OBJECTIVE Thienorphine,a new oripavine derivative,has shown to possess stronger antinociceptive effects and better oral bioavailability compared to buprenorphine.The present study examines the effect of thienorphine o...OBJECTIVE Thienorphine,a new oripavine derivative,has shown to possess stronger antinociceptive effects and better oral bioavailability compared to buprenorphine.The present study examines the effect of thienorphine on c AMP-dependent protein kinase A(PKA) activity in CHO cells expressing μ-,κ-,δ-and ORL1 receptors.In addition,we further examined its analgesic effect in vivo.METHODS The effect of thienorphine on cA MP-dependent PKA redistribution and cA MP inhibition were analyzed in CHO-PKAcatEGFP cells.PKA redistribution assays in CHO-PKAcatEGFP cells stably expressing μ-,κ-,δ-and ORL1 receptors were analyzed by high-throughput screening system to elucidate the efficacy of agonists or antagonists on opioid receptors.Moroever,the antinociceptive effects of thienorphine in vivo were examined using hot plate test.RESULTS Briefly,the maximum inhibition of thienorphine on PKA activity was about 36%,100%,100%and 12% in CHO-μ/κ/δ/ORL1-PKAcatE GFP cel s,respectively.In addition,thienorphine concentrationdependently inhibited the PKA activity with EC50 value of(22.7±18.1) nmol·L^(-1) in CHO-κ-PKAcatE GFP cels and(12.4±7.7) nmol·L^(-1) in CHO-δ-PKAcatE GFP cells.Thienorphine induced approximately 50%antinociceptive effect in mice lacking μ receptors compared to their wild-type controls(P<0.05).Also,the κ and δ selective antagonist nor-binaltorphimine,naltrindole decreased approximately 50%-60% in % MPE of theinorphine in μ-KO mice,respectively.The ORL1 receptor selective antagonist J113397 had no effect in %MPE of theinorphine in μ-KO mice.CONCLUSION Thienorphine induces analgesia through bindingκ-and δ-,or by partially binding μ-opioid receptor,thus further regulating the cAMP-PKA activity.Therefore,thienorphine may be used in acute or chronic pain with minimal addictive potential.展开更多
OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel m...OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.展开更多
目的探讨不同剂量右美托咪定复合舒芬太尼用于口腔癌患者围手术期镇痛的疗效及对睡眠质量的影响。方法前瞻性选取2023年1月至2024年6月医院收治的口腔癌手术患者158例,采用随机数字表法分为A组[n=53,0.6μg/(kg·h)右美托咪定+2μg...目的探讨不同剂量右美托咪定复合舒芬太尼用于口腔癌患者围手术期镇痛的疗效及对睡眠质量的影响。方法前瞻性选取2023年1月至2024年6月医院收治的口腔癌手术患者158例,采用随机数字表法分为A组[n=53,0.6μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]、B组[n=53,0.4μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]、C组[n=52,0.2μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]。比较3组应激反应指标[脑源性神经营养因子(BDNF)、皮质醇(Cor)、白细胞介素-6(IL-6)]、围术期镇静镇痛指标[脑电双频指数(BIS)、镇痛/伤害刺激指数(ANI)]、疼痛水平、T淋巴细胞亚群CD3^(+)、CD4^(+)、CD8^(+)水平、理查兹-坎贝尔睡眠量表(RCSQ)评分及不良反应。结果与术前12 h比较,术后48 h 3组血清BDNF、Cor、IL-6水平均降低,A组低于B组、C组,B组低于C组(P<0.05);与麻醉前(T_(0))时相比,3组插管时、插管后1、5 min(T_(1)~T_(3))时间BIS差异均有统计学意义(P<0.05),T_(1)~T_(3)时BIS均低于T_(0)时(P<0.05),3组组间相同时间点BIS比较差异无统计学意义(P>0.05),T_(1)~T_(3)时ANI高于T_(0)时,A组ANI高于B组、C组(P<0.05);与术前比较,术后1、6、24、48 h 3组疼痛评分均降低,A组低于B组、C组,B组低于C组(P<0.05);与术前相比,术后3组CD3^(+)、CD4^(+)均降低,A组低于B组、C组,B组低于C组(P<0.05),3组CD8^(+)均升高,A组高于B组、C组,B组高于C组(P<0.05);与术前1 d相比,术后当晚、术后第2晚3组睡眠质量评分均降低,A组低于B组、C组,B组低于C组(P<0.05)。A组低血压、窦性心动过缓发生率高于B组、C组(P<0.05),B组、C组低血压、窦性心动过缓发生率差异无统计学意义(P>0.05),3组恶心呕吐、头晕发生率差异无统计学意义(P>0.05)。结论0.6μg/(kg·h)右美托咪定复合舒芬太尼用于口腔癌手术患者可减轻机体应激反应和免疫抑制,改善睡眠质量,但术中低血压和窦性心动过缓发生率较高。展开更多
基金National Natural Science Foundation of China(8147319481773709).
