内吗啡肽、morphiceptin及其类似物对小鼠结肠运动功能的调节作用
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摘要
内吗啡肽(endomorphins,EMs)是1997年发现的高激动性、高选择性、内源性的μ-阿片受体(μOR)激动剂。经过十多年的研究发现EMs具有广泛的药理学和生理学活性。我们的研究发现endomorphin 1(10~(-9)-10~(-6)M,EM1),endomorphin 2(10~(-9)-10~(-6)M,EM2)能够剂量依赖地显著增强小鼠结肠的环形肌和纵形肌运动的基础收缩。阿托品(10~(-5)M),L-NAME(10~(-4)M),吲哚美欣(10~(-4)M),酚妥拉明(10~(-5)M),普洛奈尔(10~(-6)M),二甲麦角新甲(3×10~(-5)M),六甲胺(10~(-4)M)不能显著拮抗EMs(10~(-7)M)诱导结肠环形肌和纵形肌的自主收缩,而纳络酮(10~(-5)M)和河豚毒素(10~(-7)M)能完全拮抗此收缩效应。Naltrindole(NTI)(10~(-6)M)并不能显著拮抗EMs诱导的近端结肠环形肌和远端结肠纵形肌收缩。Nor-binaltorphimine(nor-BNI)(3×10~(-6)M)能够显著减弱EMs诱导的结肠纵形肌的收缩作用。值得注意的是,β-funaltrexamine(β-FNA)(6×10~(-6)M)不能完全拮抗EM2引起的结肠环形肌收缩。Naloxonazine(10~(-6)M)完全抑制了EM1,EM2(10~(-7)M)引起的结肠环形肌,纵形肌收缩,但这种抑制收缩作用仅部分可逆。同时,我们利用四氧嘧啶造糖尿病模型的方法研究了EMs对糖尿病小鼠结肠运动功能的调节作用,并发现与非糖尿病小鼠相比,EM1、EM2和carbachol诱导的结肠收缩作用都明显减弱。但是,与非糖尿病小鼠相比其调节机制却没有显著改变。
另外,我们合成了一系列EMs和morphiceptin的类似物并测定了它们的生理活性。我们发现类似物[D-1-Nal~4]EM2(10~(-8)-10~(-5)M)只能够十分微弱的增强小鼠远端结肠纵行肌的收缩,而且这种作用比EM2弱很多。但是当标本与[D-1-Nal~4]-EM2预孵育5 min之后能够剂量依赖(10~(-8)-10~(-5)M,浓度呈半对数增长)地拮抗EM1和EM2(10~(-7)M)诱导的远端结肠纵行肌的收缩。类似物[1-Nal~3]EM2(10~(-9)-10~(-6)M,浓度呈半对数增长)和[D-1-Nal~3]morphiceptin(10~(-9)-10~(-6)M,浓度呈半对数增长)能够显著地、剂量依赖地增强远端结肠纵行肌和近端结肠环形肌基础收缩作用。由[1-Nal~3]EM2和[D-1-Nal~3]morphiceptin引起的E_(max)分别是50.75±1.53%和56.42±1.48%。[1-Nal~3]EM2和[D-1-Nal~3]morphiceptin的EC_(50)值(分别是34.84±6.06 nM和55.21±11.49 nM)比EM1(8.27±3.21 nM)和EM2(7.97±2.97 nM)稍高但比吗啡(229±31 nM)低。这两个类似物诱导结肠收缩的机理与EMs是类似的。所不同的是,我们发现nor-BNI(10~(-6)M)能够显著减弱类似物[D-1-Nal~3]morphiceptin(10~(-6)M)-诱导的远端结肠纵行肌的收缩作用(与EM2相似),但不能够显著减弱[1-Nal~3]EM2(10~(-6)M)-诱导的远端结肠纵行肌的收缩作用(与EM2不同)。然而与nor-BNI相反,NTI(10~(-6)M)能够显著减弱[1-Nal~3]EM2(10~(-6)M)但不能够显著减弱[D-1-Nal~3]morphiceptin(10~(-6)M)诱导的远端结肠纵行肌的收缩作用。另外,与EMs一样,β-FNA(2.5×10~(-6)M),naloxonazine(10~(-6)M)和naloxone(10~(-5)M)都能够显著减弱[1-Nal~3]EM2-(10~(-6)M)和[D-1-Nal~3]morphiceptin-(10~(-6)M)诱导的远端结肠纵行肌和近端结肠环形肌基础收缩作用。
这些结果表明,EM1、EM2、[1-Nal~3]EM2、[D-1-Nal~4]EM2和[D-1-Nal~3]morphiceptin对小鼠结肠肠运动具有显著的调节作用,而且这种调节作用是通过激活内源性阿片受体(主要是μOR)而实现的。
EM1 and EM2 are newly discovered endogenousμOR ligands.However,the functional role of these EMs in colonic mobility remains unknown.The present investigation was undertaken to evaluate the effects of the EMs on the colonic mobility in vitro and to determine the mechanisms responsible for the muscle contraction induced by EMs.EMs(10~(-9)-10~(-6)M)caused significantly contractions in longitudinal and circular muscle of isolated colon.EMs-induced longitudinal or circular muscle contractions were not significantly affected by atropine,N~ω-nitro-L-arginine methyl ester(L-NAME),indomethacin,phentolamine,propranolol and methysergide. Tetrodotoxin and naloxone completely abolished EMs-induced longitudinal or circular muscle contractions without affecting contractions in response to carbachol. Surprisingly,EMs(10~(-7)M)-induced longitudinal muscle contractions were significantly attenuated by nor-binaltorphimine(nor-BNI)(3×10~(-6)M).By contrast,pretreatment with naltrindole(NTI)(10~(-6)M)did not significantly affect EMs-induced longitudinal or circular