Consequences of receptor cross talk on inflammation and

受体串扰对炎症和

• 批准号: 7338777
• 负责人: JOOST J OPPENHEIM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338777
• 关键词: Consequences; receptor; cross; talk; inflammation

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.

我们的最终项目涉及对趋化因子受体串扰与神经肽和抗原受体的研究，以识别影响疼痛和炎症反应的新途径。我们确定在背根神经节中存在的神经元（DRG）类似于白细胞，表达了细胞因子，趋化因子，阿片类药物，anandamide和其他神经肽的多种受体。我们先前表明，先前暴露于MIP1A等趋化因子会导致PKC介导的阿片受体对阿片类药物对阿片类药物的脱敏反应脱敏，从而有可能增加疼痛。从镇痛药阿片类药物施用的大鼠对CNS的PAG之前，对阿片类药物的镇痛作用的这种降低可以明显看出。然后，我们通过表明趋化因子的趋化因子在DRG神经元上先前施用了趋化因子和启动的趋化因子和启动的趋化因子和启动钙的钙通量。这种反应也增加了疼痛，如响应胶囊在体内的趋化因子的固定剂的响应时，爪子戒断的增强表明。香草素受体的这种敏化也依赖于PKC。因此，促炎性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。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产生影响。实际上，我们目前的研究表明，事先添加腺苷会导致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会抑制白细胞在体内涌入鼠袋中的含量约为90％。腺苷A2A受体对趋化因子受体的交叉敏化为PKA。因此，这些研究揭示了受体介导的疼痛和炎症刺激的互通的新途径。需要进一步评估这些PKC和PKA依赖信号以及该受体串扰与炎症和疼痛的病理生理相关性的手段。