Multimodal Pain Control Utilizing Buprenorphine for Robotic-assisted Laparoscopic Prostatectomy: A Quality Improvement Comparison to Conventional Opioid Management.

INTRODUCTION: This study investigated the effectiveness of buprenorphine as an alternative to the use of conventional opioids perioperatively in an effort to help mitigate the impact of the use of perioperative conventional opioids for patients undergoing robotic-assisted laparoscopic prostatectomy. METHODS: Outcomes of patients with localized prostate cancer undergoing robotic-assisted laparoscopic prostatectomy were examined before and after implementation of novel quality improvement study that included receiving buprenorphine compared to conventional opioids for pain control intraoperatively and postoperatively. The primary end point was adequate pain control with secondary end points being analgesic consumption at home, opioid-related side effects, and patient satisfaction. RESULTS: When analyzing the secondary end point of oral morphine milligram equivalents, the buprenorphine group received significantly less morphine milligram equivalent compared to the conventional opioid group (15.19 vs 47.91, P = .006). The buprenorphine group also had lower reported pain scores at discharge (4.3; scale 1-10) compared to the conventional opioid group (5.4), though this did not reach significance (P = .069). In the buprenorphine group, 76.9% strongly agreed that their pain was adequately controlled in the hospital compared to 57.5% of the conventional opioid group (P = .223). There was no difference in overall satisfaction at postoperative day 5 (P = .358). CONCLUSIONS: Our study demonstrates buprenorphine's analgesic capabilities to maintain adequate pain control and patient satisfaction compared to conventional opioids during robotic-assisted laparoscopic prostatectomy, while decreasing perioperative opioid use.

Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Brief History of Opioids in Perioperative and Periprocedural Medicine to Inform the Future.

Background: Opioids and derivatives of opium had been used as analgesics for thousands of years before the introduction of inhalational anesthetic agents. Once these early volatile agents were in widespread use, opioids were used as part of anesthetic care for premedication, as intraoperative adjuncts to general anesthesia, and for the management of postoperative pain. Evidence of growing dependence on opioids in the perioperative and periprocedural patient is supported by the ongoing research to develop synthetic opioids and to customize the pharmacokinetics and pharmacodynamics to achieve specific therapeutic goals. Methods: We explore the history of opioid use in perioperative care as a means of future management in light of new persistent opioid abuse. Results: As the opium chemical structure has been modified, newer nonopioid analgesics have been approved and brought into clinical practice. Opioid-sparing and opioid-free anesthetic techniques are not only a possibility, but a reality. Conclusion: Continuing research in neurobiology and addiction genetics will ultimately lead to a pharmacogenetic approach to patients at risk for new persistent opioid abuse.

Progress in the mechanism of acupuncture intervention on pain emotion and pain cognition mediated by limbic system / 针灸推拿医学（英文版）

Pain is a complex physiological and psychological activity, involving at least three dimensions, including pain sensation, pain emotion, and pain cognition. Acupuncture can clearly relieve the pain sensation of patients and improve pain emotion and pain cognition induced by pain; acupuncture participates in the multi-dimensional regulation of pain through brain regions of the limbic system such as anterior cingulate cortex (ACC), amygdala (AMY), and hippocampus. By analyzing relevant literature, it has been found that the regulation of acupuncture on pain emotion is mainly related to the activation of pertinent opioid receptors in the ACC, the decrease of the expression of extracellular signal-regulated kinase (ERK), and the promotion of the expression of glutamic acid (Glu) A1, metabotropic glutamate receptor-1 (mGluR1), and γ-aminobutyric acid aminobutyric acid (GABA) B2 protein in the AMY. The regulation of acupuncture on pain cognition is mainly related to the elevation of the expression of protein kinase A (PKA) and phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK) and the inhibition of cyclic adenosine monophosphate (cAMP)/PKA/cAMP response element-binding protein (CREB) signaling pathway in the ACC.

mu-Opioid Receptor Polymorphisms and Breast Cancer Recurrence in Adult Korean Women Undergoing Breast Cancer Surgery: A Retrospective Study.

