Study of inhibition of dimethyl sulfoxide on morphine-induced thermal hyperalgesia

doi:10.3969/j.issn.1009-976X.2013.06.015

Abstract

Abstract: 【Abstract】 Objective To explore the influence of dimethyl sulfoxide (DMSO) on morphine-induced thermal hyperalgesia and the expression of tumor necrosis factor-alpha (TNF-α) in the spinal cord dorsal horn. Methods Thirty-two SD rats were randomly divided into 4 groups, group A (saline + morphine group), group B (10% DMSO 5 mL/kg + morphine group), group C (10% DMSO 5 mL/kg + normal saline group) and group D (saline group). In each group, morphine or normal saline was injected subcutaneously 30 min after I.P normal saline or DMSO at 3 PM respectively. Paw withdrawal thermal latency (PWTL) were measured at 1 day before injection and 3, 6, 10 days after injection respectively and the expression of TNF alpha on spinal cord dorsal horn was detected. Results Compared with 1 day before injection, the PWTL of group A became shortened from 3 days after injection, and it further shortened at 10 day after injection respectively (P<0.01). There were significant differences in the shortening of PWTL between group A and group B 6 and 10 days after injection. The spinal dorsal horn TNF alpha expression of group A was higher than other groups (P<0.01). TNF alpha expression of group B were lower than which of group A and higher than which of group D. Conclusion DMSO can reduce morphine-induced thermal hyperalgesia by inhibiting spinal dorsal horn TNF alpha generation.

Key words: Morphine, Tumor necrosis factor, Hyperalgesia, Dimethyl sulfoxide

摘要： 【摘要】目的观察二甲基亚砜(DMSO)对吗啡诱导的热痛觉过敏及其对脊髓背角肿瘤坏死因子(TNF-α)表达的影响。方法 32只SD大鼠随机分为4组,A组(生理盐水+吗啡组)、B组(10%DMSO 5 mL/kg+吗啡组),C组(10%DMSO 5 mL/kg+生理盐水组)和D组(生理盐水组)。各组大鼠分别每d3PM腹腔注射生理盐水或DMSO,30 min后皮下注射吗啡或生理盐水。观察注药前1 d,注药后3 d、6 d、10 d大鼠热刺激撤足潜伏期的变化及脊髓背角TNF?鄄α表达情况。结果与注药前相比,A组注药后3 d开始热刺激撤足潜伏期缩短,10 d进一步缩短(P<0.01)。与A组比较,B组注药后6 d、10 d热刺激撤足潜伏期延长有统计学意义(P<0.01)。A组脊髓背角TNF?鄄α表达较其它组增高(P<0.01)。B组TNF?鄄α的表达较A组低,较D组高有统计学意义(P<0.01)。结论 DMSO可能通过抑制脊髓背角TNF?鄄α的产生而减轻吗啡诱导的热痛觉过敏。

关键词: 吗啡, 肿瘤坏死因子, 痛觉过敏, 二甲基亚砜

CLC Number:

R614

Du Sujuan,Yang Tao, Chen Ruixia, Ye Xijiu. Study of inhibition of dimethyl sulfoxide on morphine-induced thermal hyperalgesia[J]. Lingnan Modern Clinics in Surgery, 2013, 13(06): 521-524.

杜素娟杨涛陈瑞霞叶西就. 二甲基亚砜抑制吗啡诱导热痛觉过敏的实验研究[J]. 岭南现代临床外科, 2013, 13(06): 521-524.

