title: Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia.
abstract: The stress-activated mitogen-activated protein kinase (MAPK) p38 is emerging as an important mediator of pain. The present study examined the possible involvement of peripheral and spinal p38 MAPK in capsaicin-induced thermal hyperalgesia. Topical capsaicin produced phosphorylation of p38 MAPK in the skin from the affected hindpaw as well as the corresponding lumbar spinal cord in a time dependent manner. Topical capsaicin produced robust C-fiber mediated thermal hyperalgesia that was inhibited by systemic, local peripheral, or central intrathecal pre-treatment with the p38 MAPK inhibitor, SD-282. Intraperitoneal SD-282 (10-60 mg/kg) significantly and dose-dependently attenuated capsaicin-induced C-fiber mediated thermal hyperalgesia. Similarly, 0.1-5mg/kg subcutaneous SD-282 in the hindpaw dose-dependently attenuated capsaicin-induced thermal hyperalgesia. Intrathecal administration of 1microg SD-282 was also anti-hyperalgesic in this model. Functionally, SD-282 decreased capsaicin-induced release of calcitonin gene related peptide in an in vitro skin release assay, consistent with a role for p38 MAPK in peripheral nerve function. These results suggest that p38 MAPK plays a role in the development of hyperalgesic states, exerting effects both centrally in the spinal cord and peripherally in sensory C fibers.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Sweitzer
authors.forename: M C
authors.initials: MC
authors.lastname: Peters
authors.forename: J Y
authors.initials: JY
authors.lastname: Ma
authors.forename: I
authors.initials: I
authors.lastname: Kerr
authors.forename: R
authors.initials: R
authors.lastname: Mangadu
authors.forename: S
authors.initials: S
authors.lastname: Chakravarty
authors.forename: S
authors.initials: S
authors.lastname: Dugar
authors.forename: S
authors.initials: S
authors.lastname: Medicherla
authors.forename: A A
authors.initials: AA
authors.lastname: Protter
authors.forename: D C
authors.initials: DC
authors.lastname: Yeomans
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000633:toxicity*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D002211:Capsaicin