Background: Genetic variations of mu-opioid receptors are well known to contribute to growth and progression of tumors. The most common single-nucleotide polymorphism (SNP) in the mu-opioid receptor 1 gene (OPRM1) is the A118G mutation. We examined the association between the recurrent breast cancer and genotypes of OPRM1 A118G SNP (AA vs. AG vs. GG) in Korean women population. Methods: We analysed medical records and genetic data of 200 patients aged more than 20 who underwent primary breast cancer surgery from June 2012 to June 2014 and diagnosed recurrent breast cancer from June 2012 to September 2019. Results: The incidence of recurrent breast cancer was 6.1%, 8.2%, and 4.8% in genotype AA, AG and GG, respectively (p=0.780). The incidence of recurrent breast cancer in volatile anaesthesia group was 7.0% and 7.1% in total intravenous anaesthesia (TIVA) group (RR = 0.984, 95% CI = 0.328 - 2.951; p = 0.978). Conclusion: OPRM1 A118G SNP had no influence on breast cancer recurrence in Korean women. Anaesthesia technique did not show significant effect on the incidence of recurrent breast cancer.

Morphine decreases the function of primary human natural killer cells by both TLR4 and opioid receptor signaling.

BACKGROUND: Opioids are commonly used to provide analgesia for cancer pain, and functional opioid receptors have been identified on natural killer (NK) cells, the lymphocytes responsible for surveillance and elimination of cancer cells. Opioids also bind to other lymphocyte receptors, such as Toll-like receptor (TLR)-4. Here, we characterized the effects of morphine on primary human NK cell cytotoxicity and mediator release, which occur through classical opioid receptor or TLR4 signaling. METHODS: Purified primary human NK cells were pretreated with inhibitors of opioid receptors or TLR4 before being cultured with target tumor cell line K562 in the presence or absence of morphine. Apoptosis of K562 cells in each treatment condition was measured with an Annexin V flow cytometry-based assay and compared to that of K562 cells cultured with NK cells alone. Supernatant concentrations of 13 cytokines and cytotoxic mediators were measured with a multiplex bead-based flow cytometry assay. RESULTS: Exposure of NK cells to morphine decreased their ability to induce apoptosis in K562 cells. Pretreating the NK cells with either naloxone, a mu- and kappa-opioid receptor antagonist, or TAK-242, a selective inhibitor of TLR4 signaling, prevented this effect. Paradoxically, morphine increased the concentration of interleukin-6, granzyme A, and granzyme B in cell supernatants. Pretreatment of NK cells with TAK-242 prevented the morphine-induced increase in interleukin-6, whereas pretreatment with naloxone inhibited the morphine-induced increase in granzymes A and B. CONCLUSIONS: Both classical opioid receptors and TLR4 participate in morphine-induced suppression of NK cell cytotoxic activity. These studies have important implications for maintenance of immune function during management of cancer pain.

An Experimental Study on Spinal Cord µ-Opioid and α2-Adrenergic Receptors mRNA Expression Following Stress-Induced Hyperalgesia in Male Rats.

BACKGROUND: Intense stress can change pain perception and induce hyperalgesia; a phenomenon called stress-induced hyperalgesia (SIH). However, the neurobiological mechanism of this effect remains unclear. The present study aimed to investigate the effect of the spinal cord µ-opioid receptors (MOR) and α2-adrenergic receptors (α2-AR) on pain sensation in rats with SIH. METHODS: Eighteen Sprague-Dawley male rats, weighing 200-250 g, were randomly divided into two groups (n=9 per group), namely the control and stress group. The stress group was evoked by random 1-hour daily foot-shock stress (0.8 mA for 10 seconds, 1 minute apart) for 3 weeks using a communication box. The tail-flick and formalin tests were performed in both groups on day 22. The real-time RT-PCR technique was used to observe MOR and α2-AR mRNA levels at the L4-L5 lumbar spinal cord. Statistical analysis was performed using the GraphPad Prism 5 software (San Diego, CA, USA). Student's t test was applied for comparisons between the groups. P<0.05 was considered statistically significant. RESULTS: There was a significant (P=0.0014) decrease in tail-flick latency in the stress group compared to the control group. Nociceptive behavioral responses to formalin-induced pain in the stress group were significantly increased in the acute (P=0.007) and chronic (P=0.001) phases of the formalin test compared to the control group. A significant reduction was also observed in MOR mRNA level of the stress group compared to the control group (P=0.003). There was no significant difference in α2-AR mRNA level between the stress and control group. CONCLUSION: The results indicate that chronic stress can affect nociception and lead to hyperalgesia. The data suggest that decreased expression of spinal cord MOR causes hyperalgesia.

