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.

我们发现，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、阿片类物质、去雄激素和其他神经肽的受体。我们以前发现，预先暴露于趋化因子如MIP1和Amp；会导致PKC介导的阿片受体对阿片类药物的趋化反应脱敏，从而潜在地增强疼痛。阿片类药物镇痛效果的这种降低从增强的甩尾实验中可以明显看出，在将止痛阿片类药物注入中枢神经系统的PAG之前，给予MIP1或RANTES的大鼠。然后，我们扩展了这些早期的研究，表明预先给予趋化因子钝化和启动辣椒素或双胺刺激的DRG神经元上的香草素(TRPV1)痛性受体的钙流。这种反应也增加了疼痛，表现为在体内鞘内注射辣椒素之前给予趋化因子后，爪子缩回的增强。香草素受体的这种敏化也依赖于PKC。因此，促炎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。在这些研究的基础上，我们预测腺苷的抗炎作用可能会影响趋化因子受体，腺苷也与GiPCR相互作用。事实上，我们的研究表明，预先加入腺苷会抑制白细胞对各种趋化因子的体外趋化反应。此外，预先体内注射腺苷可将体内白细胞流入小鼠气囊的能力抑制约90%。腺苷A2a受体对趋化因子受体的这种交叉脱敏作用依赖于PKA。腺苷作为免疫抑制效应分子的作用也已被报道，以介导Tregs的细胞接触依赖效应，并干扰宿主对肿瘤的抵抗。因此，腺苷作用的研究与肿瘤生物学和免疫学有关。因此，这些研究揭示了受体介导的炎性和疼痛刺激相互交流的新途径。干扰这些PKC和PKA依赖信号的方法以及这种受体串扰与炎症和疼痛的病理生理学相关性需要进一步评估。我们目前的项目专注于神经免疫相互作用对癌症患者痛觉的贡献，该项目由NIAID和NCI资助的INIP博士后IRA资助。如前所述，趋化因子受体串扰抑制了止痛阿片受体，但增强了痛性瞬时受体电位通道(TRP)受体，从而导致疼痛的炎症。A)NIAID与Jeffrey Cohen博士合作，在化疗诱发带状疱疹的棉鼠疱疹病毒感染模型中进行了研究。疱疹病毒感染背根神经节会导致神经束上极其痛苦的炎症反应。有报道称，VZV感染可产生TLR配体，我们发现存在于背根神经节的外周神经元表达TLR3、7和9，当受到刺激时，TLR3、7和9表达许多细胞因子和趋化因子的mRNA。此外，TLR配体对神经元的刺激可上调TLRs和TRPV1的表达。此外，将神经元与TLR配体预先孵育16小时，可增强辣椒素刺激TRPV1所诱导的钙离子通量。因此，疱疹病毒与这些TLR相互作用的产物可以直接或间接地通过诱导趋化因子，增强TRPV1疼痛受体的反应，为免疫抑制的癌症患者带状疱疹神经痛提供了可能的基础。这些在疼痛模型中的研究表明，许多癌症患者报告的外周疼痛可以通过有效调节神经免疫分子来解决。