异氟烷在脊髓水平的镇痛作用及其相关机制研究
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摘要
在科学技术迅猛发展的今天,一种不同于睡眠状态,没有意识,没有记忆,没有本能反映,没有疼痛,可逆性的麻醉状态之谜仍然悬而未解。全麻作用包括镇痛、镇静、肌松和无应激反应四大要素,以往针对全麻机理的研究结果基本上都是反应吸入麻醉四大要素的综合作用,这四者之间既相对独立、又存在复杂的内在联系,其对应的中枢作用区域和神经生理机制也存在较大的差异。多年的采用传统吸入给药方法的研究证明,吸入麻醉多种药理学效应不加区分综合研究的结果是很难取得突破性进展。
研究目的:
本研究率先采用鞘内给药技术,使异氟烷直接作用于脊髓,同时综合应用痛行为学、免疫组织化学、RT-PCR等研究方法,从脊髓水平直接探索:①异氟烷原液和乳化异氟烷在脊髓水平能否产生镇痛作用?②异氟烷原液和乳化异氟烷对脊髓Fos蛋白和c-fos mRNA表达的影响如何?研究结果为揭示吸入麻醉药在脊髓水平的镇痛作用及机制提供直接的理论依据。
研究方法:
第一部分:异氟烷原液鞘内给药的镇痛作用研究成年雄性大鼠随机分为6组,每组6只,随机均分为:A组:鞘内给予生理盐水50μl/kg;B组:鞘内给予异氟烷50μl/kg;C组:鞘内给予异氟烷25μl/kg;D组:鞘内给予生理盐水50μl/kg;E组:鞘内给予异氟烷50μl/kg;F组:鞘内给予异氟烷25μl/kg。A、B和C三组进行福尔马林实验和免疫组化实验,D、E和F三组进行Von Frey实验、Hargreaves实验和实时定量PCR实验。
第二部分:乳化异氟烷鞘内给药的镇痛作用机制研究成年雄性大鼠随机分为6组,每组6只,随机均分为:A组:鞘内给予生理盐水50μl/kg;B组:鞘内给予乳化异氟烷50μl/kg;C组:鞘内给予乳化异氟烷25μl/kg;D组:鞘内给予生理盐水50μl/kg;E组:鞘内给予乳化异氟烷50μl/kg;F组:鞘内给予乳化异氟烷25μl/kg。A、B和C三组进行福尔马林实验和免疫组化实验,D、E和F三组进行Von Frey实验、Hargreaves实验和实时定量PCR实验。
研究结果:
1.异氟烷原液和乳化异氟烷在脊髓水平镇痛作用应用鞘内注射异氟烷原液和乳化异氟烷和痛行为学相结合方法研究结果表明:①给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够明显抑制福尔马林诱发的抬足反射;②给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够显著延长热刺激的反应潜伏期;③给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够有效提高机械刺激的反应阈值。
2.异氟烷原液和乳化异氟烷对脊髓Fos蛋白和c-fos mRNA表达的影响应用鞘内注射异氟烷原液和乳化异氟烷、免疫组织化学和RT-PCR相结合技术研究结果表明:①鞘内给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够明显抑制Fos蛋白在脊髓的表达;②大鼠脊髓腰膨大段处,鞘内给予不同剂量的生理盐水(50μl/kg和25μl/kg)、异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)。结果显示:异氟烷原液和乳化异氟烷各组的c-fos mRNA表达明显低于生理盐水对应组。
3.异氟烷原液和乳化异氟烷在脊髓水平镇痛作用比较①异氟烷原液(50μl/kg)组对福尔马林诱发的大鼠抬足反射的抑制在5min、15min和25~35min强于乳化异氟烷(50μl/kg)组,而在55~60min则弱于乳化异氟烷(50μl/kg)组;②异氟烷原液(50μl/kg)组在10~15min热反射潜伏期明显长于乳化异氟烷(50μl/kg)组,而在25min热反射潜伏期明显短于乳化异氟烷(50μl/kg)组;③异氟烷原液(50μl/kg)组和乳化异氟烷(50μl/kg)组在给药前大鼠抬足的阈值无明显差别,而在给药10min后的阈值异氟烷原液(50μl/kg)组高于乳化异氟烷(50μl/kg)组;④给予5%福尔马林50μl 2h后大鼠脊髓背角的Fos蛋白的表达,发现无论是在I-II层还是III-VI层,异氟烷原液(50μl/kg)组FLI神经元数目都明显高于乳化异氟烷(50μl/kg)组;⑤给予5%福尔马林50μl 2h后大鼠脊髓背角的c-fos mRNA的表达,发现异氟烷原液(50μl/kg)组c-fos mRNA的表达明显高于乳化异氟烷(50μl/kg)组,而两组c-fos mRNA的表达都明显低于生理盐水(50μl/kg)组。
研究结论:异氟烷原液和乳化异氟烷直接作用于脊髓水平均能够产生明显的镇痛作用,其部分作用机制与抑制脊髓Fos蛋白和c-fos mRNA表达有关。
With technology developing quickly, the drugged state is still obscure which is not same as dormancy, without memoy, without instinct, without pain. The general anesthesia includes analgesia, sedation, muscle relaxation and immobility in response to pain. In previous studies, the four elements were mixed. It mixed multiple effects so that we can not know the mechanisms inhalation anesthetics produce anti-nociception.
