Pain is a common symptom in patients with terminal cancer and is the main factor that affects their quality of life. Morphine is commonly used for the treatment of acute and chronic pain, but the long-time application of morphine results in morphine tolerance and hyperalgesia, which restrict the clinical applications of the anesthetic. In this review, pertinent studies on morphine over recent years were summarized and analyzed, and the mechanism of morphine tolerance and hyperalgesia were discussed, specifically on the function of calcitonin gene-related peptide (CGRP) in clinical practice. The authors analyzed the relationship between the plastic changes in the nervous system and chronic morphine application in terms of CGRP up-regulation based on its molecular biology charac-teristics and distribution, the relationship between CGRP and chronic application of morphine, and between CGRP and hyperalgesia. The effect of CGRP up-regulation on the nociceptive system and the relationship between CGRP up-regulation and the formation of hy-peralgesia were also analyzed. We discussed the sensitized effect of CGRP up-regulation on the nociceptive system, which promotes morphine tolerance and hyperalgesia. This study provides a framework for treating morphine tolerance and can be used as a guide for further research on the topic.

Objective To evaluate the effects of a single IV lidocaine bolus dose on the minimal alveolar concentration (MAC)of sevoflurane. Methods Patients (n=90), aged 25-65 years whose Anesthesiologists (ASA) classification wasⅠorⅡand underwent elective surgery on trunk under general anesthesia, were randomly divided into 3 groups with 30 cases in each group:high-dose lidocaine group (group H), low-dose lidocaine group (group L) and control group (group C). They were induced by sevoflurane inhalation, and ventilated by LMA (laryngeal mask airway). After a 15 minutes equilibration period with the above sevoflurane concentration , the medication to be studied (2%lidocaine 1.5 mg/kg for group H , 2%lidocaine 0.75 mg/kg for group L, 0.9%saline 5mL for group C) was administered for 3 minutes before the skin incision. The response to skin incision (movement versus no movement) was recorded in the first minute after skin incision. The MAC for sevoflu?rane was determined using the Dixon′s up and down method. Values of mean arterial pressure (MAP), heart rate (HR), and BIS were recorded at 1 minute and 5 minutes after being monitored (average values were noted as T0), immediately before the administration of medication (T1), immediately before the skin incision (T2) and 1 minute after the skin incision(T3). Results MAC in group H (2.00%± 0.17%) was lower than that in group C (2.22%± 0.18%) by approximately 0.22%,and which was lower than that of group L ( 2.21%± 0.14%) by approximately 0.21%(F=7.054,P<0.05). No significant differ?ence in the MAC of sevoflurane was noted between group L and group C. The values of HR, MAP and BIS all decreased at T 2 and increased at T3 in all 3 groups (all P<0.05). No significant difference in HR, MAP or BIS was observed between T0 and T1 in all three groups. The values of HR and BIS were lower in group H than those in group C and group L at T2 and T3. The values of MAP were lower in group L and group H than those in group C at T2 and T3. The value of MAP were lower in group H than that in group L at T2(all P<0.05). Conclusion A singleⅣ1.5 mg/kg lidocaine decreases MAC of sevoflurane, but the decreased amplitude (11%) does not reach expectation.

Objective To investigate the potential mechanism of POD in the elder rat model in different depths of anesthesia. Method 120 elderly rats were randomly divided into the A1,A2,A3,B1,B2 and B3 groups. The incidence of POD in the elderly rats was assessed in different depths of anesthesia ,and then the death of neurons,and the expressions of Bid,Bim,Puma and Caspase?3 were detected by Annexin/PI ,real?time PCR and Western blot assay ,respectively. Results Compared with the A1 and A3 group ,the incidence of POD in the elderly rats was decreased and the death of neurons ,and the expressions of Bid ,Bim ,Puma and Caspase?3 were decreased in Group A2(P<0.05). Compared with the preoperative condition,the incidence of POD in the elder?ly rats was increased and the death of neurons,and the expressions of Bid,Bim,Puma and Caspase?3 were in?creased in all groups (P < 0.05). Additionally,similar results were found in the group of inhalational anesthesia. Conclusion The depth of BIS 60 ~ 75/BIS 30 ~ 45 in the elderly rats lead to the increase in the incidence of POD,and that might result from the apoptosis of neurons and the increases of Bid,Bim,Puma and Caspase?3.

Objective To evaluate the effect of dexmedetomidine on baroreflex in the patients.Methods Forty-five ASA physical status Ⅰ or Ⅱ patients,aged 20-60 yr,with body mass index 18-24 kg/m2,scheduled for elective partial thyroidectomy or nasal polypectomy under general anesthesia,were randomly divided into 3 groups (n =15 each) using a random number table:control group (group C),low-dose dexmedetomidine group (group LD) and medium-dose dexmedetomidine group (group MD).Dexmedetomidine 0.5 μg/kg was injected intravenously followed by infusion at 0.2 μg· kg-1 · h-1 in group LD.Dexmedetomidine 1.0 μg/kg was injected intravenously followed by infusion at 0.5 μg· kg-1 · h-1 in group MD.After 30 min of dexmedetomidine infusion,a modified Oxford pharmacologic technique was used for evaluating baroreflex sensitivity.Results There was no significant difference in baroreflex sensitivity between the three groups.Conclusion Dexemedtomidine exerts no effect on baroreflex in the patients.

