Role of CB2 in Analgesic Mechanisms
Role of CB2 in Analgesic Mechanisms
批准号:
9127680
负责人:
Andrea Grace Hohmann
金额:
$35.1万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-04-15 至 2021-01-31
关键词:
2-arachidonylglycerolAdverse effectsAffectAffinityAgonistAnalgesicsArrestinsAstrocytesBindingBinding SitesCNR2 geneCalcium ChannelCancer SurvivorCannabinoidsCell LineCellsChemotherapy-Oncologic ProcedureChemotherapy-induced peripheral neuropathyCombined Modality TherapyDevelopmentDose-LimitingEndocannabinoidsHumanHyperalgesiaLeadMAGL inhibitorMAPK3 geneMaintenanceMediatingMicrogliaModelingMusNeuronsNeuropathyPaclitaxelPainPathway interactionsPeripheral Nervous System DiseasesPharmaceutical PreparationsPharmacologyPhasePoint MutationPopulationPre-Clinical ModelProteinsReceptor SignalingRecruitment ActivityRegulationResearchRodentRoleSignal TransductionSpinal CordSystemTestingTraumatic Nerve InjuryTreatment EfficacyTreatment ProtocolsWorkallodyniabeta-arrestincell typecellular targetingchemotherapeutic agentconventional therapydrug developmenteffective therapyendocannabinoid signalinggabapentinimprovedin vitro Modelin vivoinflammatory neuropathic paininflammatory painnerve injurynew therapeutic targetnovelnovel strategiespainful neuropathypregabalinpublic health relevancereceptor bindingresearch studytraffickingunpublished works
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Cancer chemotherapy frequently causes a painful peripheral neuropathy that is dose-limiting and can be irreversible. Gabapentin is clinically used to treat diverse forms of neuropathic pain. However, the mechanism(s) responsible for its antinociceptive effects remain poorly understood. Unpublished work from our groups suggests that gabapentin suppresses neuropathic pain induced by the chemotherapeutic agent paclitaxel in rodents through interactions with CB2 cannabinoid receptors. At the cellular level, gabapentin selectively increases ability of the endocannabinoid 2-arachidonoylglycerol (2-AG) to recruit β-arrestin to CB2 receptors. These observations suggest a previously unrecognized interaction between CB2 receptors, β- arrestin/ERK1/2 signaling and gabapentin-induced antinociception. We postulate that gabapentin analgesic efficacy is due (at least in part) to a CB2-specific mechanism that involves increased β-arrestin signaling in microglia or neurons. We will thoroughly test this hypothesis by completing three Specific Aims: Aim 1 will characterize the impact of gabapentin on CB2 receptor signaling using transfected cells lines, cell lines natively expressing CB2 receptors and primary cultures of CB2-expressing cells. In addition, potential allosteric interactions between gabapentin and CB2 will be probed. Aim 2 will use conditional deletion of CB2 from neurons, microglia, and astrocytes to determine which cell type(s) express the CB2 receptors mediating gabapentin antinociception during the development and maintenance phases of paclitaxel neuropathy. Since CB2 agonists efficaciously relieve paclitaxel-induced allodynia and hyperalgesia, this approach will also be used to determine the cell type(s) mediating antinociception elicited by direct acting CB2-agonists. Aim 3 will extend the findings of the first two aims to determine if gabapentin efficacy is also CB2-mediated in other nerve injury and inflammatory pain models. The relevant cell type(s) will be determined using conditional deletion of CB2 as warranted and as described in the second specific aim. This aim will also investigate the mechanism of direct-acting CB2 agonists in these pain models using the above conditional deletion approach. Our research team combines expertise in (1) CB2 receptor binding, signaling, trafficking, and regulation, (2) cannabinoid pharmacology and antinociceptive mechanisms, and (3) mouse preclinical models of pain. Our studies suggest a highly novel and previously unrecognized intersection between CB2 receptors, endocannabinoids, and arrestin signaling that underlies the therapeutic efficacy of gabapentin. Understanding the cross-talk between these pathways is critical both for elucidating the mechanism of action of gabapentin to exploit and optimize its therapeutic efficacy and for identifying novel therapeutic targets for drug development that lack unwanted side effects of conventional treatments. Lastly, our studies will also identify the cellular targets of CB2 agonist as they relieve a variety of pathological pain states.
