Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist.
Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist.
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DOI：
10.1016/j.pain.2010.05.022
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发表时间：
2010-11
期刊：
影响因子：
7.4
通讯作者：
Porreca F
中科院分区：
文献类型：
--
作者：
Vardanyan M;Melemedjian OK;Price TJ;Ossipov MH;Lai J;Roberts E;Boos TL;Deschamps JR;Jacobson AE;Rice KC;Porreca F
胰腺慢性炎症引起的胰腺疼痛通常是难治性的，临床上难以用现有的镇痛药物治疗，这反映了需要更有效的治疗方法。胰腺炎疼痛的机制尚不清楚。本研究用TB-2-081 （3- o -甲酰基- 20r，21-环氧树脂丁烯酮素，EBRF）研究了白细胞介素-6 （IL-6）促进胰腺炎疼痛的可能性，TB-2-081是一种从天然来源半合成的小分子IL-6受体拮抗剂。采用二氯化二丁基锡（DBTC）诱导大鼠持续性胰腺炎，探讨TB-2-081的潜在活性及其机制。TB-2-081取代IL-6与人重组可溶性IL-6受体的结合，具有明显的高亲和力，并抑制IL-6介导的细胞生长。全身或口服，而不是鞘内给药，TB-2-081以剂量和时间依赖的方式逆转dbtc诱导的腹部超敏反应。注射DBTC后第6天胰腺炎大鼠背根神经节（DRG） IL-6水平显著升高。TB-2-081可阻断IL-6增强辣椒素诱导的DRG神经元降钙素基因相关肽的释放。我们的数据表明，TB-2-081是一种全身可用且口服活性的小分子IL-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的表达增加和(b) IL-6介导的伤害性神经元的致敏。TB-2-081的活性暗示IL-6在维持胰腺炎疼痛中的重要作用。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的途径。
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. 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 was investigated following induction of persistent pancreatitis using dibutyltin dichloride (DBTC) in rats. TB-2-081 displaces 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 upregulated 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 therapy of chronic pancreatitis and other chronic pain states.
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影响因子：
2.9
作者：
Arruda, JL;Sweitzer, SA;DeLeo, JA
通讯作者：
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影响因子：
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作者：
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DOI：
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