Objective To investigate the role of extracellular signal-regulated kinase(ERK)signal pathway in the spinal cord in the development of chronic morphine tolerance.Methods Thirty healthy male SD rats weighing 300-350 g in which intrathecal(IT)catheters were successfully implanted without complication were randomly divided into 3 groups(n = 10 each): group Ⅰ control(group C);group Ⅱ morphine tolerance(group M)and group Ⅲ morphine tolerance + PD98059(ERK upstream kinase MEK inhibitor)(group P).Morphine tolerance was induced with IT morphine 10 μg twice a day for 7 consecutive days.In group P PD98059 10 μg was injected IT at 30 min before each morphine administration.Tail flick latency(TFL)(the time between the onset of heat stimulus and voluntary tail withdrawal)was measured once a day at 30 min after first IT morphine administration and at 1 day after last IT morphine.Maximum analgesic effect(MPE)was calculated.MPE =(TFL after IT morphine - baseline TFL)/(12 - baseline TFL)× 100%.The animals were sacrificed after last TFL measurement.The L3-5 segment of the spinal cord was isolated for determination of the expression of μ-receptor and phosphorylated ERK 1/2(p-ERK1/2)by Western blot analysis and fluoroimmunoassay.Results Morphine tolerance was induced in group M and M + P.MPE was higher in group P than in group M.The expression of μ-receptor in spinal dorsal horn was significantly lower while the p-ERK1/2 expression was higher in group M than in group C.IT PD98059 significantly up-regulated μ-receptor expression and down-regulated p-ERK expression in group P as compared with group M.Conclusion ERK signal pathway is involved in the development of chronic morphine tolerance in rats.

Objective To investigate the changes in the expression of glutamate-aspartste transporter in spinal dorsal horn in rats with inflammatory pain and chronic morphine tolerance. Methods Thirty healthy male SD rats in which intrathecal (IT) catheters were successfully placed without complications were randomized into 3 groups ( n = 10 each): normal saline group ( group NS), arthritis group ( group A), and arthritis + morphine group (group AM). NS 50 μl was injected into the ankle joint of the left hindlimb in group NS, while complete Freund's adjuvant was injected in the other two groups instead. After 3 days, group NS and A received IT NS 10 μl twice a day for 7 consecutive days, group AM IT morphine 10 μg (10 μl) twice a day for 7 consecutive days. Mechanical pain threshold (MPT) was measured before IT administration and at day 2, 4, 6 and 8 after IT administration (T0-4). The animals were sacrificed after the last MPT measurement. The spinal cords were isolated for determination of GLAST expression in spinal dorsal horn. Results Compared with group NS, MPT was significantly decreased in the other groups and GLAST expression was down-regulated in group AM (P ＜ 0.05). Compared with group A, no significant change was found in MPT at T3,4 (P ＞ 0.05), while GLAST expression was down-regulated in group AM ( P ＜ 0.05). Conclusion The development of chronic morphine tolerance is related to the decrease in the function of GLAST in spinal dorsal horn in rats with inflammatory pain.

Objective To evaluate the role of extracellular signal-regulated kinase-cyclic AMP response element binding protein(ERK-CREB) signal pathway in glucocorticoid receptors-mediated chronic morphine tolerance in rats.Methods Male SD rats aged 2 months weighing 280-320 g were used in this study.A catheter was placed in subarachnoid space via foramen magnum according to Yaksh.Thirty-six rats in which intrathecal (IT) catheters were successfully implanted were randomly divided into 6 groups ( n =6 each):control group ( group C),chronic morphine tolerance group (group M),morphine + dexamethasone group (group MD),morphine + RU38486 group (group MR),dexamethasone group (group D),RU38486 group (group R).Normal saline 10 μl,morphine 10 μg,morphine 10 μg + dexamethasone 4 μg,morphine 10 μg + RU38486 2 μg,dexamethasone 4μg,RU38486 2 μg was administered IT twice a day(8:00 and 20:00)for 6 consecutive days in groups C,M,MD,MR,D,R respectively.Tail flick latency (TFL) was measured at 1 d before IT drug administration(baseline)and at 30 min after first IT drug administration during 1,3,5 d and at 1 d after last IT drug administration (T1～4).Maximum analgesic effect (MPE) was calculated.The animals were sacrificed after last TEL measurement.The L3～5 segment of the spinal cord was isolated for determination of the expression of phosphorylated ERK(pERK)and phosphorylated CREB(pCREB) by immunofluorescence staining.Results MPE was significantly T1 lower at T3,4 than at T1 in groups M and MD.Compared with group C,MPE was significantly increased,the expression of pERK and pCREB up-regulated in group M,but no significant change was found in the parameters mentioned above in groups R and D.Compared with group M,MPE was significantly increased,the expression of pERK and pCREB up-regulated in group MR,and MPE was significantly increased,the expression of pERK and pCREB down-regulated in group MD.Conclusion The mechanism by which glucocorticoid receptors-mediated chronic morphine tolerance may be associated with the inhibition of ERK-CREB pathway.

