Opioid activation of toll-like receptor 4 contributes to drug reinforcement.
Opioid activation of toll-like receptor 4 contributes to drug reinforcement.
复制标题
DOI：
10.1523/jneurosci.0684-12.2012
复制
发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Hutchinson MR;Northcutt AL;Hiranita T;Wang X;Lewis SS;Thomas J;van Steeg K;Kopajtic TA;Loram LC;Sfregola C;Galer E;Miles NE;Bland ST;Amat J;Rozeske RR;Maslanik T;Chapman TR;Strand KA;Fleshner M;Bachtell RK;Somogyi AA;Yin H;Katz JL;Rice KC;Maier SF;Watkins LR
阿片作用被认为仅通过阿片受体的初始激动作用来发挥强化作用。在这里，我们提出了一个额外的新的阿片类奖励的证据：先天免疫模式识别受体，toll样受体4 (TLR4)，及其myd88依赖性信号。通过给予非阿片类药物，纳洛酮的非天然异构体，(+)-纳洛酮（大鼠）或myd88 -TLR4依赖性信号的两个独立基因敲除（小鼠）来阻断TLR4/MD2，抑制阿片类药物诱导的条件位置偏好。（+）-纳洛酮还减少了阿片类药物（瑞芬太尼）自我给药（大鼠），这是另一种常用的药物奖励行为衡量标准。此外，吗啡- tlr4 /MD2活性的药物阻断有效地降低了吗啡诱导的大鼠伏隔核细胞外多巴胺的升高，这是一个对阿片强化至关重要的区域。重要的是，阿片类药物TLR4的作用并不是单向影响阿片类药物的药效学，因为TLR4 - / -小鼠减少了氧可酮诱导的p38和JNK磷酸化，同时表现出增强的镇痛作用。与我们最近关于吗啡-TLR4/MD2结合的报道类似，这里我们提供了硅和生物物理数据的结合来支持(+)-纳洛酮和瑞芬太尼与TLR4/MD2的结合。总的来说，这些数据表明，阿片样物质对经典阿片样物质受体的作用，以及它们新发现的TLR4/MD2的作用，影响了中边缘多巴胺系统，该系统放大了阿片样物质诱导的细胞外多巴胺水平的升高，因此可能解释了阿片样物质奖励行为的改变。因此，TLR4/MD2将阿片类药物识别为外来异种物质的发现，增加了现有假设的神经元强化机制，确定了TLR4/MD2治疗成瘾的新药物靶点，并进一步证明了中枢促炎免疫信号在药物奖励中的作用。
Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, Toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the non-opioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knockouts of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, whilst displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system which amplifies opioid-induced elevations in extracellular dopamine levels and therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.