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，神经元存在于背根神经节（DRG），像白细胞，表达各种受体的细胞因子，趋化因子，阿片类药物，花生四烯酸和神经肽。我们以前的研究表明，先前暴露于趋化因子如MIP 1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的水管周围灰质中心（PAG）之前施用MIP 1或RANTES的大鼠的增强甩尾测定中是明显的。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敏化和引发的辣椒素或花生四烯酸刺激香草素（TRPV1）痛觉受体DRG神经元诱导的钙流。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。我们目前正在研究这些途径如何在动物模型中导致带状疱疹非常疼痛的炎症病变。