Objective To investigate the effects of dexmedetomidine on serum inflammatory factor and oxidative stress response in septic rats.Methods Thirty healthy male SD rats,aged 10-14 weeks,weighing 250-300 g,were randomly divided into 3 groups( n =10 each): sham operation group (group S),sepsis group (group CLP) and sepsis + dexmedetomidine group (group CLP + D).Sepsis was induced by cecal ligation and puncture in groups CLP and CLP + D.Group CLP + D received intravenous infusion of dexmedetomidine at 10 μg· kg- 1 ·h- 1 from the end of operation until dead or 12 h after operation.Groups S and CLP received equal volume of normal saline at 1 ml·kg-1 ·h-1.Arterial blood samples were taken from 5 rats in each group before (basline) and at 1,6 and 12 h after operation for determination of serum IL-6,IL-10,SOD and MDA levels.The survival rate within 12 h after operation was recorded.Results Compared with group S,serum IL-6,IL-10 and MDA concentrations at 1,6 and 12 h after operation were increased,while serum SOD activity at 1,6 and 12 h after operation and survival rate were decreased in group CLP ( P ＜ 0.05 ).Compared with group CLP,serum IL-6 and MDA concentrations at 6 and 12 h after operation were decreased,while serum SOD activity at 12 h after operation and survival rate were increased in group CLP + D ( P ＜ 0.05 ).Conclusion Dexmedetomidine can increase the survival rate of septic rats by inhibiting inflammatory factor release and oxidative stress response.

Objective To explore the role of excitatory amino acid carrier 1 (EAAC1)in dorsal root ganglion (DRG) in the mechanism of developing morphine tolerance. Methods Thirty male SD rats were implanted intrathecal catheters and randomized into 6 groups with 5 rats each. The rats of 4 groups were made into the model of adjuvant-induced arthritis in the left hind limb and were administered intrathecally, morphine 10 μg(group M_(10)), morphine 20μg(group M_(20)), morphine 20 μg plus naloxone 10 μg(group MN) ,or saline(group C) respectively. The other 2 groups without were administered intrathecally saline (group C_0) or morphine 20 μg (group M0). The drugs were administered twice daily for 7 days. Mechanical withdrawl threshold(MWT) of the left hind limb was examined to evaluate the behavior. Immunohistochemistry was used to detect the expression of EAAC1 in the left L_(3-4) and L_(4-5) DRG. Results Morphine tolerance was formmed stably in the arthritis rats of group M_(10) and group M_(20) after administering morphine for 7 days. The expression of EAAC1 in DRG was downregulated. Conclusion DRG EAAC1 may be involved in the mechanism of developing morphine tolerance in rats with inflammatory pain.

Objective To investigate the clinical effects of continuous 3-in-1 femoral nerve block with stimulating catheters for patient controlled regional anesthesia(PCRA) in elderly patients after unilateral total knee replacement (TKR)surgery.Methods Thirty ASA Ⅰ - Ⅱ elderly patients wererandomly divided into two groups: FB group and Ⅳ group.FB group received continuous 3-in-1 femoral nerve block for postoperative analgesia with 0.2% ropivacaine plus 0.1 μg/ml sufentanil continuous infusion at 5 ml/h plus PCA boluses (1.0 ml/15 min).Ⅳ group received continuous intravenous analgesia with 1 μg/ml sufentanil plus 0.04 mg/ml tropisetron hydrochloride at 2 ml/h plus PCA boluses (0.5 ml/15 min).All patients were maintained analgesia for 48 hours.Results In FB group, the visual analogue scale(VAS) scores were 1.3 ±1.1, 1.2 ± 1.0, 1.1±0.9, 1.1 ± 1.0,1.0±0.9 at 4, 8, 12, 24, 48 hours after surgery under rest status respectively and were 3.04±1.4,2.3±1.3 at 24, 48 hours after surgery in active function training.These parameters in Ⅳ group were 4.0±1.6, 3.5±1.6, 3.2±1.4, 3.0±1.3, 2.5±1.2, 4.7±1.5 and 3.3±1.5 respectively, which were significantly different compared with FB group (t=5.358, 4.707, 4.852, 3.784, 3.743, 3.254,1.932,all P<0.05 or P<0.01).The incidence of nausea was higher in IV group than in FB group(P = 0.0022).Postoperative satisfaction ratings was higher (χ2 =41.1 ,P<0.01) and the total morphine use for 48 hours after operation was less(uc=2.412, P<0.01) in FB group than in Ⅳ group.Conclusions After TKR surgery, the continuous 3-in-1 femoral nerve block with stimulating catheters is an effective method with better pain relief,fewer side effects and higher satisfaction ratings in the elderly.