Effect of sec-O-glucosylhamaudol on mechanical allodynia in a rat model of postoperative pain

BACKGROUND: This study was performed in order to examine the effect of intrathecal sec-O-glucosylhamaudol (SOG), an extract from the root of the Peucedanum japonicum Thunb., on incisional pain in a rat model. METHODS: The intrathecal catheter was inserted in male Sprague-Dawley rats (n = 55). The postoperative pain model was made and paw withdrawal thresholds (PWTs) were evaluated. Rats were randomly treated with a vehicle (70% dimethyl sulfoxide) and SOG (10 μg, 30 μg, 100 μg, and 300 μg) intrathecally, and PWT was observed for four hours. Dose-responsiveness and ED50 values were calculated. Naloxone was administered 10 min prior to treatment of SOG 300 μg in order to assess the involvement of SOG with an opioid receptor. The protein levels of the δ-opioid receptor, κ-opioid receptor, and μ-opioid receptor (MOR) were analyzed by Western blotting of the spinal cord. RESULTS: Intrathecal SOG significantly increased PWT in a dose-dependent manner. Maximum effects were achieved at a dose of 300 μg at 60 min after SOG administration, and the maximal possible effect was 85.35% at that time. The medial effective dose of intrathecal SOG was 191.3 μg (95% confidence interval, 102.3–357.8). The antinociceptive effects of SOG (300 μg) were significantly reverted until 60 min by naloxone. The protein levels of MOR were decreased by administration of SOG. CONCLUSIONS: Intrathecal SOG showed a significant antinociceptive effect on the postoperative pain model and reverted by naloxone. The expression of MOR were changed by SOG. The effects of SOG seem to involve the MOR.

Influence of δ-opioid receptor in the central nervous system / 中国医师杂志

The delta-opioid receptor (DOR),which is a classic analgesic drug widely existed in the central system and peripheral system,is a kind of inhibitory G-protein coupled receptor with seven transmembrane regions.In addition to pain modulation,the opioid receptors are involved in various physiological and pathological activities through gene or cytokines.This review addresses the influence and possible mechanisms of the delta-opioid receptor in ischemic brain injury,analgesia,anti-anxiety and depression,learning and memory,and Parkinson's disease.

Role of different opioid receptors in morphine postconditioning-induced reduction of ischemia-reperfusion injury in isolated rat hearts / 中华麻醉学杂志

Objective To evaluate the role of different opioid receptors in morphine postconditioning-induced reduction of ischemia-reperfusion (Ⅰ/R) injury in isolated rat hearts.Methods Healthy adult male Sprague-Dawley rats,aged 7-8 weeks,weighing 250-300 g,were anesthetized with chloral hydrate.The hearts were removed and retrogradely perfused with oxygenated K-H solution in a Langendorff apparatus.Forty-eight Langendorff-perfused rat hearts were divided into 4 groups (n=12 each) by a random number table method:Ⅰ/R group,morphine postconditioning group (M group),δ receptor antagonist naltrexone plus morphine postconditioning group (N+M group) and κ receptor antagonist nor-binaltorphimine plus morphine postconditioning group (B+M group).Hearts were subjected to 4 cycles of perfusion with K-H solution containing 1 μmol/L morphine for 15 s and then with K-H solution containing no morphine for 15 s in group M.In N+M group and B+M group,hearts were perfused with 5 μmol/L naltrindole and 5 μmol/L nor-binaltorphimine,respectively,starting from 10 nin of equilibration until 5 min of reperfusion,and morphine postconditioning was similar to those previously described in group M.Heart rate and the maximum rate of increase or decrease in left ventricular pressure (±dp/dtmax) were recorded at 20 min of equilibration and 30 and 60 nin of reperfusion.Corona~ effluent was collected at 20 min of equilibration and 60 min of reperfusion for measurement of the activity of creatine kinase by colorimetric assay.Eight hearts were obtained at 60 min of reperfusion for determination of myocardial infarct size.Four hearts were obtained at 60 min of reperfusion for detection of the expression of microtubule-associated protein 1 light chain 3 Ⅰ (LC3 Ⅰ) and LC3 Ⅱ by Western blot.LC3 Ⅱ/LC3 Ⅰ ratio was calculated.Results Compared with the baseline value at 20 min of equilibration,heart rate and +dp/dt were significantly decreased at 30 and 60 min of reperfusion,and the activity of creatine kinase in coronary effluent was increased at 60 min of reperfusion in four groups (P＜0.05).Compared with group Ⅰ/R,the activity of creatine kinase in coronary effluent,percentage of myocardial infarct size and LC3 Ⅱ/LC3 Ⅰ ratio were significantly decreased in group M (P＜0.05).Compared with group M,the activity of creatine kinase in coronary effluent,percentage of myocardial infarct size and LC3 Ⅱ/LC3 Ⅰ ratio were significantly increased in N+M and B+M groups (P＜0.05).Conclusion δ and κ opioid receptors are involved in morphine postconditioning-induced reduction of Ⅰ/R injury in isolated rat hearts,and the mechanism may be related to inhibiting the level of autophagy.