Objective:
In our study, we administered isoflurane by intrathecal administration directly to the spinal cord for the first time. By using behavioral, immunohistochemistry and RT-PCR research works, we studied below problems:
1.Can isoflurane liquid and emulsified isoflurane exert antinociceptive effects at the spinal level?
2. Can isoflurane liquid and emulsified isoflurane alter Fos protein and the c-fos expression in the dorsalhorn of spinal cord?
Our results can provide direct evidence that inhalation anesthetics produce anti-nociception at the spinal level.
Methods:
We observed the change of the number of flinches of the injected paw of intrathecal isoflurane liquid and emulsified isoflurane. Moreover, the rat’s paw withdrawal threshold for mechanical stimuli and latency forheat stimuli were measured. At the same time, we also observed the effects of isoflurane liquid and emulsified isoflurane on Fos protein and the c-fos expression in the dorsalhorn of spinal cord by using immunohistochemistry technique.
Results:
A: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can inhibit the flinching induced by formalin.
B: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can prolong the rat’s paw withdrawal latency forheat stimuli.
C: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can increase the rat’s paw withdrawal threshold for mechanical stimuli.
D: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can inhibit Fos protein expression in the dorsalhorn of spinal cord.
E: The c-fos expression in groups of the intrathecal administration of isoflurane liqid or emulsified isoflurane was lower than that of group of the intrathecal administration of saline significantly.
Conclusion:
The results indicate that intrathecal administration of isoflurane liquid or emulsified isoflurane exert antinociceptive effects at the spinal level.
研究目的:
本研究率先采用鞘内给药技术,使异氟烷直接作用于脊髓,同时综合应用痛行为学、免疫组织化学、RT-PCR等研究方法,从脊髓水平直接探索:①异氟烷原液和乳化异氟烷在脊髓水平能否产生镇痛作用?②异氟烷原液和乳化异氟烷对脊髓Fos蛋白和c-fos mRNA表达的影响如何?研究结果为揭示吸入麻醉药在脊髓水平的镇痛作用及机制提供直接的理论依据。
研究方法:
第一部分:异氟烷原液鞘内给药的镇痛作用研究成年雄性大鼠随机分为6组,每组6只,随机均分为:A组:鞘内给予生理盐水50μl/kg;B组:鞘内给予异氟烷50μl/kg;C组:鞘内给予异氟烷25μl/kg;D组:鞘内给予生理盐水50μl/kg;E组:鞘内给予异氟烷50μl/kg;F组:鞘内给予异氟烷25μl/kg。A、B和C三组进行福尔马林实验和免疫组化实验,D、E和F三组进行Von Frey实验、Hargreaves实验和实时定量PCR实验。
第二部分:乳化异氟烷鞘内给药的镇痛作用机制研究成年雄性大鼠随机分为6组,每组6只,随机均分为:A组:鞘内给予生理盐水50μl/kg;B组:鞘内给予乳化异氟烷50μl/kg;C组:鞘内给予乳化异氟烷25μl/kg;D组:鞘内给予生理盐水50μl/kg;E组:鞘内给予乳化异氟烷50μl/kg;F组:鞘内给予乳化异氟烷25μl/kg。A、B和C三组进行福尔马林实验和免疫组化实验,D、E和F三组进行Von Frey实验、Hargreaves实验和实时定量PCR实验。
研究结果:
1.异氟烷原液和乳化异氟烷在脊髓水平镇痛作用应用鞘内注射异氟烷原液和乳化异氟烷和痛行为学相结合方法研究结果表明:①给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够明显抑制福尔马林诱发的抬足反射;②给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够显著延长热刺激的反应潜伏期;③给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够有效提高机械刺激的反应阈值。
2.异氟烷原液和乳化异氟烷对脊髓Fos蛋白和c-fos mRNA表达的影响应用鞘内注射异氟烷原液和乳化异氟烷、免疫组织化学和RT-PCR相结合技术研究结果表明:①鞘内给予不同剂量异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)均能够明显抑制Fos蛋白在脊髓的表达;②大鼠脊髓腰膨大段处,鞘内给予不同剂量的生理盐水(50μl/kg和25μl/kg)、异氟烷原液(50μl/kg和25μl/kg)和乳化异氟烷(50μl/kg和25μl/kg)。结果显示:异氟烷原液和乳化异氟烷各组的c-fos mRNA表达明显低于生理盐水对应组。
