Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta.
Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta.
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DOI：
10.1016/j.neuroscience.2009.10.011
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发表时间：
2010-01-20
期刊：
影响因子：
3.3
通讯作者：
Watkins, L. R.
中科院分区：
文献类型：
--
作者：
Lewis, S. S.;Hutchinson, M. R.;Rezvani, N.;Loram, L. C.;Zhang, Y.;Maier, S. F.;Rice, K. C.;Watkins, L. R.
吗啡-3-葡萄糖醛酸苷（M3 G）是在接受全身吗啡的人的脑脊液中检测到的主要吗啡代谢物。M3 G对阿片受体几乎没有亲和力，并通过未知机制诱导疼痛。随着新陈代谢的发生，M3 G的疼痛增强作用被认为可以显着且逐渐地对抗吗啡镇痛。我们最近发现吗啡激活Toll样受体4（TLR 4），这超出了它对μ-阿片受体的经典作用。这表明M3 G可以类似地激活TLR 4。这种激活可以为M3 G介导的疼痛增强提供新的机制，因为（a）TLR 4主要由脊髓中的小胶质细胞表达，并且（B）TLR 4激活释放疼痛增强物质，包括白细胞介素-1（IL 1）。我们目前在体外的证据表明，M3 G激活TLR 4，TLR 4抑制剂阻断的效果，M3 G激活小胶质细胞产生IL 1。在体内，鞘内注射M3 G（0.75 μg）可诱导有效的异常性疼痛和痛觉过敏，可被白细胞介素-1受体拮抗剂、米诺环素（小胶质细胞抑制剂）和（+）-和（−）-纳洛酮阻断或逆转。后一项研究扩展了我们先前的证明，即纳洛酮非立体选择性地抑制TLR 4信号传导。（+）-和（−）-纳洛酮的这些结果也表明，这些作用不能通过对经典立体选择性阿片受体的作用来解释。痛觉过敏（异常性疼痛未测试）和体外M3 G诱导的TLR 4信号传导均被17-DMAG阻断，17-DMAG是热休克蛋白90（HSP 90）的抑制剂，可促进TLR 4信号传导。M3 G上调背侧脊髓中的TLR 4和CD 11b（小胶质细胞/巨噬细胞活化标记物）mRNA以及腰骶部脑脊液中的IL 1蛋白，提供了促炎激活的进一步证据。最后，计算机模拟和体内数据支持葡萄糖醛酸部分能够诱导TLR 4/MD-2活化和增强疼痛。这些数据为TLR 4和IL 1介导的组分对M3 G诱导的作用提供了第一个证据，可能至少是小胶质细胞来源的。
Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine. M3G has little-to-no affinity for opioid receptors and induces pain by unknown mechanisms. The pain-enhancing effects of M3G have been proposed to significantly and progressively oppose morphine analgesia as metabolism ensues. We have recently documented that morphine activates toll-like receptor-4 (TLR4), beyond its classical actions on μ-opioid receptors. This suggests that M3G may similarly activate TLR4. This activation could provide a novel mechanism for M3G-mediated pain enhancement, as (a) TLR4 is predominantly expressed by microglia in spinal cord and (b) TLR4 activation releases pain-enhancing substances, including interleukin-1 (IL1). We present in vitro evidence that M3G activates TLR4, an effect blocked by TLR4 inhibitors, and that M3G activates microglia to produce IL1. In vivo, intrathecal M3G (0.75 μg) induced potent allodynia and hyperalgesia, blocked or reversed by interleukin-1 receptor antagonist, minocycline (microglial inhibitor), and (+)- and (−)-naloxone. This latter study extends our prior demonstrations that TLR4 signaling is inhibited by naloxone nonstereoselectively. These results with (+)- and (−)-naloxone also demonstrate that the effects cannot be accounted for by actions at classical, stereoselective opioid receptors. Hyperalgesia (allodynia was not tested) and in vitro M3G-induced TLR4 signaling were both blocked by 17-DMAG, an inhibitor of heat shock protein 90 (HSP90) that can contribute to TLR4 signaling. Providing further evidence of proinflammatory activation, M3G upregulated TLR4 and CD11b (microglial/macrophage activation marker) mRNAs in dorsal spinal cord as well as IL1 protein in the lumbosacral cerebrospinal fluid. Finally, in silico and in vivo data support that the glucuronic acid moiety is capable of inducing TLR4/MD-2 activation and enhanced pain. These data provide the first evidence for a TLR4 and IL1 mediated component to M3G-induced effects, likely of at least microglial origin.
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5.3
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