muscle contractions.Interestingly,the circular muscle contractions in response to EM2(10~(-7)M)were not fully blocked byβ-funaltrexamine(β-FNA)(6×10~(-6)M). Naloxonazine(10~(-6)M)almost fully abolished the EMs-induced longitudinal or circular muscle contractions,and these effects could be only partially reversed by extensive washing.All the results indicated that activation of multiple subtypes of opioid receptors,possiblyμ_1(naloxonazine-sensitive),μ_2 and even other forms ofμORs(β-FNA-insensitive),was required for EMs-induced mouse colonic mobility.And these results also indicated that the machanisms responsible for the contractile effects induced by EMs in the longitudinal muscle of distal colon and in the circular muscle of proximal colon may be different.
At 4 weeks and 8 weeks after the onset of diabetes,EMs and carbachol-induced contractions in the longitudinal muscle of distal colon were significantly reduced compared to those of non-diabetic mice.But mechanisms in both diabetes and non-diabetes were similar.All the results indicated that type 1 diabetes significantly attenuated the modulatory effects of EMs on the mouse colonic motility,but the mechanisms responsible for these effects were not significantly altered.
We also characterized the effects of endomorphin-2(Tyr~1-Pro~2-Phe~3-Phe~4-NH_2, EM2)and morphiceptin(Tyr~1-Pro~2-Phe~3-Pro~4-NH_2)analogs,in which Phe~3 or Phe~4/Pro~4 were substituted by naphthyl group-containing amino acids,on the colonic motility.[D-1-Nal~4]EM2 fail to significantly induce but can dose-dependently antagonize endomorphins(EMs)(10~(-7)M)-induced longitudinal muscle contractions.[1-Nal~3]EM2 and[D-1-Nal~3]morphiceptin displayed strong stimulatory effects(their EC_(50)values were 34.84±6.06 nM and 55.21±11.49 nM,respectively)on the colonic motility,and these were in agreement with the results obtained from binding assays and GPI/MVD assays.Tetrodotoxin(TTX,10~(-7)M)and naloxone(10~(-5)M)but not N~G-nitro-L-arginine methyl ester(L-NAME)(10~(-4)M)completely abolished the[1-Nal~3]EM2-(10~(-6)M)and [D-1-Nal~3]morphiceptin(10~(-6)M)-induced colonic contractions.β-funaltrexamine(β-FNA)(2.5×10~(-6)M)and naloxonazine(10~(-6)M)significantly reduced but not fully blocked longitudinal and circular muscle contractions in response to[1-Nal~3]EM2(10~(-6) M)and[D-1-Nal~3]-morphiceptin(10~(-6)M).Interestingly,nor-binaltorphimine(nor-BNI) (10~(-6)M)significantly attenuated[D-1-Nal~3]morphiceptin(10~(-6)M)-but not[1-Nal~3]EM2(10~(-6)M)-induced colonic contractions.However,naltrindole(NTI)(10~(-6)M) was able to antagonize[1-Nal~3]EM2(10~(-6)M)-but not[D-1-Nal~3]morphiceptin(10~(-6) M)-induced colonic contractions.These results suggest that opoiod receptors especiallyμ-opioid receptor play critical role in the modulation of analogs[1-Nal~3]EM2-and[D-1-Nal~3]morphiceptin-induced mouse colonic motility and the heterocyclic modifications on the position 3 and 4 significantly change the effects and mechanisms of EM2 and morphiceptin on the colonic motility.