3.异氟烷原液和乳化异氟烷在脊髓水平镇痛作用比较①异氟烷原液(50μl/kg)组对福尔马林诱发的大鼠抬足反射的抑制在5min、15min和25~35min强于乳化异氟烷(50μl/kg)组,而在55~60min则弱于乳化异氟烷(50μl/kg)组;②异氟烷原液(50μl/kg)组在10~15min热反射潜伏期明显长于乳化异氟烷(50μl/kg)组,而在25min热反射潜伏期明显短于乳化异氟烷(50μl/kg)组;③异氟烷原液(50μl/kg)组和乳化异氟烷(50μl/kg)组在给药前大鼠抬足的阈值无明显差别,而在给药10min后的阈值异氟烷原液(50μl/kg)组高于乳化异氟烷(50μl/kg)组;④给予5%福尔马林50μl 2h后大鼠脊髓背角的Fos蛋白的表达,发现无论是在I-II层还是III-VI层,异氟烷原液(50μl/kg)组FLI神经元数目都明显高于乳化异氟烷(50μl/kg)组;⑤给予5%福尔马林50μl 2h后大鼠脊髓背角的c-fos mRNA的表达,发现异氟烷原液(50μl/kg)组c-fos mRNA的表达明显高于乳化异氟烷(50μl/kg)组,而两组c-fos mRNA的表达都明显低于生理盐水(50μl/kg)组。
研究结论:异氟烷原液和乳化异氟烷直接作用于脊髓水平均能够产生明显的镇痛作用,其部分作用机制与抑制脊髓Fos蛋白和c-fos mRNA表达有关。
With technology developing quickly, the drugged state is still obscure which is not same as dormancy, without memoy, without instinct, without pain. The general anesthesia includes analgesia, sedation, muscle relaxation and immobility in response to pain. In previous studies, the four elements were mixed. It mixed multiple effects so that we can not know the mechanisms inhalation anesthetics produce anti-nociception.
Objective:
In our study, we administered isoflurane by intrathecal administration directly to the spinal cord for the first time. By using behavioral, immunohistochemistry and RT-PCR research works, we studied below problems:
1.Can isoflurane liquid and emulsified isoflurane exert antinociceptive effects at the spinal level?
2. Can isoflurane liquid and emulsified isoflurane alter Fos protein and the c-fos expression in the dorsalhorn of spinal cord?
Our results can provide direct evidence that inhalation anesthetics produce anti-nociception at the spinal level.
Methods:
We observed the change of the number of flinches of the injected paw of intrathecal isoflurane liquid and emulsified isoflurane. Moreover, the rat’s paw withdrawal threshold for mechanical stimuli and latency forheat stimuli were measured. At the same time, we also observed the effects of isoflurane liquid and emulsified isoflurane on Fos protein and the c-fos expression in the dorsalhorn of spinal cord by using immunohistochemistry technique.
Results:
A: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can inhibit the flinching induced by formalin.
B: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can prolong the rat’s paw withdrawal latency forheat stimuli.
C: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can increase the rat’s paw withdrawal threshold for mechanical stimuli.
D: Intrathecal isoflurane liquid(50μl/kg and 25μl/kg) and emulsified isoflurane(50μl/kg and 25μl/kg) can inhibit Fos protein expression in the dorsalhorn of spinal cord.
E: The c-fos expression in groups of the intrathecal administration of isoflurane liqid or emulsified isoflurane was lower than that of group of the intrathecal administration of saline significantly.
Conclusion:
The results indicate that intrathecal administration of isoflurane liquid or emulsified isoflurane exert antinociceptive effects at the spinal level.
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