Role of μ-δ heterodimer in down-regulation of expression of excitatory amino acid transporter 3 in hippocampi caused by reinstatement of morphine-induced conditioned place preference in rats / 中华麻醉学杂志

Objective To evaluate the role of μ-δ heterodimer in down-regulation of the expression of excitatory amino acid transporter 3 (EAAT3) in hippocampi caused by reinstatement of morphine-induced conditioned place preference (CPP) in rats.Methods Thirty-two healthy clean-grade male Sprague-Dawley rats,weighing 200-240 g,were assigned into 4 groups (n =8 each) using a random number table method:control group (group C),extinction group (group E),reinstatement group (group R) and reinstatement plus interference plasmid group (group RI).The model of morphine-induced CPP was established,and extinction of CPP was gradually induced by stopping administration.A small dose of morphine 5 mg/kg was intraperitoneally injected again to induce CPP reinstatement,and dwell time around the medicine box was recorded.μ-δ heterodimer interference plasmid 5 μl was injected into the lateral cerebral ventricle after successful establishment of CPP model in group RI.The content of glutamate (Glu) in hippocampi was measured using high-performance liquid chromatography.The EAAT3 expression in hippocampal CA1 and CA3 regions was detected using Western blot.Results Compared with group C,no significant change was found in the dwell time around the medicine box or content of Glu in hippocampi (P＞0.05),and the expression of EAAT3 in hippocampal CA1 and CA3 regions was significantly up-regulated in group E,and the dwell time around the medicine box was significantly prolonged,the content of Glu in hippocampi was increased (P＜0.05),and no significant change was found in the expression of EAAT3 in hippocampal CA1 and CA3 regions in group R (P＞0.05).Compared with group E,the dwell time around the medicine box was significantly prolonged,the content of Glu in hippocampi was increased,and the expression of EAAT3 in hippocampal CA1 and CA3 regions was down-regulated in group R (P＜0.05).Compared with group R,the dwell time around the medicine box was significantly shortened,the content of Glu in hippocampi was decreased,and the expression of EAAT3 in hippocampal CA 1 and CA3 regions was upregulated in group RI (P＜0.05).Conclusion μ-δ heterodimer is involved in down-regulation of EAAT3 expression in the hippocampus caused by reinstatement of morphine-induced CPP in rats.

Role of μ opioid receptor in morphine preconditioning-induced reduction of myocardial ischemia-reperfusion injury in rats with chronic heart failure: an in vitro experiment / 中华麻醉学杂志

Objective To evaluate the role of μ opioid receptor in morphine preconditioning-induced reduction of myocardial ischemia-reperfusion (I/R) injury in rats with chronic heart failure.Methods Adult male Sprague-Dawley rats,weighing 170-230 g,in which chronic heart failure was induced by injecting doxorubicin via the tail vein,were studied.The rats were sacrificed and their hearts were excised and perfused in a Langendorff apparatus with K-H solution saturated with 95％ O2-5％ CO2 at 37 ℃.Forty isolated rat hearts with I/R injury were randomly divided into 4 groups (n=10 each):group I/R,morphine preconditioning group (group MP),μ opioid receptor antagonist CTOP plus morphine preconditioning group (group CTOP+MP) and CTOP group.Myocardial I/R was induced by occlusion of the left coronary artery for 30 min followed by 120 min of reperfusion.In group MP,the hearts were perfused with K-H solution for 15 min,with K-H solution containing 1 μmol/L morphine for 5 min and with K-H solution for 5 min,3 cycles in total,and then the model of myocardial I/R was established.The hearts were perfused with K-H solution containing 1 μmol/L CTOP starting from 10 min before morphine preconditioning until 5 min of ischemia in group CTOP + MP.The hearts were perfused with K-H solution containing 1 μmol/L CTOP starting from 40 min before ischemia until 5 min of ischemia in group CTOP.The coronary effluent was collected at 15 min of equilibration (baseline) and 5 and 10 min of reperfusion to detect the activity of lactate dehydrogenase (LDH).Myocardial infarct size (IS) and the area at risk (AAR) were measured by 2,3,5-triphenyl-tetrazolium staining,and IS/AAR percentage was calculated.The expression of Bcl-2 and Bax mRNA was determined using uantitative real-time polymerase chain reaction,and the ratio of Bcl-2/Bax was calculated.Results Compared with group I/R,the IS and IS/AAR percentage were significantly decreased,the activity of LDH in coronary effluent was decreased,the expression of Bax mRNA was downregulated,the expression of Bcl-2 mRNA was up-regulated,and the Bcl-2/Bax ratio was increased in group MP (P＜0.05),and no significant change was found in the IS or IS/AAR percentage in CTOP and CTOP+ MP groups (P＞0.05).Compared with group MP,the IS and IS/AAR percentage were significantly increased,the activity of LDH in coronary effluent was increased,the expression of Bax mRNA was up-regulated,the expression of Bcl-2 mRNA was down-regulated,and the Bcl-2/Bax ratio was decreased in group CTOP+MP (P＜0.05).Conclusion The mechanism by which morphine preconditioning reduces myocardial I/R injury may be related to activating μ opioid receptors and thus maintaining the balance between Bcl2 and Bax gene expression in the rats with chronic heart failure.

Effect of oxycodone pretreatment on oxygen-glucose deprivation and restoration-induced injury to small intestinal epithelial cells of rats and the role of different opioid receptors / 中华麻醉学杂志

Objective To evaluate the effect of oxycodone pretreatment on oxygen-glucose deprivation and restoration (OGD/R)-induced injury to small intestinal epithelial cells of rats and the role of different opioid receptors.Methods IEC-6 cells were divided into 5 groups (n=15 each) using a random number table:control group (group C),group OGD/R,oxycodone group (group O),μ opioid receptor antagonist CTOP plus oxycodone group (group CTOP+O) and κ opioid receptor antagonist BNI plus oxycodone group (group BNI+O).Cells were cultured for 8 h in normal culture atmosphere in group C.Cells were subjected to OGD for 4 h followed by restoration of oxygen-glucose supply in normal culture medium for 4 h in OGD/R,O,CTOP+O and BNI+O groups.Oxycodone at a final concentration of 1 μg/ml was added at 5 min before OGD/R in O,CTOP+O and BNI+O groups.CTOP and BNI at a final concentration of 5 μmol/L were added at 10 min before OGD/R in group CTOP+O and group BNI+O,respectively.Five holes in each group were selected at 8 h of OGD/R for determination of the cell viability (by MTT assay),lactic dehydrogenase (LDH) release rate (by colorimetry) and levels of tumor necrosis factor-alpha (TNF-α),interleukin-1beta (IL-1β) and high-mobility group box 1 protein (HMGB1) in supernatant (by enzyme-linked immunosorbent assay).Results Compared with group C,the cell viability was significantly decreased,and the LDH release rate and levels of TNF-α,IL-1β and HMGB1 were increased in OGD/R,O,CTOP+Oand BNI+ O groups (P＜ 0.05).Compared with group OGD/R,the cell viability was significantly increased,and the LDH release rate and levels of TNF-o,IL-1β and HMGB1 were decreased in group O (P＜0.05).Compared with group O,the cell viability was significantly decreased,and the LDH release rate and levels of TNF-α,IL-1β and HMGB1 were increased in CTOP+O and BNI+O groups (P＜0.05).Conclusion Oxycodone pretreatment can mitigate OGD/R-induced injury to small intestinal epithelial cells of rats and the mechanism is related to activating μ and κ opioid receptors.

Effects of U50488H on postoperative cognitive dysfunction induced by cardiopulmonary bypass in rats / 中华麻醉学杂志

Objective To investigate the effect of U50488H on postoperative cognitive dysfunction induced by cardiopulmonary bypass (CPB) in rats.Methods Forty-eight adult male Sprague-Dawley rats,weighing 400-450 g,were divided into 3 groups (n=16 each) using a random number table:sham operation group (group S),CPB group and CPB plus U50488H group (group U).CPB was performed for 60 min in group CPB.U50488H 1.5 mg/kg was injected into the left lateral cerebral ventricle at 30 min prior to CPB,and then CPB was performed for 60 min in group U.Eight rats in each group were selected at 1 day after CPB,and venous blood samples were collected for determination of serum S100β protein,interleukin-lbeta (IL-1 β) and tumor necrosis factor-alpha (TNF-α) concentrations (by enzyme-linked immunosorbent assay).Then the rats were sacrificed and right hippocampi were removed for examination of the pathological changes after haematoxylin and eosin staining.Eight rats were selected from each group at 7 days after CPB for assessment of cognitive function.Results Compared with group S,the concentrations of serum S100β protein,IL-1β and TNF-α were significantly increased in group CPB,and the escape latency was prolonged,the number of crossing original platform was reduced,and the swimming distance in target quadrant and time of staying at target quadrant were shortened in CPB and U groups (P＜0.05).Cormpared with group CPB,the concentrations of serum S100β protein,IL-1β and TNF-α were significantly decreased,the escape latency was shortened,the number of crossing original platform was increased,the swimming distance in target quadrant and time of staying at target quadrant were prolonged (P＜0.05),and the pathological changes of hippocampal tissues were significantly attenuated in group U.Conclusion U50488H can mitigate the postoperative cognitive dysfunction induced by CPB in rats.

Effect of oxycodone on migration of human colon cancer cells : the role of μ and κ receptors / 中华麻醉学杂志

Objective To evaluate the effect of oxycodone on migration of human colon cancer cells and the role of μ and κ receptors.Methods The human colon cancer HCT116 cells at the logarithmic growth phase were seeded in 24-well or in 6-well plates at a density of 1 × 106 cells/mnl (0.5 ml/well or 2 ml/well,144 wells in total).The cells were divided into 6 groups (n=24 each) using a random number table:control group (group C),1,5 and 10 μmol/L oxycodone groups (group O1,group O2 and group O3),oxycodone plus μ receptor antagonist CTOP group (group O2+CTOP) and oxycodone plus κ receptor antagonist nor-binaltorphimine group (group O2+BNI).The cells were incubated for 24 h with oxycodone 1,5 and 10 μmol/L in O1,O2 and O3 groups,respectively.The cells were incubated for 24 h with 5 μmol/L oxycodone plus 20 μmol/L CTOP and 5 μmol/L oxycodone plus nor-binahorphimin 20 μmol/L in O2+CTOP and O2+BNI groups,respectively.The invaded and migrated cells were counted,and the levels of Ras homolog gene family member A (RhoA),Rho-associated protein kinase 1 (ROCK1),matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected.Results Compared with group C,the number of invaded and migrated cells was gradually decreased,and the levels of RhoA,ROCK1,MMP-2 and MMP9 were gradually decreased in O1,O2 and O3 groups (P＜0.05),and no significant change was found in the parameters mentioned above in group O2+BNI (P＞0.05).Compared with group O2,the number of invaded and migrated cells was significantly increased,and the levels of RhoA,ROCK1,MMP-2 and MMP9 were increased in group O2 + BNI (P＜0.05),and no significant change was found in the parameters mentioned above in group O2+CTOP (P＞0.05).Conclusion Oxyc odone can inhibit the migration of human colon cancer cells,and the mechanism is totally related to inhibition of RhoA/ROCKl signaling pathway activation after activating κ receptors,but not related to μ receptors.

Role of δ-opioid receptors in hydromorphone postconditioning-induced maintenance of electrophysio-logical stability during ischemia-reperfusion in isolated rat hearts / 中华麻醉学杂志

Objective To evaluate the role of δ-opioid receptors in hydromorphone postcondition-ing-induced maintenance of electrophysiological stability during ischemia-reperfusion(I∕R)in isolated rat hearts. Methods Healthy male Sprague-Dawley rats, aged 2-3 months, weighing 280-360 g, were used in this study. The animals were anesthetized with intraperitoneal pentobarbital 60 mg∕kg. Their hearts were immediately removed and perfused in a Langendorff apparatus. Thirty-two isolated hearts were divided into 4 groups after successful preparation of Langendorff perfusion model(n=8 each)using a random number ta-ble: control group(group C), group I∕R, hydromorphone postconditioning group(group HP)and hydro-morphone plus δ-opioid receptor antagonist naltridole postconditioning group(group HNP). In HP and HNP groups, the hearts were perfused for 10 min with K-H solution containing 41 ng∕ml hydromorphone and 41 ng∕ml hydromorphone plus 5 μmol∕L naltridole, respectively, and then with K-H solution for 50 min. At 20 min of stabilization(T0)and 10, 25 and 60 min of reperfusion(T1-2), heart rate(HR), monophasic action potential(MAP)duration at 90% repolarization(MAPD90)of the two layers(endocar-dium, epicardium)of the anterior left ventricular wall were recorded. Transmural dispersion of repolariza-tion(TDR)was calculated. The development of arrhythmia, time for restoration of spontaneous heart beat and duration of arrhythmia were recorded during the period of reperfusion. Results Compared with group C, MAPD90of endocardium at T1-2and MAPD90of epicardium at T1were significantly prolonged in I∕R and HP groups, HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3in group HNP, TDR was significantly enlarged at T1in group I∕R and at T2in group HNP, and TDR was decreased at T3in group HP(P<005). Compared with group I∕R, no significant change was found in arrhythmia score(P>005), the time for restoration of spontaneous heart beat was significantly shortened, and TDR was decreased at T1in HP and HNP groups, duration of arrhythmia was significantly shortened, and MAPD90of endocardium was shortened at T1in group HP, and HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was decreased at T2-3in group HNP(P<005). Compared with group HP, no significant change was found in time for restoration of spon-taneous heart beat, duration of arrhythmia or arrhythmia score(P>005), HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was increased at T3in group HNP(P<005). Conclusion The mechanism underlying hydromorphone postconditioning-induced maintenance of electrophysiological stability during I∕R is related to activating δ-opioid receptors in isolated rat hearts.

Efficacy of nalmefene in preventing sufentanil-induced cough during induction of general anesthesia / 中华麻醉学杂志

Objective To evaluate the efficacy of nalmefene in preventing sufentanil-induced cough during induction of general anesthesia.Methods One hundred American Society of Anesthesiologists physical status Ⅰ orⅡ patients of both sexes,aged 21-62 yr,weighing 45-82 kg,undergoing elective laparoscopic cholecystectomy under general anesthesia,were divided into 2 groups (n =50 each) using a random number table:nalmefene group (group N) and control group (group C).Nalmefene 0.25 μg/kg was injected intravenously at 2 min before anesthesia induction in group N,and the equal volume of normal saline was given instead in group C.Anesthesia was induced with target-controlled infusion of propofol,and sufentanil 0.5 μg/kg was injected over 5 s when bispectral index value reached 55.The number of patients who developed cough within 2 min after sufentanil injection and severity of cough were observed.Other iv anesthetics were given for induction after the end of observation.Results The incidence of sufentanil-induced cough was 8％ in group N and 48％ in group C.Compared with group C,the incidence and severity of cough were significantly decreased in group N (P＜0.05).Conclusion Nalmefene 0.25 μg/kg injected at 2 min before induction of anesthesia can effectively decrease the development of sufentanil-induced cough during induction of general anesthesia.

Role of spinal κ-opioid receptors in remifentanil-induced postoperative central sensitization in a rat model of incisional pain: by in vivo electrophysiology / 中华麻醉学杂志

Objective To evaluate the role of spinal κ-opioid receptors in remifentanil-induced postoperative central sensitization in a rat model of incisional pain by in vivo electrophysiology.Methods Sixty adult male Sprague-Dawley rats in which intrathecal catheters were successfully implanted,weighing 230-270 g,were divided into 5 groups (n=12 each) using a random number table:control group (group C),incisional pain group (group I),remifentanil group (group R),remifentanil plus incisional pain group (group R+I),and κ-opioid receptor agonist U50488H group (group U).A 1 cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the right hind paw in isofiurane-anesthetized rats to establish the model of incisional pain.Remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg 1 · min-1 in group R.In group R+I,remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg-1 · min 1,and the model of incisional pain was established at the same time.In group U,U50488H 10 μg/10μl was injected intrathecally,30 min later remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg-1 · min-1,and the model of incisional pain was established.Six rats in each group were randomly selected,the mechanical pain threshold (MPT) was measured in bilateral hind paws before implanting intrathecal catheter (T0),before operation (T1),and at 1 h,4 h and 1,2 and 3 clays after operation (T2-6).Six rats in each group were randomly selected to record the C fiber-evoked filed potentials in the spinal dorsal horn from 60 min before administration or operation to 180 min after administration or operation,the long-term potentiation (LTP) induced was also recorded,and the area under the curve (AUC) of C-fiber-evoked field potentials was calculated.Results No LTP was recorded in C,I and U groups,and the LTP was recorded in R and R+I groups.Compared with group C,the MPT in bilateral hind paws at T5,6 was significantly decreased in group R,the MPT in ipsilateral hind paws at T2 6 was decreased in group I,the MPT in ipsilateral hind paws at T2-6 and in contralateral hind paws at T5,6 was decreased in group R+I,the MPT in ipsilateral hind paws at T2-4 was decreased in group U,and the AUC of C-fiber-evoked field potentials was increased in R and R+I groups (P＜0.05).Compared with group Ⅰ,the MPT in ipsilateral hind paws at T4-6 and in contralateral hind paws at T5,6 was significantly decreased,and the AUC of C-fiber-evoked field potentials was increased in group R+I (P＜0.05).Compared with group R+ I,the MPT in ipsilateral hind paws at T2-6 and in contralateral hind paws at T5,6 was significantly increased,and the AUC of C-fiber-evoked field potentials was decreased in group U (P＜0.05).Conclusion The results of in vivo electrophysiology confirm that inhibition of spinal κ-opioid receptor function mav be involved in the mechanism by which remifentanil induces postoperative central sensitization in a rat model of incisional pain.

