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: 7965553
• 负责人: JOOST J OPPENHEIM
• 金额: $ 8.25万
• 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/7965553
• 关键词: Address; Adenosine; Air; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Cancer Patient; Capsaicin; Cells; Collaborations; Cotton Rats; Cyclic AMP-Dependent Protein Kinases; Cytokine Receptors; Esthesia; Exposure to; Funding; Grant; Herpes zoster disease; Herpesviridae; Host resistance; Hour; Immunology; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Leukocytes; Ligands; Mediating; Messenger RNA; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nerve; Neurons; Neuropeptides; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Peripheral; RANTES; Rattus; Reaction; Receptor Cross-Talk; Regulation; Reporting; Role; Signal Transduction; Spinal Ganglia; Stimulus; TLR3 gene; TRPV1 gene; Tail; Tumor Biology; Vanilloid; Virus Diseases; Withdrawal; anandamide; base; capsaicin receptor; chemokine; chemokine receptor; chemotherapy; cytokine; desensitization; immunosuppressed; in vivo; novel; pain receptor; receptor; release of sequestered calcium ion into cytoplasm; response; tumor

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 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 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 studies showed 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 inhibited 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. The role of adenosine as an immunosuppressive effector molecule also has been reported to mediate the cell contact dependent effects of Tregs and to interfere with host resistance to tumors. Thus, studies of adenosine effects are relevant to tumor biology and immunology. These studies therefore reveal novel pathways of receptor mediated intercommunication of inflammatory as well as painful 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. Our current project focuses on neuroimmune interactions contributing to pain sensation in cancer patients funded by an INIP postdoctoral IRA financial grant from NIAID and NCI. As previously shown, chemokine receptor cross-talk suppresses analgesic opioid receptors, but enhances algesic transient receptor potential channel (TRP) receptors, thus resulting in painful inflammation. a) In collaboration with Dr. Jeffrey Cohen, NIAID we have investigated this in a cotton rat herpes virus infection model for chemotherapy induced Herpes Zoster. Herpes infection of dorsal root ganglia results in extremely painful inflammatory responses along nerve tracts. It has been reported that VZV infection produces TLR ligands and we have found that peripheral neurons present in dorsal root ganglia express TLR3, 7 and 9 which when stimulated express mRNA for many cytokines and chemokines. In addition, TLR ligand stimulation of neurons upregulate the expression of TLRs and TRPV1. Furthermore, preincubation of neurons for 16 hours with the TLR ligands, enhances the calcium flux induced by capsaicin stimulation of TRPV1. Consequently, products of the herpes virus interacting with these TLR's can either directly or indirectly, by inducing chemokines, enhance the response of TRPV1 pain receptors, providing one possible basis for herpes Zoster neuralgesia in immunosuppressed cancer patients. These studies in a pain model indicate that the peripheral pain reported by many cancer patients may be addressed by effective regulation of neuroimmune molecules.

我们建立了存在于背根神经节（DRG）的神经元，类似于 白细胞表达多种细胞因子、趋化因子、阿片样物质、大麻素受体 和其他神经肽。我们先前的研究表明，先前接触趋化因子， MIP 1 #945;导致PKC介导的对以下的趋化反应脱敏： 阿片类药物通过阿片受体，从而潜在地增强疼痛。的减小 阿片样物质的镇痛作用从大鼠的增强甩尾试验中是明显的 在将镇痛阿片样物质施用到患者的PAG中之前施用MIP 1#945;或RANTES。 CNS。然后我们扩展了这些早期的研究，表明先前给予趋化因子 辣椒素或花生四烯酸刺激的香草素对钙流的敏化和启动作用 （TRPV 1）痛觉受体的表达。这种反应也增加了疼痛，如图所示。 响应于鞘内施用趋化因子的缩爪增强 辣椒素之前在体内。香草酸受体的这种增敏作用也是PKC 依赖。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。基于这些研究，我们预测， 腺苷的抗炎作用也与GiPCR相互作用， 对趋化因子受体的影响。事实上，我们的研究表明，预先添加腺苷 导致抑制白细胞对多种 趋化因子此外，在体内注射腺苷之前， 白细胞进入小鼠气囊约90%。这种趋化因子的交叉脱敏 腺苷A2 a受体介导的腺苷A2 a受体依赖PKA。腺苷作为一种 免疫抑制效应分子也被报道介导细胞接触 TdR的依赖性作用和干扰宿主对肿瘤的抗性。因此，研究 腺苷的作用与肿瘤生物学和免疫学有关。这些研究揭示了 受体介导的炎症和疼痛相互作用的新途径 刺激。干扰这些PKC和PKA依赖性信号的方法和 这种受体相互作用与炎症和疼痛的病理生理学相关性需要 进一步评价。我们目前的项目重点是神经免疫相互作用， 癌症患者的疼痛感觉由INIP博士后伊拉财政拨款资助， NIAID和NCI。如前所述，趋化因子受体串扰抑制镇痛阿片类药物 受体，但增强痛觉瞬时受体电位通道（TRP）受体，因此 导致疼痛的炎症。a）与杰弗里·科恩博士合作，NIAID我们有 在化疗诱导的疱疹的棉鼠疱疹病毒感染模型中研究了这一点 带状疱疹背根神经节疱疹感染导致极度疼痛的炎症 沿着神经束的反应。据报道，VZV感染产生TLR配体， 我们发现背根神经节中的外周神经元表达TLR 3、7和9， 其在受到刺激时表达许多细胞因子和趋化因子的mRNA。此外，TLR配体 神经元的刺激上调TLR和TRPV 1的表达。此外，预孵育 与TLR配体作用16小时，增强辣椒素诱导的钙流 刺激TRPV 1。因此，疱疹病毒与这些TLR相互作用的产物 可以通过诱导趋化因子直接或间接地增强TRPV 1疼痛的反应， 受体，为免疫抑制的带状疱疹神经痛提供了一个可能的基础 癌症患者。在疼痛模型中的这些研究表明， 许多癌症患者可以通过有效调节神经免疫分子来解决。