Consequences of receptor cross talk on inflammation and algesia

我们已经证实，存在于背根神经节(DRG)的神经元，像白细胞一样，表达各种各样的细胞因子、趋化因子、阿片样物质、去雄激素和神经肽的受体。我们以前发现，预先暴露于趋化因子，如MIP1；导致PKC通过阿片受体介导阿片类药物趋化反应的脱敏，从而潜在地增强疼痛。在阿片类药物进入中枢导水管周围灰质中心(PAG)之前，给予MIP1或RANTES的大鼠的甩尾增强实验表明，阿片类药物的止痛效果明显减弱。然后，我们扩展了这些早期的研究，表明预先给予趋化因子敏化和启动由辣椒素或双胺诱导的钙离子流量，刺激DRG神经元上的香草素(TRPV1)痛觉受体。这种反应也增加了疼痛，表现为在体内鞘内注射辣椒素之前给予趋化因子后，爪子缩回的增强。香草素受体的这种敏化也依赖于PKC。因此，促炎趋化因子可以通过抑制阿片类药物和增强香草素受体反应来增加疼痛。在这些研究的基础上，我们预测腺苷的抗炎作用可能会影响趋化因子受体，腺苷也与GiPCR相互作用。事实上，我们目前的研究表明，预先加入腺苷会抑制白细胞对各种趋化因子的体外趋化反应。此外，预先体内注射腺苷可抑制体内白细胞流入小鼠气囊约90%。腺苷A2a受体对趋化因子受体的这种交叉脱敏作用依赖于PKA。因此，这些研究揭示了受体介导的疼痛和炎症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学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症损害的。

We have established that neurons present in dorsal root ganglia (DRG), like leukocytes, express a wide variety of receptors for cytokines, chemokines, opioids, anandamide and neuropeptides. We previously showed that prior exposure to chemokines such as MIP1α 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 MIP1α or RANTES prior to an analgesic opioid into the periaquaductal gray center (PAG) of the CNS. We then extended these earlier studies by showing that prior administration of chemokines sensitized and primed calcium flux induced by 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 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 painful and inflammatory 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.