文摘OBJECTIVE Thienorphine,a new oripavine derivative,has shown to possess stronger antinociceptive effects and better oral bioavailability compared to buprenorphine.The present study examines the effect of thienorphine on c AMP-dependent protein kinase A(PKA) activity in CHO cells expressing μ-,κ-,δ-and ORL1 receptors.In addition,we further examined its analgesic effect in vivo.METHODS The effect of thienorphine on cA MP-dependent PKA redistribution and cA MP inhibition were analyzed in CHO-PKAcatEGFP cells.PKA redistribution assays in CHO-PKAcatEGFP cells stably expressing μ-,κ-,δ-and ORL1 receptors were analyzed by high-throughput screening system to elucidate the efficacy of agonists or antagonists on opioid receptors.Moroever,the antinociceptive effects of thienorphine in vivo were examined using hot plate test.RESULTS Briefly,the maximum inhibition of thienorphine on PKA activity was about 36%,100%,100%and 12% in CHO-μ/κ/δ/ORL1-PKAcatE GFP cel s,respectively.In addition,thienorphine concentrationdependently inhibited the PKA activity with EC50 value of(22.7±18.1) nmol·L^(-1) in CHO-κ-PKAcatE GFP cels and(12.4±7.7) nmol·L^(-1) in CHO-δ-PKAcatE GFP cells.Thienorphine induced approximately 50%antinociceptive effect in mice lacking μ receptors compared to their wild-type controls(P<0.05).Also,the κ and δ selective antagonist nor-binaltorphimine,naltrindole decreased approximately 50%-60% in % MPE of theinorphine in μ-KO mice,respectively.The ORL1 receptor selective antagonist J113397 had no effect in %MPE of theinorphine in μ-KO mice.CONCLUSION Thienorphine induces analgesia through bindingκ-and δ-,or by partially binding μ-opioid receptor,thus further regulating the cAMP-PKA activity.Therefore,thienorphine may be used in acute or chronic pain with minimal addictive potential.
基金National Natural Science Foundation of China(8167328281273355).
文摘OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.
文摘目的探讨不同剂量右美托咪定复合舒芬太尼用于口腔癌患者围手术期镇痛的疗效及对睡眠质量的影响。方法前瞻性选取2023年1月至2024年6月医院收治的口腔癌手术患者158例,采用随机数字表法分为A组[n=53,0.6μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]、B组[n=53,0.4μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]、C组[n=52,0.2μg/(kg·h)右美托咪定+2μg/kg舒芬太尼]。比较3组应激反应指标[脑源性神经营养因子(BDNF)、皮质醇(Cor)、白细胞介素-6(IL-6)]、围术期镇静镇痛指标[脑电双频指数(BIS)、镇痛/伤害刺激指数(ANI)]、疼痛水平、T淋巴细胞亚群CD3^(+)、CD4^(+)、CD8^(+)水平、理查兹-坎贝尔睡眠量表(RCSQ)评分及不良反应。结果与术前12 h比较,术后48 h 3组血清BDNF、Cor、IL-6水平均降低,A组低于B组、C组,B组低于C组(P<0.05);与麻醉前(T_(0))时相比,3组插管时、插管后1、5 min(T_(1)~T_(3))时间BIS差异均有统计学意义(P<0.05),T_(1)~T_(3)时BIS均低于T_(0)时(P<0.05),3组组间相同时间点BIS比较差异无统计学意义(P>0.05),T_(1)~T_(3)时ANI高于T_(0)时,A组ANI高于B组、C组(P<0.05);与术前比较,术后1、6、24、48 h 3组疼痛评分均降低,A组低于B组、C组,B组低于C组(P<0.05);与术前相比,术后3组CD3^(+)、CD4^(+)均降低,A组低于B组、C组,B组低于C组(P<0.05),3组CD8^(+)均升高,A组高于B组、C组,B组高于C组(P<0.05);与术前1 d相比,术后当晚、术后第2晚3组睡眠质量评分均降低,A组低于B组、C组,B组低于C组(P<0.05)。A组低血压、窦性心动过缓发生率高于B组、C组(P<0.05),B组、C组低血压、窦性心动过缓发生率差异无统计学意义(P>0.05),3组恶心呕吐、头晕发生率差异无统计学意义(P>0.05)。结论0.6μg/(kg·h)右美托咪定复合舒芬太尼用于口腔癌手术患者可减轻机体应激反应和免疫抑制,改善睡眠质量,但术中低血压和窦性心动过缓发生率较高。
