Liang DeYong, Shi Xiaoyou, Qiao Yanli, Angst Martin S, Yeomans David C, Clark J David
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
Mol Pain. 2008 Feb 22;4:7. doi: 10.1186/1744-8069-4-7.
The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored.
In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.
The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.
术前长期使用阿片类药物会导致疼痛阈值降低，术后疼痛程度加剧。人们提出了几种机制来解释这种通常被称为阿片类药物诱导的痛觉过敏（OIH）的高度敏感性。这些提出的机制大多涉及中枢或外周神经系统的可塑性事件。之前尚未探索伤害感受外周介质丰度的改变。
在这些实验中，给小鼠注射生理盐水（对照组）或每日递增剂量的吗啡以产生OIH状态，随后进行后爪切开术。在其他实验中，在切开时开始吗啡治疗。测量机械性异常性疼痛和切开周围皮肤细胞因子水平。使用髓过氧化物酶（MPO）测定法来确定伤口附近的中性粒细胞活性。细胞因子产生抑制剂己酮可可碱用于确定先前用吗啡治疗的动物中过量细胞因子的功能意义。与生理盐水预处理的对照组相比，发现术前长期用吗啡治疗的小鼠在切开后的一个或多个时间点，其皮肤中IL-1β、IL-6、G-CSF、KC和TNFα水平升高。各个细胞因子的时间进程遵循不同模式。长期吗啡治疗对伤口区域中性粒细胞浸润没有明显影响。己酮可可碱降低了细胞因子水平，并逆转了术前长期给予吗啡引起的过度机械性敏感化。切开时开始的吗啡治疗并未导致细胞因子产生或伤害性敏感化的普遍增强，超过单独切开后观察到的水平。
在长期暴露于吗啡的动物中，切开后观察到的伤害性敏感化水平增强与先前报道的与这种切开疼痛模型相关的几种细胞因子水平升高有关。这些细胞因子可能在支持伤害性敏感化方面发挥作用，因为己酮可可碱可逆转切开周围皮肤细胞因子水平和OIH。切开时开始给予阿片类药物似乎没有相同的细胞因子增强作用。涉及减少细胞因子的术后疼痛控制方法可能是控制术前长期使用阿片类药物的患者过度疼痛的有效方法。
