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: 8349111
• 负责人: JOOST J OPPENHEIM
• 金额: $ 7.66万
• 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/8349111
• 关键词: Address; Analgesics; Biological Assay; Cancer Patient; Capsaicin; Collaborations; Cotton Rats; Cytokine Receptors; Esthesia; Exposure to; Funding; Grant; Heating; Herpes zoster disease; Herpesviridae; Hour; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Leukocytes; Ligands; Mediating; Messenger RNA; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nerve; Neurons; Neuropeptides; Oligonucleotides; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Peripheral; RANTES; Rattus; Reaction; Receptor Cross-Talk; Regulation; Reporting; Spinal Ganglia; TLR3 gene; TRPV1 gene; Tail; 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 MIP1-alpha 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 MIP-alpha 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 sensitized 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. 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 transactivate 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. Furthermore, in a mouse tumor model administration of suppressive oligonucleotides that block TLR9 were found to inhibit enhanced sensitivity to heat, which is considered to be mediated by TRPV1. This provides additional evidence for the cross-talk between immune and pain sensing receptors. 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.

我们建立了背根神经节（DRG）中的神经元，类似于白细胞，表达多种细胞因子，趋化因子，阿片类药物，花生四烯酸和其他神经肽的受体。我们以前的研究表明，先前暴露于趋化因子如MIP 1-α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PAG之前给予MIP-α或RANTES的大鼠的增强甩尾试验中是明显的。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致敏和引发的钙流辣椒素或花生四烯酸刺激香草素（TRPV 1）的DRG神经元上的痛觉受体。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。 我们目前的项目重点是神经免疫相互作用，有助于癌症患者的疼痛感觉，由NIAID和NCI的INIP博士后伊拉财政资助。如前所述，趋化因子受体串扰抑制镇痛阿片受体，但增强痛觉瞬时受体电位通道（TRP）受体，从而导致疼痛性炎症。a）与NIAID的Jeffrey Cohen博士合作，我们在棉鼠疱疹病毒感染模型中研究了化疗诱导的带状疱疹。背根神经节的疱疹感染导致沿着神经束的极度疼痛的炎症反应。已经报道VZV感染产生TLR配体，并且我们已经发现存在于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配体刺激神经元上调TLR的表达并反式激活TRPV 1。此外，与TLR配体一起预孵育神经元16小时，增强了由辣椒素刺激TRPV 1诱导的钙流。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疼痛受体的反应，为免疫抑制癌症患者的带状疱疹神经痛提供了一个可能的基础。此外，在小鼠肿瘤模型中，发现阻断TLR 9的抑制性寡核苷酸的施用抑制对热的敏感性增强，这被认为是由TRPV 1介导的。这为免疫和疼痛感受受体之间的串扰提供了额外的证据。这些疼痛模型的研究表明，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。