Eliav Eli, Benoliel Rafael, Herzberg Uri, Kalladka Mythili, Tal Michael
UMDNJ-New Jersey Dental School, Carmel Endowed Chair in Algesiology, Department of Diagnostic Sciences, Division of Orofacial Pain, 110 Bergen Street, Newark, NJ 07103, USA.
Brain Behav Immun. 2009 May;23(4):474-84. doi: 10.1016/j.bbi.2009.01.012. Epub 2009 Jan 29.
Inflammation along a nerve trunk (perineural inflammation), without detectable axonal damage, has been shown to induce transient pain in the organ supplied by the nerve. The aims of the present study were to study the role IL-6 and IL-1beta, in pain induced by perineural inflammation.
IL-6 and IL-1beta secretion from rat's sciatic nerves, L-5 Dorsal Root Ganglia (DRG), and the hind paw skin, 3 and 8 days following exposure of the nerve to Complete Freund's Adjuvant (CFA), were measured using ELISA method. Hind paw tactile-allodynia, mechano-hyperalgesia, heat-allodynia and electrical detection thresholds were tested up to 8 days following the application of CFA, IL-6 or IL-1beta adjacent to the sciatic nerve trunk. Employing electrophysiological recording, saphenous nerve spontaneous activity, nerve trunk mechano-sensitivity and paw tactile detection threshold (determined by recording action potential induced by the lowest mechanical stimulus) were assessed 3 and 8 days following exposure of the nerve trunk to CFA, IL-6, or IL-1beta.
IL-6 and IL-1beta secretion from the nerve was significantly elevated on the 3rd day post-operation (DPO). On the 8th DPO, IL-6 levels returned to baseline while IL-1beta levels remained significantly elevated. The DRG cytokine's level was increased on the 3rd and 8th DPOs, contralateral cytokine's level was increased on the 3rd DPO. The skin IL-6 level was increased bilaterally on the 3rd DPO and returned to baseline on the 8th DPO. IL-1beta levels increased in the affected side on the 3rd and bilaterally on the 8th DPO. Direct application of IL-6 or CFA on the sciatic nerve induced significant hind paw tactile-allodynia from the 1st to 5th DPOs, reduced electrical detection threshold from the 1st to 3rd DPOs, mechano-hyperalgesia from 3rd to 5th DPOs and heat-allodynia on the 3rd DPO. Direct application of IL-1beta induced paw tactile and heat-allodynia on the 7-8th DPOs and mechano-hyperalgesia on the 5-8th DPOs. Perineural inflammation significantly increased spontaneous activity myelinated fibres 3 and 8 days following the application. Direct application of IL-6 induced elevation of spontaneous activity on the 3rd while IL-1beta on the 8th DPO. Nerve mechano-sensitivity was significantly increased on the 3rd day following exposure to CFA and IL-6 and on the 8th following CFA application. The rat's paw lowest mechanical force necessary for induction of action potential, was significantly reduced 3 days following CFA application.
IL-6 and IL-1beta play an important role in pain induced by perineural inflammation. IL-6 activity is more prominent immediately following application (2-5th DPOs), while IL-1beta, activity is more significant in a later stage (5-8th DPOs).
沿神经干的炎症（神经周围炎症），在未检测到轴突损伤的情况下，已被证明会在该神经所支配的器官中诱发短暂性疼痛。本研究的目的是研究白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）在神经周围炎症诱发疼痛中的作用。
采用酶联免疫吸附测定（ELISA）法，检测大鼠坐骨神经、L-5背根神经节（DRG）和后爪皮肤在神经暴露于完全弗氏佐剂（CFA）后3天和8天的IL-6和IL-1β分泌情况。在坐骨神经干旁应用CFA、IL-6或IL-1β后，检测后爪触觉异常性疼痛、机械性痛觉过敏、热异常性疼痛和电检测阈值，持续8天。采用电生理记录，在神经干暴露于CFA、IL-6或IL-1β后3天和8天，评估隐神经自发活动、神经干机械敏感性和爪触觉检测阈值（通过记录最低机械刺激诱发的动作电位来确定）。
术后第3天（DPO）神经的IL-6和IL-1β分泌显著升高。在第8 DPO，IL-6水平恢复到基线，而IL-1β水平仍显著升高。DRG细胞因子水平在第3和8 DPO升高，对侧细胞因子水平在第3 DPO升高。皮肤IL-6水平在第3 DPO双侧升高，并在第8 DPO恢复到基线。IL-1β水平在第3天患侧升高，在第8天双侧升高。在坐骨神经上直接应用IL-6或CFA，在第1至5 DPO诱发显著的后爪触觉异常性疼痛，在第1至3 DPO降低电检测阈值，在第3至5 DPO引起机械性痛觉过敏，在第3 DPO引起热异常性疼痛。直接应用IL-1β在第7 - 8 DPO引起爪触觉和热异常性疼痛，在第5 - 8 DPO引起机械性痛觉过敏。神经周围炎症在应用后3天和8天显著增加有髓纤维的自发活动。直接应用IL-6在第3天诱发自发活动升高，而IL-1β在第8 DPO诱发。暴露于CFA和IL-6后第3天神经机械敏感性显著增加，暴露于CFA后第8天增加。应用CFA后3天，诱发大鼠爪动作电位所需的最低机械力显著降低。
IL-6和IL-1β在神经周围炎症诱发的疼痛中起重要作用。IL-6的活性在应用后立即（第2 - 5 DPO）更为突出，而IL-1β的活性在后期（第5 - 8 DPO）更为显著。
