Consequences of receptor cross talk on inflammation and algesia

受体串扰对炎症和痛觉的影响

• 批准号: 7592870
• 负责人: JOOST J OPPENHEIM
• 金额: $ 39万
• 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/7592870
• 关键词: Adenosine; Air; Analgesics; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Capsaicin; Cyclic AMP-Dependent Protein Kinases; Cytokine Receptors; Exposure to; Gray unit of radiation dose; Herpes zoster disease; Hormonal; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Lesion; Leukocytes; Mediating; Mus; Neurons; Neuropeptides; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Purinergic P1 Receptors; RANTES; Rattus; Reaction; Receptor Cross-Talk; Signal Transduction; Spinal Ganglia; Stimulus; TRPV1 gene; Tail; Transactivation; Vanilloid; Withdrawal; anandamide; base; capsaicin receptor; chemokine; chemokine receptor; cytokine; desensitization; in vivo; novel; receptor; release of sequestered calcium ion into cytoplasm; response

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.

我们已经确定，在背根神经节（DRG）中存在的神经元，如白细胞，表达了细胞因子，趋化因子，阿片类药物，阿甘丹酰胺和神经肽的多种受体。我们先前表明，先前暴露于趋化因子（例如MIP1α）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，从而有可能增强疼痛。阿片类药物的镇痛作用的减少是从加入MIP1α或RANTES的大鼠镇痛药阿片类药物中的大鼠尾部轻弹测定中可以明显看出的。然后，我们通过表明在DRG神经元上先前施用了由辣椒素或anandamide刺激的香草胶（TRPV1）AlgeIC受体诱导的钙化和引发钙通量的趋化因子的趋化因子的趋化因子剂量的趋化因子的趋化因子。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。我们目前正在研究这些途径如何导致动物模型中疱疹带状疱疹非常痛苦的炎症性病变。