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MIP1＆＃945;结果导致PKC介导的阿片受体对阿片类药物的趋化反应脱敏，从而有可能增强疼痛。通过对MIP1＆＃945的大鼠的增强尾部轻弹测定，阿片类药物的镇痛作用的这种降低是明显的。或在镇痛阿片类药物之前进入中枢神经系统的PAG。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，先前体内注射腺苷会抑制白细胞的体内涌入鼠气袋中约90％。腺苷A2A受体对趋化因子受体的交叉敏化为PKA。还报道了腺苷作为免疫抑制效应分子的作用，可以介导Treg的细胞接触依赖性作用，并介导宿主对肿瘤的抗性。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症和疼痛刺激的互通性的新途径。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。我们当前的项目着重于神经免疫相互作用，导致由Niaid和NCI的INIP博士后IRA金融赠款资助的癌症患者的疼痛感。如前所述，趋化因子受体串扰抑制了镇痛性阿片类药物受体，但增强了高度的瞬态受体电位通道（TRP）受体，从而导致疼痛的炎症。 a）与杰弗里·科恩（Jeffrey Cohen）博士合作，我们已经在化学疗法诱导的棉大鼠疱疹病毒感染模型中调查了这一点。背根神经节的疱疹感染会导致神经界的炎症反应极为痛苦。据报道，VZV感染会产生TLR配体，我们发现背根神经节中存在的周围神经元Express TLR3、7和9刺激许多细胞因子和趋化因子刺激表达mRNA时。另外，神经元的TLR配体刺激上调TLR和TRPV1的表达。此外，与TLR配体的神经元预孵育16小时可增强TRPV1辣椒素刺激诱导的钙通量。因此，与这些TLR相互作用的疱疹病毒的产物可以通过诱导趋化因子直接或间接地增强TRPV1疼痛受体的反应，从而在免疫抑制的癌症患者中为疱疹带状疱疹神经神经提供一个可能的基础。在疼痛模型中的这些研究表明，许多癌症患者报告的周围疼痛可以通过有效调节神经免疫分子来解决。