title: Spinal mitogen-activated protein kinase phosphatase-3 (MKP-3) is necessary for the normal resolution of mechanical allodynia in a mouse model of acute postoperative pain.
abstract: The mechanisms that drive the normal resolution of acute postoperative pain are not completely understood. We hypothesize a pivotal role of a major spinal mitogen-activated protein kinase (MAPKs) regulator, MAPK phosphatase (MKP)-3, in the resolution of postoperative pain. We used wild-type and MKP-3 knock-out (KO) mice, a paw incision model of acute postoperative pain, and behavioral and molecular biology experiments. We observed persistent mechanical allodynia in mice lacking MKP-3 (postoperative day 21), concurrently with persistent phosphorylation of spinal p38 and extracellular signal-regulated kinases (ERK)-1/2 on postoperative day 12, while both MAPK phosphorylation and allodynia resolved on postoperative day 7 in wild-type mice. Spinal p-ERK was expressed mainly in neurons and microglia, while spinal p-p38 was expressed mostly in microglia in MKP-3 KO mice, and their selective pharmacological inhibition reduced the persistent allodynia observed in these mice. Our findings strongly suggest that dysregulation of MKP-3 prevents spontaneous resolution of acute postoperative pain and drives its transition to persistent pain via persistent neuronal and microglial MAPK phosphorylation in the spinal cord.
authors.affiliation: Department of Anesthesiology and Department of Pharmacology/Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, and Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, South Carolina 29325.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Saha
authors.forename: Sladjana
authors.initials: S
authors.lastname: Skopelja
authors.forename: Elena
authors.initials: E
authors.lastname: Martinez
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alvarez
authors.forename: Brenna S
authors.initials: BS
authors.lastname: Liponis
authors.forename: E Alfonso
authors.initials: EA
authors.lastname: Romero-Sandoval
mesh_terms: D059787:Acute Pain / Q000201:enzymology*; D000818:Animals; D004195:Disease Models, Animal; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000201:enzymology*; D020935:MAP Kinase Signaling System; D051379:Mice; D017628:Microglia / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D010149:Postoperative Pain / Q000201:enzymology*; D010766:Phosphorylation; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse