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 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 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 investigate the role of glucocorticoid receptor (GR) in the induction of neuronal apoptosis in spinal dorsal horn in chronic morphine tolerant rats. Methods Twenty healthy male SD rats weighing 300-350 g in which intrathecal (IT) catheter was successfully implanted without complication were randomized into 4 groups ( n = 5 each): group Ⅰ control ( group C);group Ⅱ morphine ( group M );group Ⅲ morphine +RU38486 (GR antagonist) (group MR) and group Ⅳ morphine + dexamethasone (GR agonist) (group MD).Normal saline 10 μl, morphine 10 μg, morphine 10 μg + RU38486 2 μg and morphine 10μg + dexamethasone 4 μg were injected IT twice a day at 8:00 and 20:00 for6 consecutive days in group C, M, MR and MD respectively. Tail flick latency (TFL) to a thermal nociceptive stimulus was measured every day at 30 min after IT administration in the morning (8:00). Hyperalgesia was considered to be a sign of morphine tolerance. The animals were killed at 7 days after IT drug administration. The L3-5 segment of the spinal cord was isolated for determination of neuronal apoptosis in spinal dorsal horn by TUNEL staining. Apoptotic index was calculated ( the number of apoptotic neurons/the total number of neurons × 100% ). Results TFL was significantly prolonged at day 1 and 3 of IT morphine 10 μg twice a day and returned to baseline at day 5 and 7 indicating morphine tolerance. RU38486 inhibited while dexamethasone enhanced morphine tolerance. IT morphine significantly increased the number of apoptotic neurons in spinal dorsal horn. Morphine-induced neuronal apoptosis was decreased by IT RU38486 and increased by IT dexamethasone. Conclusion Glucocorticoid receptors may be involved in morphine tolerance by inducing neuronal apoptosis in spinal dorsal horn.

Objective To investigate the changes in the expression of calcitonin gene-related peptide (CGRP), substance P (SP) and brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) and the effect of electroacupuncture (EA) on morphine tolerance in rats with chronic inflammatory pain (CIP) and morphine tolerance. Methods Twenty-five 8-month-old male SD rats weighing 230-250 g in which intrathecal (IT)catheters were successfully implanted without complications were randomly divided into 5 groups ( n = 5 each):groupA CIP + normal saline (NS) 10 μl IT twice a day for 7 consecutive days; group B CIP + morphine 10 μg/kg ( 10 μl) IT twice for the first day only; group C CIP + morphine 10 μg/kg ( 10 μl) IT twice a day for 7 consecutive days; group D CIP + EA (intensity 2 mA, frequency 2 Hz, wave length 0.6 ms) + morphine 10 μ g/kg (10 μl) IT twice a day for7 consecutive days; group E CIP + EA (intensity 2 mA, frequency 15 Hz,wave length 0.4 ms) + morphine 10μg/kg (10 μl) IT twice a day for7 consecutive days. CIP was induced by injecting complete Freund's adjuvant (CFA) into the ankle joint of the left hindlimb. IT morphine or NS was started on the 4th day after induction of CIP. EA of Yanglingquan and Zusanli lasting 30 min was performed once a day after first IT administration of morphine for 7 days. Paw withdrawal latency (PWL) to a thermal nociceptive stimulus was measured before induction of CIP, 1 day before (baseline) and at day 1-7 after administration (T0-8) . The animals were sacrificed after the last PWL measurement. The DRGs of the lumbar segment (L4-6) were removed for determination of CGRP, SP and BDNF mRNA expression using RT-PCR. Results PWL was significantly shorter at T1 than at T0 in all groups, and at T3-8 than at T2 in group B-E, while longer at T2 than at T1 in group B-E ( P ＜0.05). PWL was significantly longer in group B-E and CGRP, SP and BDNF mRNA expression higher in group C than in group A ( P ＜ 0.05). PWL was significantly longer in group C-E than in group B ( P ＜ 0.05). PWL was significantly longer and CGRP, SP and BDNF mRNA expression lower in group D and E than in group C ( P ＜0.05). PWL was significantly lower and CGRP, SP and BDNF mRNA expression higher in group E than in group D ( P ＜ 0.05). Conclusion Up-regulation of the expression of CGRP, SP and BDNF mRNA in DRG is involved in the devepopment of morphine tolerance. EA can inhibit the devepopment of morphine tolerance by inhibiting the expression of CGRP2 SP and BDNF mRNA.

Objective To investigate the influence of gender on the enmcement of neuromuscular blocking effects of cisatracurium or rocuronium by sevoflurane. Methods Two hundred and forty ASA Ⅰ or Ⅱ patients, aged 20-60 yr, weighing 45-85 kg, scheduled for elective surgery under general anesthesia were assigned into 2 groups ( n = 120 each): cisatracurium group and rocuronium group. Each group were divided into 4 subgroups according to gender and anesthetics ( n = 30 each): female propofol group, male propofol group, female sevoflurane group and male sevoflurane group. Anesthesia was induced with midazolam, propofol and fentanyl. After loss of consciousness, the laryngeal mask was inserted and the patients were mechanically ventilated. Propofol groups received target-controlled infusion (TCI) of propofol (target plasma concentration 2-6 μg/ml), and sevoflurane groups inhalation of sevoflurane. Cisatracurium 0.15 mg/kg or rocuronium 0.6 mg/kg was injected intravenously 5 min after propofol infusion or after the end-tidal concentrion of sevoflurane was maintained at 1.71% (1 MAC) for 5 min. Neuromuscular block was assessed with accelerograph F (TOF-watch SX). Train-of-four (TOF) stimulation of ulnar nerve was used. The onset time, duration of peak effect and times for recovery of T1 to 25% and TOF ratio (TOFR) to 25% were recorded.Results Compared with propofol groups, the time for recovery of TOFR to 25 % for rocuronium, and the duration of peak effect and times for recovery of T1 to 25 % and TOFR to 25% for cisatracurium were significantly prolonged in female sevoflurane group, the onset time of rocuronium was significantly shortened, while the duration of peak effect and times for recovery of T1 to 25% and TOFR to 25% for rocuronium and cisatracurium were significantly prolonged in male sevoflurane group ( P ＜ 0.05 or 0.01 ). The times for recovery of T1 to 25% and TOFR to 25% for rocuronium and onset time of cisatracurium were significantly shorter in female than in male during sevoflurane anesthesia (P ＜ 0. 05 or 0.01 ). Conclusion The enhancement of rocuronium-induced neuromuscular block by sevoflurane is stronger in male than in female,but there is no gender variation in the enhancement of cisatracurium-induced neuromuscular block by sevoflurane.

