Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

作者：Skopelja Gardner Sladjana; Saha Madhurima; Alvarado Vazquez Perla Abigail; Liponis Brenna S; Martinez Elena; Romero Sandoval E Alfonso^*

来源：Journal of Pain Research, 2017, 10: 763-774.

DOI：10.2147/JPR.S129826

• DUSP-6
• p38
• ERK

Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69 +/- 0.17 g baseline vs 0.13 +/- 0.08 g day 1), which resolved normally by postoperative day 12 (0.46 +/- 0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19 +/- 0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4 +/- 6 cells/0.1 mm(2)) than WT mice (8.7 +/- 1.2 cells/0.1 mm(2)) on postoperative day 1 (vs 5-6 cells/0.1 mm(2) at baseline) that returned to baseline 12 days after surgery (10-12 cells/0.1 mm2). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5-and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7-12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2.

• 出版日期2017