Celecoxib Reverts Oxaliplatin-Induced Neuropathic Pain Through Inhibiting PI3K/Akt2 Pathway In The Mouse Dorsal Root Ganglion

Background:Oxaliplatin(OXA)is the common and extremely potent anti-advanced colorectal cancer chemotherapeutic.Accumulating evidence reveals that OXA evokes mechanical and cold hypersensitivity.However,the mechanism underlying these bothersome and dose-limiting adverse effects is poorly understood.It is well known that cyclooxygenase-2(COX-2)as well as phosphoinositide 3-kinase(PI3K)/Akt signaling mediate the neuropathic pain.But it is still unclear whether COX-2 or PI3K/Akt signaling participates in the regulation of OXA-induced hypersensitivity,as well as the linkage between COX-2 and PI3K/Akt signaling in mediating OXA-induced hypersensitivity.In this paper,we investigated the above issues and the anti-nociceptive effect of celecoxib,an inhibitor of COX-2,on the OXA-induced neuropathic pain.Methods:1.Mice were randomly divided into 2 groups with 8 mice in each group: a vehicle group and an OXA treatment group(OXA group).In the OXA group,the mice were injected intraperitoneally with two doses of 10 mg/kg body weight of OXA dissolved in 5% glucose solution at d0 and d2,respectively.The same volume of 5%glucose solution was intraperitoneally injected in a vehicle control group.The pain behaviors were tested once every 3 days for 6 times since d0 before the first dose of OXA administration.At d3,the pain behaviors were tested 24 h after the second OXA administration.At d15,all the mice were deeply anesthetized with pentobarbital sodium(100 mg/kg sodium pentobarbital,i.p.)and sacrificed by decapitation.The expressions of Akt1,Akt2,Akt3 and COX-2 m RNA in L4-5 dorsal root ganglia(DRG)were detected by real-time quantitative PCR,the expressions of Akt2 and COX-2 proteins were detected by Western Blot.2.Mice were randomly divided into 4 groups with 10 mice in each group: a vehicle group,an OXA group,an OXA +celecoxib(10 mg/kg/day),and an OXA +celecoxib(30 mg/kg/day).OXA was administrated as described above.Celecoxib was dissolved in 0.5% methylcellulose vehicle and was delivered twice daily by oral gavage for 13 days,beginning on d2 after the second dose of OXA administration.The behavior of mice was determined as above.The expressions of Akt2 and COX-2m RNA in L4-5 dorsal root ganglia(DRG)were detected by real-time quantitative PCR,the expressions of COX-2,Akt2,p-Akt2 and PI3 K proteins were detected by Western Blot.3.The human colon cancer cell line HCT-116 cells viability was measured by MTT :the cells treated by various doses of OXA(12.5,25,50,100 ?M),celecoxib(10,25,50,75 ?M),or their combination(100 ?M OXA and 75 ?M celecoxib).The experiment were also set up blank group and vehicle control group.Results:1.The administration of OXA increased the expression of COX-2 and Akt2 in L4-5 DRG.2.COX-2 inhibitor celecoxib alleviated the OXA-caused neuropathic pain.3.Celecoxib suppressed the COX-2 and PI3K/Akt2 pathway in L4-5 DRG of OXA-treated mice.4.Celecoxib enhanced the OXA-induced growth inhibition of colon cancer cells HCT-116 in vitro.Conclusion:COX-2 and PI3K/Akt2 signaling in DRG contributed to the OXA-induced neuropathic pain.In addition,celecoxib enhanced the OXA-induced mortality of the human colon cancer cell line HCT-116.Thus,celecoxib might play a dual role in colorectal cancer treatment: alleviating OXA-induced neuropathic pain and facilitating the anti-tumor effects of OXA through their synergistic role.