title: Early treatment with UR13870, a novel inhibitor of p38α mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain.
abstract: Microglia cell activation plays a role in the development of neuropathic pain partly due to the activation of the p38α MAPK signaling pathway after nerve injury. In this study we assessed the effect of UR13870, a p38α MAPK inhibitor, in the "spared nerve injury" (SNI) model, to study its effects on modulation of spinal microglial activation and to test behavioral hyperreflexia responses and cerebral-mediated pain behavior. The effect of daily administration of UR13870 (10mg/kg p.o.) and Pregabalin (50mg/kg p.o.) on reflex hypersensitivity to mechanical and cold test stimuli and on affective related pain responses measured with the place escape avoidance paradigm and the open field-induced anxiety test, were evaluated after SNI in Sprague Dawley rats. Microglial reactivity in the ipsilateral lumbar laminae I/II dorsal horn was evaluated with OX-42 immunohistochemistry. UR13870 treatment significantly decreased hindlimb hyperreflexia to both mechanical and cold stimuli after SNI without loss of general motor function, in addition to a reduction in pain-related anxiety behavior at day 21 after SNI, accompanied by normalization of OX-42 immunoreactivity within the ipsilateral lumbar dorsal horn. Pregabalin treatment only reduced mechanical hyperreflexia and affected general motor function. Oral administration of the p38α MAPK inhibitor, UR13870, mediates antinociception to both mechanical and cold stimuli, and significantly restored inner-zone exploration in the open field test, accompanied by normalization in dorsal horn microglial activation in the SNI model.
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain; Escuela Internacional de Doctorado (EID), Universidad Rey Juan Carlos I. Móstoles, Madrid, Spain. Electronic address: igalan@jccm.es.
authors.forename: Iriana
authors.initials: I
authors.lastname: Galan-Arriero
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain. Electronic address: gavila@sescam.jccm.es.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Avila-Martin
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain. Electronic address: agata9364@hotmail.com.
authors.forename: Agueda
authors.initials: A
authors.lastname: Ferrer-Donato
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain; Escuela de Enfermeria y Fisioterapia Universidad Castilla La Mancha, Toledo, Spain. Electronic address: Julio.Soriano@uclm.es.
authors.forename: Julio
authors.initials: J
authors.lastname: Gomez-Soriano
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain; Neural Rehabilitation Group, Cajal Institute CSIC, Madrid, Spain. Electronic address: stefano.piazza@csic.es.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain; Stoke Mandeville Spinal Research, National Spinal Injuries Centre, Buckinghamshire Healthcare Trust, Stoke Mandeville, Aylesbury, UK; Harris Manchester College, University of Oxford, Oxford, UK. Electronic address: jscott@sescam.org.
authors.forename: Julian
authors.initials: J
authors.lastname: Taylor
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001007:Anxiety / Q000517:prevention & control* / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects; D003080:Cold Temperature; D008161:Lumbosacral Region; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D010812:Physical Stimulation; D000069583:Pregabalin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012021:Reflex, Abnormal / Q000187:drug effects*; D012584:Sciatic Nerve / Q000293:injuries; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism; D014110:Touch
chemical_list: D000700:Analgesics; C530087:Org 48762-0; D011725:Pyridines; D000069583:Pregabalin; D048308:Mitogen-Activated Protein Kinase 14
keywords: Antinociception; Microglia; Neuropathic pain; OX-42; Open field induced anxiety test; Place escape/avoidance paradigm; Spared nerve injury; p38α MAPK inhibitor