title: Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms.
abstract: Nerve growth factor (NGF) is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans, but the actual mechanisms underlying the persistent effects of NGF remain incompletely understood. We developed a rat model of NGF-induced persistent thermal hyperalgesia and mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of NGF. Persistent thermal hypersensitivity and mechanical allodynia require de novo protein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar) injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal hypersensitivity via peripheral and spinal sites of action and mechanical allodynia via only a spinal site of action. Therefore, NGF-evoked thermal and mechanical allodynia are mediated by spatially distinct mechanisms. NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased capsaicin-evoked nocifensive responses, increased calcitonin gene-related peptide release from hindpaw skin biopsies, and increased capsaicin-evoked inward current and membrane expression of TRPV1 protein in dorsal root ganglia neurons. Finally, we showed that NGF treatment increased concentrations of linoleic and arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active lipids were reduced by peripheral and spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized lipid TRPV1 agonists.
authors.affiliation: Department of Pharmacology.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eskander
authors.affiliation: Department of Endodontics.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ruparel
authors.affiliation: Department of Physiology.
authors.forename: Dustin P
authors.initials: DP
authors.lastname: Green
authors.affiliation: Department of Endodontics.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chen
authors.affiliation: Department of Pharmacology.
authors.forename: Elaine D
authors.initials: ED
authors.lastname: Por
authors.affiliation: Department of Pharmacology, Department of Physiology, Department of Oral and Maxillofacial Surgery, and.
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Jeske
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmacology.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Flores
authors.affiliation: Department of Pharmacology, Department of Endodontics, Department of Physiology, Hargreaves@UTHSCSA.edu.
authors.forename: Kenneth M
authors.identifier: http://orcid.org/0000-0002-1076-4931
authors.initials: KM
authors.lastname: Hargreaves
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000209:etiology; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects* / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects; D018689:Sensory System Agents / Q000494:pharmacology; D012867:Skin / Q000294:innervation; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D011500:Protein Synthesis Inhibitors; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D020932:Nerve Growth Factor; D003513:Cycloheximide; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin
keywords: TRPV1; allodynia; arachidonic acid; hyperalgesia; linoleic acid; nerve growth factor