Uncovering the roles of oxysterols in neuropathic pain
揭示氧甾醇在神经性疼痛中的作用
基本信息
- 批准号:10504409
- 负责人:
- 金额:$ 52.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnalgesicsAstrocytesBehavioralBiochemicalBiological AssayBiological AvailabilityCell LineageCellsChronicCoupledDataDevelopmentDiseaseDockingDoseDrug KineticsExtracellular Signal Regulated KinasesFemaleGenesHelping to End Addiction Long-termHypersensitivityIn SituIn VitroInjectionsIpsilateralKnockout MiceLigandsLinkMaintenanceMedicalMetabolicMicrogliaMissionMitogen-Activated Protein KinasesModelingMolecularMotorMusNational Institute of Mental HealthNervous System TraumaNeurogliaNeurotoxinsNociceptionOpioidOpioid ReceptorOralPainPersistent painPersonsPertussis ToxinPharmaceutical ChemistryPharmacologic ActionsPharmacologyPropertyProteinsPublicationsPublishingRattusReaction TimeReflex actionRewardsRodentRoleSignal TransductionSignaling MoleculeSiteSolubilitySpinalSpinal CordSpinal cord posterior hornStimulusStructure-Activity RelationshipSystemTestingTherapeutic InterventionTimeTissuesTranscriptTraumaTraumatic Nerve InjuryWithdrawalabsorptionallodyniaanalogantagonistbasebehavioral phenotypingbehavioral responsebehavioral studychemical propertychronic neuropathic paindesigndrug discoveryendogenous opioidsimprovedin silicoin vivointerdisciplinary approachmalenerve injuryneuroinflammationnon-opioid analgesicnovelp38 Mitogen Activated Protein Kinasepain modelpainful neuropathypharmacophorereceptorrelease of sequestered calcium ion into cytoplasmside effectsmall moleculetargeted treatmenttooltranscriptomics
项目摘要
Chronic neuropathic pain afflicts 15-20 million people in the U.S.1 Defining the molecular mechanisms involved
is key to developing novel non-opioid analgesics.2 We recently discovered that the Gαi protein-coupled receptor
(GPCR) Gpr183 transcript increases in glial cells of the dorsal horn of the spinal cord (DH-SC) following nerve
injury and contributes to ensuing neuropathic pain.3 The primary endogenous ligand for GPR183 is the potent
signaling oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC).4-6 However, little is known about the roles of 7α,25-
OHC/GPR183 in pain beyond our recent publication.3 Moreover, commercial GPR183 antagonists are very
limited and have chemical properties that raise questions about their in vivo utility.3,7 To address this, we initiated
an in silico drug discovery approach that screened 5.5 million commercial compounds with similarities to a
GPR183 pharmacophore model, then docked and ranked the highest similar docking scores.3 The top 16
compounds were tested in calcium mobilization (FLIPR) assays to identify several small-molecule selective
GPR183 antagonists with IC50 values in the nM range, exemplified by SAE-14.3 SAE-14 was counter-screened
against the GPCRome at NIMH PDSP8 with no significant activity for over 300 receptors. Systemic SAE-14
administration reversed mechano-and cold allodynia (behavioral hypersensitivities) induced by nerve injury in
male and female rodents with no observable side effects or engaging the endogenous opioid system.3 These
effects were mimicked by intrathecal (i.th.) injection of SAE-14, identifying the spinal cord as a potential site of
GPR183 antagonist action.3 Moreover, pain behavioral phenotypes were recapitulated by i.th. injection of 7α,25-
OHC or a fluorinated analog that activated Gαi/o-linked (pertussis toxin), GPR183-dependent mitogen-activated
protein kinase (MAPK) signaling (preliminary data). MAPK signaling in the DH-SC is crucial in regulating
neuroinflammatory/pro-nociceptive genes and maintaining persistent pain sensitization.9,10 GPR183-dependent
MAPK signaling was supported by unbiased transcriptomic analysis of the DH-SC from SAE-14-treated rats with
neuropathic pain (preliminary data). SAE-14 lacks sufficient metabolic stability and solubility/absorption
(preliminary data) and structure-activity relationship studies on SAE-14 are necessary for optimization and
discovery of druggable GPR183 antagonists. Based on our published work3 and preliminary data, we
hypothesize that 7α,25-OHC/GPR183 signaling in the DH-SC contributes to the development and maintenance
of neuropathic pain states. Proposed studies in Aim 1 will investigate the role of 7α,25-OHC/GPR183 on MAPK
activation and neuroinflammation in the DH-SC. Then in Aim 2, we will develop GPR183 antagonists based on
SAE-14 and use a testing funnel to screen to find those with optimal stability and bioavailability for in vivo
pharmacological profiling in rodent neuropathic pain models in Aim 3. Our findings will further our understanding
of GPR183 signaling in neuropathic pain and identify the first small molecule GPR183 antagonists with properties
suitable for non-addictive analgesics development addressing a key mission of the HEAL initiative.
