Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA Scripps Research Institute, La Jolla, CA 92037, USA Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute On Drug Abuse, the National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375, USA.
Pain. 2010 Nov;151(2):257-265. doi: 10.1016/j.pain.2010.05.022. Epub 2010 Jul 4.
Pancreatic pain resulting from chronic inflammation of the pancreas is often intractable and clinically difficult to manage with available analgesics reflecting the need for more effective therapies. The mechanisms underlying pancreatitis pain are not well understood. Here, the possibility that interleukin-6 (IL-6) may promote pancreatitis pain was investigated with TB-2-081 (3-O-formyl-20R,21-epoxyresibufogenin, EBRF), a small molecule IL-6 receptor antagonist that was semi-synthetically derived from natural sources. The potential activity and mechanism of TB-2-081 were investigated following the induction of persistent pancreatitis using dibutyltin dichloride (DBTC) in rats. TB-2-081 displaces the binding of IL-6 to the human recombinant soluble IL-6 receptor with apparent high affinity and inhibits IL-6 mediated cell growth. Systemic or oral, but not intrathecal, administration of TB-2-081 reversed DBTC-induced abdominal hypersensitivity in a dose- and time-dependent manner. IL-6 levels were significantly up-regulated in the dorsal root ganglia (DRG) of rats with pancreatitis on day 6 after DBTC injection. IL-6-enhanced capsaicin-evoked release of calcitonin gene-related peptide from cultured DRG neurons was blocked by TB-2-081. Our data demonstrate that TB-2-081 acts as a systemically available and orally active small molecule IL-6 receptor antagonist. TB-2-081 effectively reduces pancreatitis-induced pain through peripheral mechanisms that are likely due to (a) increased expression of IL-6 in the DRG and (b) IL-6-mediated sensitization of nociceptive neurons. The activity of TB-2-081 implicates an important role for IL-6 in sustaining pancreatitis pain. Strategies targeting IL-6 actions through small molecule antagonists may offer novel approaches to improve the therapy of chronic pancreatitis and other chronic pain states.
慢性胰腺炎炎症导致的胰腺疼痛通常难以控制，临床治疗中可用的镇痛药效果有限，这反映出需要更有效的治疗方法。胰腺炎疼痛的机制尚不清楚。本研究探讨了白细胞介素 6（IL-6）是否可以促进胰腺炎疼痛，使用的是一种小分子白细胞介素 6 受体拮抗剂 TB-2-081（3-O-甲酰基-20R,21-环氧瑞舒伐他汀，EBRF），它是从天然来源半合成得到的。使用二丁基锡二氯化物（DBTC）在大鼠中诱导持续性胰腺炎，研究了 TB-2-081 的潜在活性和作用机制。TB-2-081 以高亲和力置换 IL-6 与人类重组可溶性 IL-6 受体的结合，并抑制 IL-6 介导的细胞生长。TB-2-081 全身性或口服给予，但不是鞘内给予，可剂量和时间依赖性地逆转 DBTC 诱导的大鼠腹部过敏。DBTC 注射后第 6 天，胰腺炎大鼠背根神经节（DRG）中 IL-6 水平显著上调。TB-2-081 阻断了 IL-6 增强的辣椒素诱导培养 DRG 神经元中降钙素基因相关肽的释放。我们的数据表明，TB-2-081 是一种具有全身活性和口服活性的小分子白细胞介素 6 受体拮抗剂。TB-2-081 通过外周机制有效减轻胰腺炎引起的疼痛，这可能是由于（a）DRG 中 IL-6 表达增加和（b）IL-6 介导的伤害感受神经元敏化。TB-2-081 的活性表明 IL-6 在维持胰腺炎疼痛中起着重要作用。通过小分子拮抗剂靶向 IL-6 作用的策略可能为改善慢性胰腺炎和其他慢性疼痛状态的治疗提供新方法。