Objective To evaluate the relationship between pharmacodynamics of sufentanil-induced respiratory depression and age factors. Methods Forty ASA Ⅰ or Ⅱ patients scheduled for elective abdominal surgery were randomly divided into 2 groups according to the age: young and middle-aged group (25-64 yr, group M) and elderly group (65-80 yr, group E). EC50 was determined by up-and-down sequential trail. The initial target effect-site concentration (Ce) of sufentanil was set at 0.40 and 0.35 μg/ml in group M and E respectively.Each time Ce decreased/increased by 10% in the next patient depending on whether or not the respiratory depression occurred. Respiratory depression was defined as VT ≤ 5 ml/kg, RR ≤ 8 bpm/min, SpO2 ≤ 94%,PET CO2 ≥ 55 mm Hg, and/or apnea ≥ 15 s. Results The EC50 and 95 % confidence interval of sufentanil causing respiratory depression were 0.61 (0.54-0.70) μg/ml and 0.41 (0.38-0.45) μg/ml in group M and E respectively with the significant difference. Conclusion The efficacy of sufentanil-induced respiratory depression is related to age factors and the elderly patients are more sensitive to sufentanil-induced respiratory depression.

ObjectiveTo evaluate the role of the spinal cord proteasome in chronic morphine tolerance in rats.MethodsTwenty-four healthy male SD rats in which intrathecal catheters were successfully placed without complications were randomized into 4 groups ( n =6 each):normal saline group ( group NS),chronic morphine tolerance group (group M),chronic morphine tolerance + proteasome inhibitor MG-132 group (group M + MG) and MG-132 group (group MG).Normal saline 10 μl,morphine 10 μg,morphine 10 μg+ MG-132 2.5 μg and MG-132 2.5 μg were injected intrathecally twice a day for 7 consecutive days in groups NS,M,M + MG and MG respectively.Tail flick latency was measured on day 1 before intrathecal injection and on day 1,3,5 and 7 of intrathecal injection to calculate the percentage of maximum possible antinociceptive effect (MPAE).After the last intrathecal injection,5 rats were sacrificed,and L3-5 spinal cord was removed for determination of the expression of glutamate-aspartate transporter (GLAST) and excitatory amino acids carrier 1 (EAAC1)by Western blot.Results MPAE was gradually decreased during the intrathecal injection in groups M and M + MG( P ＜ 0.05).Compared with group NS,MPAE was gradually incresed during the intrathecal injection in groups M and M + MG,and the expression of GLAST and EAAC1 in the spinal cord was significantly down-regulated in group M (P ＜ 0.05).There was no significant difference in the parameters mentioned above between group MG and group NS ( P ＞0.05 ).Compared with group M,MPAE was significantly increased and the expression of GLAST and EAAC1 in the spinal cord was significantlyup-regulatedingroupM+MG(P＜0.05or0.01).ConclusionSpinal cord proteasome is involved in the development of chronic morphine tolerance in rats.

ObjectiveTo investigate the effects of ginsenoside Rg1 on apoptosis in spinal dorsal horn in development of morphine tolerance in rats with arthritis.MethodsTwenty-four healthy male SD rats weighing 280-320 g in which intrathecal(IT) catheters were succcessfully implanted without complication were randomized into 4 groups ( n =6 each):group normal saline ( group C) ; group morphine ( group M ) ; group ginsenoside Rg1 (group G) and group morphine + ginsenoside Rg1 (group MG).Arthritis was induced with complete Freund adjuivant injected into the ankle joint of right hind limb according to the method described by Butler et al in all 24 animals.Chronic morphine tolerance was induced by IT morphine 10 μg twice a day for 7 consecutive days in groups M and MG.Ginsenoside Rg1 100 μg was given IT once a day for 7 consecutive days in groups G and MG.Paw withdrawal threshold to mechanical stimulation with yon Frey filaments (MWT) was measured before induction of arthritis (T1,baseline),and IT drug administration (T2) and at day 1,3,5,7 (T3-6) after IT administration.The rats were sacrificed after last MWT measurement and their lumbar segments of the spinal cord ( L3-5 ) were removed for detection of apoptosis in the spinal dorsal horn by TUNEL.ResultsMWT was significantly decreased after induction of arthritis at T2-6 compared with the baseline value before arthritis at T1 in all 4 groups.In group M IT morphine significantly increased MWT at T3.4 compared with the baseline at T2 but the MWT was decreasing at T5.6 indicative of development of morphine tolerance.In group MG,addition of ginsenoside Rgl to IT morphine significantly attenuate the decrease in MWT at T5.6.The number of apoptotic cells in spinal dorsal horn was significantly higher in groups M and MG than in group C,but was significantly lower in group MG than in group M.Concluson Ginsenoside Rg1 can prevent the development of morphine tolerance in rats with arthritis by inhibiting apoptosis in spinal dorsal horn.