Consequences of receptor cross talk on inflammation and algesia

我们发现，与白细胞类似，存在于背根神经节（DRG）中的神经元表达多种细胞因子、趋化因子、阿片样物质、anandamide和其他神经肽的受体。我们之前的研究表明，先前暴露于趋化因子如MIP1alpha会导致PKC介导的阿片受体对阿片的趋化反应脱敏，从而潜在地增强疼痛。阿片类药物镇痛作用的减弱，在将镇痛阿片类药物注入中枢神经系统PAG之前，通过给药MIP1alpha或RANTES的大鼠摇尾实验可以明显看出。然后，我们扩展了这些早期的研究，表明事先给药的趋化因子可使DRG神经元上的香草样蛋白（TRPV1）痛觉受体变敏感并启动辣椒素或anandamide的钙通量。这种反应也增加了疼痛，正如在体内使用辣椒素之前，在鞘内施用趋化因子时，脚爪退缩的增强所显示的那样。这种香草素受体的敏化也依赖于PKC。因此，促炎趋化因子可以通过抑制阿片样物质和增强香草样物质受体反应来增加疼痛。基于这些研究，我们预测腺苷的抗炎作用，也与GiPCR相互作用，可能对趋化因子受体有影响。事实上，我们目前的研究表明，事先添加腺苷可以抑制白细胞对多种趋化因子的体外趋化反应。此外，先前在体内注射腺苷可抑制白细胞在体内流入小鼠气囊约90%。这种趋化因子受体与腺苷A2a受体的交叉脱敏是PKA依赖性的。因此，这些研究揭示了受体介导的炎症和疼痛刺激相互交流的新途径。干扰这些PKC和PKA依赖信号的方法以及这种受体串扰与炎症和疼痛的病理生理相关性需要进一步评估。我们目前正在研究这些途径是如何在动物模型中导致带状疱疹非常痛苦的炎性病变的。腺苷作为免疫抑制效应分子的作用也被报道介导Tregs的细胞接触依赖效应并干扰宿主对肿瘤的抗性。因此，腺苷效应的研究与肿瘤生物学和免疫学相关。我实验室的项目集中在炎症和癌症的解决和控制上，为了实现这一目标，我们采取了三种不同的方法，包括研究疼痛和炎症受体之间的串扰，T调节细胞的肿瘤保护作用以及识别可能被证明有用的抗肿瘤疫苗佐剂的警报。

We established that neurons present in dorsal root ganglia (DRG), similar to leukocytes, express a wide variety of receptors for cytokines, chemokines, opioids, anandamide and other neuropeptides. We previously showed that prior exposure to chemokines such as MIP1alpha results in PKC mediated desensitization of the chemotactic response to opioids by opioid receptors, and thus potentially enhances pain. This decrease in the analgesic effect of opioids was evident from the enhanced tail flick assay of rats administered MIP1alpha or RANTES prior to an analgesic opioid into the PAG of the CNS. We then extended these earlier studies by showing that prior administration of chemokines Asensitized and primed the calcium flux of capsaicin or anandamide stimulated vanilloid (TRPV1) algesic receptor on DRG neurons. This response also increased pain as shown by the enhancement of paw withdrawal in response to the intrathecal administration of the chemokine prior to capsaicin in vivo. This sensitization of the vanilloid receptor was also PKC dependent. Consequently, proinflammatory chemokines can increase pain both by suppressing opioid and enhancing vanilloid receptor responses. Based on these studies, we predicted that the anti-inflammatory effects of adenosine, which also interacts with GiPCR, might have effects on chemokine receptors. Indeed our current studies show that prior addition of adenosine results in suppressing the in vitro chemotactic response of leukocytes to a variety of chemokines. Furthermore, prior in vivo injection of adenosine inhibits the in vivo influx of leukocytes into a murine air pouch by about 90%. This cross-desensitization of chemokine receptors by adenosine A2a receptors was PKA dependent. These studies therefore reveal novel pathways of receptor mediated intercommunication of inflammatory as well as painful stimuli. Means of interfering with these PKC and PKA dependent signals and the pathophysiological relevance of this receptor cross-talk to inflammation and pain need to be further evaluated. We are currently investigating how these pathways may be contributing to the very painful inflammatory lesions of Herpes Zoster in animal models. The role of adenosine as an immunosuppressive effector molecule also has been reported to mediate the cell contact dependent effects of Tregs and to interfere with host resistance to tumors. Thus, studies of adenosine effects are relevant to tumor biology and immunology. The projects of my laboratory are focused on the resolution and control of inflammation and cancer, to achieve this goal we have taken three diverse approaches involving studies of the cross-talk between pain and inflammatory receptors, the tumor protective effects of T regulatory cells and the identification of alarmins that may prove useful as anti tumor vaccine adjuvants.