Dexmedetomidine Alleviates Presurgical Anxiety-induced Persistent Postsurgical Pain Via The Activation Of Glucocorticoids

Objective:To investigated the role of dexmedetomidine in presurgical anxiety-induced persistent postoperative pain and the potential mechanisms behind the effects.Methods:164 adult male Sprague Dawley rats were randomly divided into 10 groups:control group(C group, n=35),SPS group(SPS group, n=8), plantar incision group (Ⅰ group, n=8), model group (S+Igroup, n=38), saline group (NS group, n=17), metyrapone group (M group, n=8), Dexmedetomidine group1 (D1 group, n=8), Dexmedetomidine group 2 (D2 group, n=8),Dexmedetomidine group 3 (D3 group, n=17), Dexmedetomidine+corticosterone group (D+C group, n=17)。 in the present study,we used single-prolonged stress (SPS) to induce anxiety behaviors.SPS plus plantar incision model in rats could mimic presurgical anxiety induced postsurgical pain in clinic.Intraperitoneal injection of 0.2ml saline was performed 24h after the SPS procedure,and 0.5h before plantar incision.Intraperitoneal injection of metyrapone(25mg/kg) was performed 1h before the SPS procedure.Intraperitoneal injection of dexmedetomidine(10μg/kg,20μg/kg, 40μg/kg) was performed 24h after the SPS procedure,and 0.5h before plantar incision.Intraperitoneal injection of dexmedetomidine(40μg/kg) and corticosterone (10μg/kg)was performed 24h after the SPS procedure,and 0.5h before plantar incision.PWMT (paw withdrawal threshold) was tested on day 1 before the SPS procedure and on days 1,4,7,14,21, and 28 after surgical incision. Serum corticosterone levels were determined using a commercially available enzyme competitive ELISA test.GR (glucocorticoid receptor)protein expression was tested by Western blot.Results:(1)The"SPS-plus-incision" group decreased PWMT in the right hindpaw compared to the control group(p< 0.05).The"SPS-plus-incision" group underwent incision surgery 24 h after the SPS procedure and exhibited a significantly decreased PWMT compared to the incision alone group(p< 0.05) from 1 to 28 days after surgery.SPS combined with incision increased plasma corticosterone levels from day 1 to day 28 after plantar incision compared with the control group.A time-dependent increase in GR expression was observed in the"SPS-plus-incision"group, but not in the control group, from 1 to 28 days after paw incision(p< 0.05).To further investigate the involvement of glucocorticoids in SPS-induced persistent incisional pain, rats were intraperitoncally injected with 25 mg/kg metyrapone, a corticosterone synthesis inhibitor, before surgical incision. Metyrapone significantly blunted the SPS-induced exacerbation and prolongation of incisional pain in the right hind paw.(2) Intraperitoneal administration of dexmedetomidine inhibits SPS-induced persistent pain.Compared to the rats that received saline,the expression of GR decreased significantly after the intraperitoneal administration of dexmedetomidine(p< 0.05).However,pretreatment with corticosterone blocked the pain inhibition provided by dexmedetomidine.Conclusion:SPS-exposure increased incisional pain from days I to 28 after incision surgery, and this was accompanied by increases in circulating corticosterone concentration and spinal cord GR expression.Therefore,in this animal model, glucocorticoids contributed to presurgical anxiety-induced persistent postsurgical pain.Dexmedetomidine, which inhibits the release of glucocorticoids,alleviates anxiety-induced persistent pain. The results of the present study indicate that dexmedetomidine may be an effective pharmacological agent for preventing presurgical anxiety-induced persistent postoperative pain...