Consequences of receptor cross talk on inflammation and

我们最后的项目涉及研究趋化因子受体与神经肽和痛觉受体的相互作用，以确定影响疼痛和炎症反应的新途径。我们建立了背根神经节（DRG）中的神经元，类似于白细胞，表达多种细胞因子，趋化因子，阿片类药物，花生四烯酸和其他神经肽的受体。我们以前的研究表明，先前暴露于趋化因子如MIP 1a导致PKC介导的阿片受体对阿片类药物的趋化反应脱敏，从而可能增强疼痛。阿片类镇痛作用的这种降低从在镇痛阿片类药物进入CNS的PAG之前给予MIP 1a或RANTES的大鼠的增强甩尾试验中是明显的。然后，我们扩展了这些早期的研究表明，事先管理的趋化因子A敏化和引发的辣椒素或花生四烯酸刺激的香草素（TRPV 1）的DRG神经元上的痛觉受体的钙流。这种反应也增加了疼痛，如在体内辣椒素之前鞘内施用趋化因子所引起的缩爪反应的增强所示。香草酸受体的这种敏化作用也是PKC依赖性的。因此，促炎趋化因子可以通过抑制阿片样物质和增强香草素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，事先加入腺苷的结果在体外抑制白细胞对各种趋化因子的趋化反应。此外，预先体内注射腺苷抑制白细胞体内流入鼠气囊约90%。腺苷A2a受体对趋化因子受体的交叉脱敏作用是PKA依赖性的。因此，这些研究揭示了受体介导的疼痛和炎症刺激相互作用的新途径。干扰这些PKC和PKA依赖性信号的方法以及这种受体与炎症和疼痛的病理生理相关性需要进一步评估。

Our final project involved studies of chemokine receptor cross-talk with neuropeptide and algesic receptors in an effort to identify novel pathways influencing painful and inflammatory reactions. 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 MIP1a 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 MIP1a 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 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.