Consequences of receptor cross talk on inflammation and algesia
受体串扰对炎症和痛觉的影响
基本信息
- 批准号:7965553
- 负责人:
- 金额:$ 8.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenosineAirAnalgesicsAnti-Inflammatory AgentsAnti-inflammatoryBiological AssayCancer PatientCapsaicinCellsCollaborationsCotton RatsCyclic AMP-Dependent Protein KinasesCytokine ReceptorsEsthesiaExposure toFundingGrantHerpes zoster diseaseHerpesviridaeHost resistanceHourImmunologyImmunosuppressive AgentsIn VitroInfectionInflammationInflammatoryInflammatory ResponseInjection of therapeutic agentLeukocytesLigandsMediatingMessenger RNAModelingMusNational Institute of Allergy and Infectious DiseaseNerveNeuronsNeuropeptidesOpioidOpioid AnalgesicsOpioid ReceptorPainPathway interactionsPeripheralRANTESRattusReactionReceptor Cross-TalkRegulationReportingRoleSignal TransductionSpinal GangliaStimulusTLR3 geneTRPV1 geneTailTumor BiologyVanilloidVirus DiseasesWithdrawalanandamidebasecapsaicin receptorchemokinechemokine receptorchemotherapycytokinedesensitizationimmunosuppressedin vivonovelpain receptorreceptorrelease of sequestered calcium ion into cytoplasmresponsetumor
项目摘要
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,与白细胞类似,存在于背根神经节(DRG)中的神经元表达多种细胞因子、趋化因子、阿片样物质、anandamide和其他神经肽的受体。我们之前表明,先前暴露于趋化因子,如MIP1&;#945;导致PKC介导的阿片受体对阿片的趋化反应脱敏,从而潜在地增强疼痛。阿片类药物镇痛作用的减弱从给药mip1的大鼠的摇尾实验中可以明显看出。在阿片类镇痛药物进入中枢神经系统PAG之前使用RANTES。然后,我们扩展了这些早期的研究,表明事先给药的趋化因子可使DRG神经元上的香草样蛋白(TRPV1)痛觉受体变敏感并启动辣椒素或anandamide的钙通量。这种反应也增加了疼痛,正如在体内使用辣椒素之前,在鞘内施用趋化因子时,脚爪退缩的增强所显示的那样。这种香草素受体的敏化也依赖于PKC。因此,促炎趋化因子可以通过抑制阿片样物质和增强香草样物质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,我们的研究表明,事先添加腺苷可以抑制白细胞对多种趋化因子的体外趋化反应。此外,先前在体内注射腺苷可抑制白细胞在体内流入小鼠气囊约90%。这种趋化因子受体与腺苷A2a受体的交叉脱敏是PKA依赖性的。腺苷作为免疫抑制效应分子的作用也被报道介导Tregs的细胞接触依赖效应并干扰宿主对肿瘤的抗性。因此,腺苷效应的研究与肿瘤生物学和免疫学相关。因此,这些研究揭示了受体介导的炎症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相关性需要进一步评估。我们目前的项目重点是神经免疫相互作用对癌症患者疼痛感觉的影响,由NIAID和NCI资助的INIP博士后IRA财务资助。如前所述,趋化因子受体串话抑制镇痛类阿片受体,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,我们在化疗诱导带状疱疹的棉花大鼠疱疹病毒感染模型中对此进行了研究。背根神经节疱疹感染导致沿神经束极度疼痛的炎症反应。据报道,VZV感染产生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配体刺激神经元可上调TLR和TRPV1的表达。此外,TLR配体对神经元进行16小时的预孵育,可以增强辣椒素刺激TRPV1诱导的钙通量。因此,疱疹病毒的产物与这些TLR的相互作用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能通过有效调节神经免疫分子来解决。
项目成果
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{{ truncateString('JOOST J OPPENHEIM', 18)}}的其他基金
Role of T regulatory suppression in autoimmunity and can
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Consequences of receptor cross talk on inflammation and algesia
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- 批准号:
7592870 - 财政年份:
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Role of T regulatory suppression in autoimmunity and cancer
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