• Madhurima Saha, Sladjana Skopelja, Elena Martinez, Daniel L Alvarez, Brenna S Liponis, and E Alfonso Romero-Sandoval.
• 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.
• J. Neurosci. 2013 Oct 23;33(43):17182-7.

AbstractThe 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.

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