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会议论文
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批准号:9910117
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项目类别:
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资助金额:$30.0万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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依托单位:
CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence
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批准号:9914099
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资助金额:$51.72万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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依托单位:
CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence
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批准号:10579196
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项目类别:
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资助金额:$51.72万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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依托单位:
Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain
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批准号:10259561
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资助金额:$91.59万
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CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence
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批准号:10343812
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项目类别:
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资助金额:$51.72万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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依托单位:
Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain
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批准号:10401479
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资助金额:$106.31万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence
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批准号:10117221
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资助金额:$51.72万
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财政年份:2019
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负责人:Andrea Grace Hohmann
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A Novel Mechanism for Decreasing Opioid Reward
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批准号:9197559
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资助金额:$19.52万
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财政年份:2016
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负责人:Andrea Grace Hohmann
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依托单位:
2013 Cannabinoid Function in the CNS Gordon Research Conference & Gordon Research
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批准号:8597593
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项目类别:
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资助金额:$4.04万
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财政年份:2013
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负责人:Andrea Grace Hohmann
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依托单位:
Protein-protein interaction inhibitors as novel analgesics
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批准号:8731190
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项目类别:
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资助金额:$23.4万
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财政年份:2013
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负责人:Andrea Grace Hohmann
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依托单位:
Protein-protein interaction inhibitors as novel analgesics
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批准号:8459637
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项目类别:
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资助金额:$19.5万
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财政年份:2013
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负责人:Andrea Grace Hohmann
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依托单位:
2011 Gordon Research Seminar on Cannabinoid Function in The CNS
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批准号:8061151
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项目类别:
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资助金额:$1.5万
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财政年份:2011
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负责人:Andrea Grace Hohmann
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依托单位:
An Animal Model of Therapeutic Self-Medication for Neuropathic Pain
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批准号:7938622
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项目类别:
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资助金额:$39.64万
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财政年份:2009
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负责人:Andrea Grace Hohmann
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依托单位:
An Animal Model of Therapeutic Self-Medication for Neuropathic Pain
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批准号:7816899
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项目类别:
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资助金额:$49.61万
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财政年份:2009
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负责人:Andrea Grace Hohmann
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依托单位:
INTEGRATIVE PREDOCTORAL TRAINING IN DRUG ABUSE RESEARCH AT INDIANA UNIVERSITY
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批准号:10163150
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项目类别:
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资助金额:$21.41万
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财政年份:2008
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负责人:Andrea Grace Hohmann
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依托单位:
INTEGRATIVE PREDOCTORAL TRAINING IN DRUG ABUSE RESEARCH AT INDIANA UNIVERSITY
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批准号:10436816
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项目类别:
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资助金额:$22.72万
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财政年份:2008
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负责人:Andrea Grace Hohmann
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依托单位:
INTEGRATIVE PREDOCTORAL TRAINING IN DRUG ABUSE RESEARCH AT INDIANA UNIVERSITY
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批准号:10620859
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项目类别:
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资助金额:$23.13万
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财政年份:2008
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负责人:Andrea Grace Hohmann
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依托单位:
AN ENDOCANNABINOID MECHANISM FOR STRESS-INDUCED ANALGESIA
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批准号:7636738
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项目类别:
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资助金额:$49.0万
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财政年份:2006
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负责人:Andrea Grace Hohmann
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依托单位:
ENDOCANNABINOID ANALGESIA: AN IN VIVO GENE TRANSFER - LIPIDOMICS APPROACH
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批准号:7286847
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项目类别:
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资助金额:$14.57万
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财政年份:2006
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负责人:Andrea Grace Hohmann
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依托单位:
AN ENDOCANNABINOID MECHANISM FOR STRESS-INDUCED ANALGESIA
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批准号:7132223
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项目类别:
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资助金额:$44.66万
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财政年份:2006
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负责人:Andrea Grace Hohmann
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依托单位:
海外基金