另外,我们合成了一系列EMs和morphiceptin的类似物并测定了它们的生理活性。我们发现类似物[D-1-Nal~4]EM2(10~(-8)-10~(-5)M)只能够十分微弱的增强小鼠远端结肠纵行肌的收缩,而且这种作用比EM2弱很多。但是当标本与[D-1-Nal~4]-EM2预孵育5 min之后能够剂量依赖(10~(-8)-10~(-5)M,浓度呈半对数增长)地拮抗EM1和EM2(10~(-7)M)诱导的远端结肠纵行肌的收缩。类似物[1-Nal~3]EM2(10~(-9)-10~(-6)M,浓度呈半对数增长)和[D-1-Nal~3]morphiceptin(10~(-9)-10~(-6)M,浓度呈半对数增长)能够显著地、剂量依赖地增强远端结肠纵行肌和近端结肠环形肌基础收缩作用。由[1-Nal~3]EM2和[D-1-Nal~3]morphiceptin引起的E_(max)分别是50.75±1.53%和56.42±1.48%。[1-Nal~3]EM2和[D-1-Nal~3]morphiceptin的EC_(50)值(分别是34.84±6.06 nM和55.21±11.49 nM)比EM1(8.27±3.21 nM)和EM2(7.97±2.97 nM)稍高但比吗啡(229±31 nM)低。这两个类似物诱导结肠收缩的机理与EMs是类似的。所不同的是,我们发现nor-BNI(10~(-6)M)能够显著减弱类似物[D-1-Nal~3]morphiceptin(10~(-6)M)-诱导的远端结肠纵行肌的收缩作用(与EM2相似),但不能够显著减弱[1-Nal~3]EM2(10~(-6)M)-诱导的远端结肠纵行肌的收缩作用(与EM2不同)。然而与nor-BNI相反,NTI(10~(-6)M)能够显著减弱[1-Nal~3]EM2(10~(-6)M)但不能够显著减弱[D-1-Nal~3]morphiceptin(10~(-6)M)诱导的远端结肠纵行肌的收缩作用。另外,与EMs一样,β-FNA(2.5×10~(-6)M),naloxonazine(10~(-6)M)和naloxone(10~(-5)M)都能够显著减弱[1-Nal~3]EM2-(10~(-6)M)和[D-1-Nal~3]morphiceptin-(10~(-6)M)诱导的远端结肠纵行肌和近端结肠环形肌基础收缩作用。
这些结果表明,EM1、EM2、[1-Nal~3]EM2、[D-1-Nal~4]EM2和[D-1-Nal~3]morphiceptin对小鼠结肠肠运动具有显著的调节作用,而且这种调节作用是通过激活内源性阿片受体(主要是μOR)而实现的。
EM1 and EM2 are newly discovered endogenousμOR ligands.However,the functional role of these EMs in colonic mobility remains unknown.The present investigation was undertaken to evaluate the effects of the EMs on the colonic mobility in vitro and to determine the mechanisms responsible for the muscle contraction induced by EMs.EMs(10~(-9)-10~(-6)M)caused significantly contractions in longitudinal and circular muscle of isolated colon.EMs-induced longitudinal or circular muscle contractions were not significantly affected by atropine,N~ω-nitro-L-arginine methyl ester(L-NAME),indomethacin,phentolamine,propranolol and methysergide. Tetrodotoxin and naloxone completely abolished EMs-induced longitudinal or circular muscle contractions without affecting contractions in response to carbachol. Surprisingly,EMs(10~(-7)M)-induced longitudinal muscle contractions were significantly attenuated by nor-binaltorphimine(nor-BNI)(3×10~(-6)M).By contrast,pretreatment with naltrindole(NTI)(10~(-6)M)did not significantly affect EMs-induced longitudinal or circular muscle contractions.Interestingly,the circular muscle contractions in response to EM2(10~(-7)M)were not fully blocked byβ-funaltrexamine(β-FNA)(6×10~(-6)M). Naloxonazine(10~(-6)M)almost fully abolished the EMs-induced longitudinal or circular muscle contractions,and these effects could be only partially reversed by extensive washing.All the results indicated that activation of multiple subtypes of opioid receptors,possiblyμ_1(naloxonazine-sensitive),μ_2 and even other forms ofμORs(β-FNA-insensitive),was required for EMs-induced mouse colonic mobility.And these results also indicated that the machanisms responsible for the contractile effects induced by EMs in the longitudinal muscle of distal colon and in the circular muscle of proximal colon may be different.
