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. |