Nω-nitro-L-arginine methyl ester inhibits the up-regulated expression of neuronal nitric oxide synthase/NMDA receptor in the morphine analgesia tolerance rats
- Author:
- No author available
- Journal Title:
- ACTA PHYSIOLOGICA SINICA
- Issue:
- 6
- DOI:
- 10.3321/j.issn:0371-0874.2006.06.012
- Key Word:
- 吗啡;镇痛耐受;一氧化氮合酶;N-甲基-D-天冬氨酸受体
Abstract： 采用热甩尾测痛法观察全身应用非特异性一氧化氮合酶(nitric oxide synthase,NOS)抑制剂--Nω-硝基-L-精氨酸甲酯(L-NAME)对吗啡镇痛耐受形成的影响,并通过观察脊髓和中脑神经元型NOS(nNOS)和N-甲基-D-天冬氨酸(NMDA)受体亚单位表达的变化来阐释NO/NMDA受体在吗啡镇痛耐受形成中的作用.将36只健康成年Sprague-Dawley大鼠平均分为6组(每组6只):1组为对照组,皮下注射生理盐水1 ml;2、3、4、5和6组为处理组,分别皮下注射L-NAME 10 mg/kg、L-NAME 20 mg/kg、吗啡10 mg/kg、L-NAME 10 mg/kg+吗啡10 mg/kg、L-NAME 20 mg/kg+吗啡10 mg/kg,每天2次.在注射前测量大鼠的热甩尾潜伏期(tail-flick latency,TFL)基础值,随后每天第一次给药50 min后测量其TFL.第8天最后一次给药80 min后(除2组和5组之外)断头取脊髓和中脑,采用RT-PCR技术测量nNOS以及NMDA受体1A(NR1A)和2A(NR2A)亚单位的表达.结果显示,2组大鼠第1天至第7天的TFL与基础值相比无显著差异;3组第7天时的TFL仍显著高于基础值;4组的TFL在第1天时最高,第2至第6天期间逐渐降低,第6天时与基础值相比无显著差异;5组的TFL在实验过程中呈下降趋势,虽然第7天时较第1天有所降低,但是仍然显著高于基础值;6组的TFL变化趋势与5组相同.PT-PCR分析结果显示,与1组相比,3组脊髓和中脑的nNOS mRNA表达显著降低,但NR1A mRNA和NR2A mRNA表达无显著改变;4组的nNOS mRNA、NR1A mRNA和NR2A mRNA表达均显著高于1组.与4组相比,6组的nNOS mRNA、NR1A mRNA和NR2A mRNA表达均显著降低.结果提示,吗啡镇痛耐受大鼠脊髓和中脑的nNOS和NMDA受体表达增加,联合应用L-NAME可抑制长期应用吗啡所致的nNOS表达增加和NMDA受体上调,延缓吗啡镇痛耐受的形成.本研究结果提示,脊髓和中脑的NO/NMDA受体与吗啡镇痛耐受形成密切相关.
- [1]刘惠芬,周文华,谢小虎,等.M受体对吗啡戒断大鼠脊髓和脑干NMDA受体基因表达及中脑导水管周围灰质中谷氨酸释放的调节[J].2004,(1).
- [2]Liang DY,Clark JD.Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice.[J].2004,365(1).
- [3]C S, Wong,M M, Hsu,Y Y, Chou,etc.Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord.[J].2000,85(4).
- [4]H, Machelska,B, Ziólkowska,J, Mika,etc.Chronic morphine increases biosynthesis of nitric oxide synthase in the rat spinal cord.[J].1997,8.
- [5]Christie MJ,Williams JT,Manzoni O.Cellular and synaptic adaptations mediating opioid dependence.[J].2001,81(1).
- [6]Beczkowska I.W.,Gracy K.N.,Pickel V.M.,etc.Detection of delta opioid receptor and N\u2010methyl\u2010D\u2010aspartate receptor\u2010like immunoreactivity in retinoic acid\u2010differentiated neuroblastoma x glioma (NG108\u201015) cells[J].1997.
- [7]H N, Bhargava,J T, Bian.N(G)-nitro-L-arginine reverses L-arginine induced changes in morphine antinociception and distribution of morphine in brain regions and spinal cord of the mouse.[J].1997,749(2).
- [8]Awobuluyi M,Lipton SA,Sucher NJ.Translationally distinct populations of NMDA receptor subunit NR1 mRNA in the developing rat brain.[J].2003,87(5).
- [9]Yaksh TL,Dunbar S.Effect of spinal infusion of L-NAME, a nitric oxide synthase inhibitor, on spinal tolerance and dependence induced by chronic intrathecal morphine in the rat.[J].1996,207(1).
- [10]N.H. Majeed,B. Przewłocka,H. Machelska,etc.Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice[J].1994,33(2).
- [11]Juan-Carlos Leza,Ignacio Lizasoain,Olivia San-Martín-Clark,etc.Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity[J].1995,285(1).
- [12]Bajo M,Roberto M,Madamba SG,etc.Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala.[J].2006,83(4).
- [13]Lizasoain I,Moro MA,Rodrigo J,etc.Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal.[J].2000,148(1).
- [14]Pollack GM,Heinzen EL.The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice.[J].2004,67(4).
- [15]Cebers G,Cebere A,Kovacs AD,etc.Increased ambient glutamate concentration alters the expression of NMDA receptor subunits in cerebellar granule neurons.[J].2001,39(2).
- [16]D S, Bredt,S H, Snyder.Nitric oxide, a novel neuronal messenger.[J].1992,8(1).
- [17]Y A, Kolesnikov,C G, Pick,G, Ciszewska,etc.Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.[J].1993,90.
- [18]Soares-Mota M,Henze I,Mendez-Otero R.Nitric oxide synthase-positive neurons in the rat superior colliculus: colocalization of NOS with NMDAR1 glutamate receptor, GABA, and parvalbumin.[J].2001,64(5).
- [19]Sakurada T,Watanabe C,Sakurada C,etc.Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats.[J].2003,990(1).
- [20]Zhu H,Brodsky M,Gorman AL,etc.Region-specific changes in NMDA receptor mRNA induced by chronic morphine treatment are prevented by the co-administration of the competitive NMDA receptor antagonist LY274614.[J].2003,114(2).
- [21]Pataki I,Telegdy G.Further evidence that nitric oxide modifies acute and chronic morphine actions in mice.[J].1998,357(2).
- [22]Nurten A,Yamanturk P,Nurten R,etc.The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine.[J].1999,39(4).