Effect of opioid switch from morphine to sufentanil on expression of μ-opioid receptors in midbrain periaqueductal gray of rats / 中华麻醉学杂志

Objective To evaluate the effect of the opioid switch from morphine to sufentanil on the expression of μ-opioid receptors in the midbrain periaqueductal gray (PAG) of rats.Methods Forty healthy male Wistar rats,aged 8 weeks,weighing 250-290 g,were randomly assigned into 5 groups (n=8 each) using a random number table:control group (group C),7 day sufentanil group (group S),7 day morphine group (group M),14 day morphine group (group MM),and 14 day alternate administration of morphine and sufentanil group (group MS).Normal saline 2 ml/kg,sufentanil 0.01 mg/kg and morphine 10 mg/kg were injected subcutaneously in the cervical region twice a day for 7 consecutive days in C,S and M groups,respectively.In group MM,morphine 10 mg/kg was injected subcutaneously in the cervical region twice a day for 14 consecutive days.In group MS,morphine 10 mg/kg was injected subcutaneously in the cervical region twice a day for 7 consecutive days (1st-7th days),and sufentanil 0.01 mg/kg was then injected subcutaneously in the cervical region twice a day for 7 consecutive days (8th-14th days).The tail flick latency (TFL) to a thermal nociceptive stimulus was measured at 15 and 30 min after the initial administration every day.After the last administration,the rats were sacrificed,and the midbrain PAG was isolated for determination of the expression of the μ-opioid receptor and μ-opioid receptor mRNA using Western blot and real-time reverse transcriptase polymerase chain reaction,respectively.Results Compared with group C,the TFL was significantly prolonged on 1st-6th days after the beginning of administration in M,MM and MS groups,the TFL was significantly prolonged on 1st-7th days after the beginning of administration in group S,and the expression of the μ-opioid receptor and μ-opioid receptor mRNA in the midbrain PAG was significantly down-regulated in M,MM and MS groups (P＜0.05).Compared with group MM,the TFL was significantly prolonged on 8th-14th days after the beginning of administration,and the expression of the μ-opioid receptor and μ-opioid receptor mRNA in the midbrain PAG was significantly up-regulated in group MS (P＜0.05).Conclusion The mechanism by which the opioid switch from morphine to sufentanil reduces morphine tolerance is related to enhanced activity of μ-opioid receptors in the midbrain PAG of rats.

Progress in opioid receptor and opioids for the treatment of cancer pain / 肿瘤研究与临床

Cancer pain is the most important factor affecting the cancer patients' quality of life, and the approach to relieve and control cancer pain is becoming the focus. Pain mechanism research can offer solutions to pain treatment, such as blocking the happening and conduction of analgesia. The earliest μ, κ, σopioid receptors were found in the research of morphine and opioid peptides, especially μ receptor's leading role in pain treatment. Currently, μ opioid agonist is basically used in clinical pain treatment. Morphine, the third level drug, is still the classic pain therapy drugs. Novel drugs such as fentanyl transdermal and controlled-release oxycodone provide new ideas for the pain ease. Opioid combined with non-opioid drugs, the change of opioid drugs delivery way and joint application of controlled release drug and relievers, have dramatically reduced opioid drugs' side effects.