References

OIH的发生机制目前还不完全明了。比较一致的观点是，吗啡诱导痛觉过敏是由中枢敏感化引起的。外周传入神经纤维传导痛觉，与脊髓背角神经元形成突触联系，再将痛信号向上一级神经元传递，因此脊髓背角是中枢敏感化的关键部位，也是阿片类药物诱导痛觉过敏的关键部位。故本文选择脊髓背角为研究部位。本研究发现A组注射吗啡10d后脊髓背角TNF-α表达明显增高，与Suneeta Tumati的结果一致［5］。TNF-α是一种重要的促炎因子和免疫调节因子。大量文献表明脊髓背角的TNF-α在中枢敏感化方面起重要作用［6］。它通过受体TNF-α1和TNF-α2［7］,改变钠通道活性；激活其他细胞因子；还能作用于突触前受体，增加传入神经末梢伤害性神经递质的释放[8]；作用于突触后神经元上受体，激发胞内信号转导，使N-甲基-D-天冬氨酸(N-methyl-D-aspartate; NMDA)受体表达增多和功能增强，从而提高神经元的兴奋性，导致中枢敏感化的发生[9、10]。在疼痛的产生过程起关键作用。 DMSO是存在于许多植物中的一种低毒性物质，具有多种生物学效应，它是强效自由基清除剂［11］。可抑制内毒素诱导血浆TNF-α产生［12］；还能抑制NMDA、AMPA受体介导的离子流和过量的钙内流进入细胞［13］。大量文献显示它有神经保护作用。但它对吗啡诱导的痛觉过敏有无影响还未见报道。本研究显示，C组和D组在注药前后各时间点热刺激撤足潜伏期无统计学差异，说明单纯10%DMSO 5ml/kg对大鼠基础热痛阈没有影响。在应用吗啡前预先给予DMSO的B组脊髓背角TNF-α的表达较A组减少，说明DMSO可抑制吗啡诱导的TNF-α增高。与TNF-α表达对映的是B组大鼠热痛阈较A组增高，说明DMSO可抑制吗啡诱导的热痛觉过敏。B组虽较A组热痛阈增高，但仍较生理盐水组缩短，提示DMSO仅能部分抑制吗啡诱导的OIH。其机制可能是DMSO通过抑制脊髓背角TNF-α的表达［14］；从而抑制TNF-α的一系列生物学效应，进而抑制吗啡诱导的OIH。至于DMSO抑制TNF-α表达的机制还有待进一步研究。总之，本研究显示DMSO可抑制吗啡诱导的脊髓背角TNF-α表达增高，具有较好的缓解吗啡诱导痛觉过敏的作用。另，DMSO是一种广泛用于实验研究的溶剂，本文提示在进行吗啡诱导痛觉过敏研究时若使用DMSO作为溶剂，不能忽略DMSO的镇痛作用。参考文献［1］Angst MS, Clark JD. Opioid-induced hyperalgesia,a qualitative systematic review. Anesthesiology， 2006，04：570–587. ［2］Hoang BX, Tran DM, Tran HQ, et al. Dimethyl Sulfoxide and Sodium Bicarbonate in the Treatment of Refractory cancer pain. J Pain Palliat Care Pharmacother， 2011,25:19-24. ［3］Clark JD. Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage, 2002, 23:131–137. ［4］Wanigasekera V, Lee MCH, Rogers R, Hu P, Tracey I. Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans. J Neurosci, 2011,31:2835–2842. ［5］Tumati S, Largent-Milnes TM, Keresztes A, et al. Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist. J Neuroimmunol, 2012 , 244: 23–31. ［6］Xu JT， Xin WJ， Zang y，et al. The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. pain. 2006,123:306-321. ［7］hang L, Berta T, Xu ZZ, et al. TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain.2011, 152:419-427. ［8］Duffy S, MacVicar BA. In vitro ischemia promotes calcium influx and intracellular calcium release in hippocampal astrocytes. J Neurosci, 1996, 16: 71-81. ［9］Parri R, Crunelli V. Astrocytes target presynaptic NMDA receptors to give synapses a boost. Nat Neurosci, 2007, 10: 271-273. ［10］Kawasaki Y, Zhang L, Cheng JK,et al. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci, 2008, 28: 5189-5194. ［11］Santos NC, Figueira-Coelho J, Martins-Silva J, et al. Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular, and molecular aspects, Biochem. Pharmacol, 2003, 65 :1035–1041. ［12］Essani NA, Fisher MA, Jaeschke H, et al. Inhibition of NF- kappa B activation by dimethyl sulfoxide correlates with suppression of TNF-alpha formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury. Shock, 1997, 7 :90-96. ［13］Lu C, Mattson MP. Dimethyl sulfoxide suppresses NMDA- and AMPA-induced ion currents and calcium influx and protects against excitotoxic death in hippocampal neurons. Exp Neurol, 2001, 170：180–185. ［14］Kelly KA, Hill MR, Youkhana K, et al. Dimethyl sulfoxide mod- ulates NF-kB and cytokine activation in lipopolysaccharide-treated murine macrophages. Infect Immun, 1994,62:3122–3128.

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