Role of spinal sigma-1 receptors in maintenance of bone cancer pain in rats: the relationship with ERK

Abstract

Objective To evaluate the role of spinal sigma-1 receptors in the maintenance of bone cancer pain (BCP) in rats and the relationship with extracellular signal-regulated kinase (ERK).Methods Part Ⅰ Twenty-four female Sprague-Dawley rats,weighing 180-220 g,were randomized into 2 groups using a random number table:sham operation group (S group,n =4) and BCP group (n =20).BCP was induced by inoculating Walker 256 mammary gland carcinoma cells into the medullary cavity of the right tibia.Four rats were sacrificed on day 10 after inoculation in S group or on day 3,5,7,10 and 14 after inoculation in BCP group,and the L4-6 segments of the spinal cord were removed to measure the expression of sigma-1 receptors by Western blot.Part Ⅱ Forty female Sprague-Dawley rats,weighing 180-220 g,were randomized into 4 groups (n =10 each) using a random number table:sham operation group (S group),sigma-1 receptor inhibitor BD1047 group (BD group),BCP group,and BCP + BD1047 group (BCP + BD group).On day 10 to 14 after inoculation,normal saline 20 μl was injected intrathecally once a day in S and BCP groups,or BD1047 120 nmol/20μl was injected intrathecally once a day in BD and BCP + BD groups.Mechanical paw withdrawal threshold (MWT) to yon Frey filament stimulation was measured one day before inoculation,on day 3,5 and 7 after inoculation,and on day 10,12 and 14 after administration.After measurement of MWT on day 14 after inoculation,the rats were sacrificed and the L4-6 segments of the spinal cord were removed to determine the expression of phosphorylated ERK (p-ERK) by Western blot.Results Part Ⅰ Compared with group S,the expression of sigma-1 was significantly up-regulated and peaked on day 10 after operation in group BCP.Part Ⅱ Compared with S group,no significant changes were found in MWT and p-ERK expression at each time point in BD group,and MWT was decreased and p-ERK expression was up-regulated in BCP and BCP + BD groups.Compared with group BCP,after intrathecal injection of BD1047,MWT was significantly increased and the expression of p-ERK was down-regulated in BCP + BD group.Conclusion Spinal sigma-1 receptors are involved in the maintenance of BCP in rats possibly through promoting phosphorylation of ERK. Key words: Bone neoplasms ; Pain ; Receptors, sigma ; Spinal cord ; Extracellular signal-regulated MAPKinases