At 4 weeks and 8 weeks after the onset of diabetes,EMs and carbachol-induced contractions in the longitudinal muscle of distal colon were significantly reduced compared to those of non-diabetic mice.But mechanisms in both diabetes and non-diabetes were similar.All the results indicated that type 1 diabetes significantly attenuated the modulatory effects of EMs on the mouse colonic motility,but the mechanisms responsible for these effects were not significantly altered.
We also characterized the effects of endomorphin-2(Tyr~1-Pro~2-Phe~3-Phe~4-NH_2, EM2)and morphiceptin(Tyr~1-Pro~2-Phe~3-Pro~4-NH_2)analogs,in which Phe~3 or Phe~4/Pro~4 were substituted by naphthyl group-containing amino acids,on the colonic motility.[D-1-Nal~4]EM2 fail to significantly induce but can dose-dependently antagonize endomorphins(EMs)(10~(-7)M)-induced longitudinal muscle contractions.[1-Nal~3]EM2 and[D-1-Nal~3]morphiceptin displayed strong stimulatory effects(their EC_(50)values were 34.84±6.06 nM and 55.21±11.49 nM,respectively)on the colonic motility,and these were in agreement with the results obtained from binding assays and GPI/MVD assays.Tetrodotoxin(TTX,10~(-7)M)and naloxone(10~(-5)M)but not N~G-nitro-L-arginine methyl ester(L-NAME)(10~(-4)M)completely abolished the[1-Nal~3]EM2-(10~(-6)M)and [D-1-Nal~3]morphiceptin(10~(-6)M)-induced colonic contractions.β-funaltrexamine(β-FNA)(2.5×10~(-6)M)and naloxonazine(10~(-6)M)significantly reduced but not fully blocked longitudinal and circular muscle contractions in response to[1-Nal~3]EM2(10~(-6) M)and[D-1-Nal~3]-morphiceptin(10~(-6)M).Interestingly,nor-binaltorphimine(nor-BNI) (10~(-6)M)significantly attenuated[D-1-Nal~3]morphiceptin(10~(-6)M)-but not[1-Nal~3]EM2(10~(-6)M)-induced colonic contractions.However,naltrindole(NTI)(10~(-6)M) was able to antagonize[1-Nal~3]EM2(10~(-6)M)-but not[D-1-Nal~3]morphiceptin(10~(-6) M)-induced colonic contractions.These results suggest that opoiod receptors especiallyμ-opioid receptor play critical role in the modulation of analogs[1-Nal~3]EM2-and[D-1-Nal~3]morphiceptin-induced mouse colonic motility and the heterocyclic modifications on the position 3 and 4 significantly change the effects and mechanisms of EM2 and morphiceptin on the colonic motility.
引文
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