpOME, and 12(13)-EpOME, that was reduced after intrathecal (i.t.) injection of the oxidative enzyme inhibitor ketoconazole. Moreover, we found that these four lipid metabolites were capable of specifically activating both TRPV1 and TRPA1. Intrathecal injection of specific antagonists to TRPV1 (AMG-517) or TRPA1 (HC-030031) significantly reduced post-burn mechanical and thermal allodynia. Finally, i.t. injection of ketoconazole significantly reversed post-burn mechanical and thermal allodynia. Our data indicate that spinal cord TRPV1 and TRPA1 contributes to pain after burn and identifies a novel class of oxidized lipids elevated in the spinal cord after burn injury. Since the management of burn pain is problematic, these findings point to a novel approach for treating post-burn pain.
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: Dustin
authors.initials: D
authors.lastname: Green
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ruparel
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: Nikita
authors.initials: N
authors.lastname: Ruparel
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: Mayur
authors.initials: M
authors.lastname: Patil
authors.affiliation: University of Texas Health Science Center at San AntonioUniversity of Texas Health Science Center at San AntonioUniversity of Texas Health Science Center at San AntonioUniversity of Texas Health Science Center at San AntonioUniversity of Texas Health Science Center at San AntonioUniversity of Texas Health Science Center at San Antonio.
authors.forename: Armen
authors.initials: A
authors.lastname: Akopian
authors.affiliation: University of Texas Health Science Center at San Antonio hargreaves@uthscsa.edu.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D002056:Burns / Q000150:complications* / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D019787:Linoleic Acid / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D019787:Linoleic Acid