在美国,慢性神经性疼痛折磨着1500万到2000万人定义所涉及的分子机制
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Christopher K Arnatt其他文献
41 - Lysophosphatidylserine/GPR34 Signaling in Neuropathic Pain
41 - 神经病理性疼痛中的溶血磷脂酰丝氨酸/GPR34 信号通路
- DOI:
10.1016/j.jpain.2025.104837 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:4.000
- 作者:
Janaine P. Oliveira;Luigi Giancotti;Timothy Doyle;Isaac Readnour;Christopher K Arnatt;John Walker;Daniela Salvemini - 通讯作者:
Daniela Salvemini
Christopher K Arnatt的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Christopher K Arnatt', 18)}}的其他基金
Uncovering the roles of oxysterols in neuropathic pain
揭示氧甾醇在神经性疼痛中的作用
- 批准号:
10659247 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
相似海外基金
Planning Study for the Development of Sigma 2 ligands as Analgesics
Sigma 2 配体镇痛药开发规划研究
- 批准号:
10641500 - 财政年份:2023
- 资助金额:
$ 52.03万 - 项目类别:
Designing and validating optimal nonaddictive analgesics using the CANDO paradigm
使用 CANDO 范式设计和验证最佳的非成瘾性镇痛药
- 批准号:
10485593 - 财政年份:2023
- 资助金额:
$ 52.03万 - 项目类别:
Identification of botanical hHv1 channel blockers as analgesics for neuropathic pain
植物 hHv1 通道阻滞剂作为神经性疼痛镇痛药的鉴定
- 批准号:
10728526 - 财政年份:2023
- 资助金额:
$ 52.03万 - 项目类别:
Development of LPA5 Antagonists as Analgesics
LPA5 拮抗剂镇痛药的开发
- 批准号:
10638278 - 财政年份:2023
- 资助金额:
$ 52.03万 - 项目类别:
Designed Multiple Ligands as Non-opioid Analgesics for Treating Chronic Pain
设计多种配体作为非阿片类镇痛药,用于治疗慢性疼痛
- 批准号:
10621646 - 财政年份:2023
- 资助金额:
$ 52.03万 - 项目类别:
Single-administration microneedles with controlled sustained release of non-opioid analgesics to treat osteoarthritis pain
单次给药微针控制缓释非阿片类镇痛药治疗骨关节炎疼痛
- 批准号:
10425794 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
Elucidation of the mechanism of pain suppression by exercise and development of new analgesics
阐明运动镇痛机制及开发新型镇痛药
- 批准号:
22K19602 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Allosteric Targeting of Cannabinoid CB1 Receptor to Develop Non-Addictive Small Molecule Analgesics
大麻素 CB1 受体变构靶向开发非成瘾性小分子镇痛药
- 批准号:
10512672 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
Single-administration microneedles with controlled sustained release of non-opioid analgesics to treat osteoarthritis pain
单次给药微针控制缓释非阿片类镇痛药治疗骨关节炎疼痛
- 批准号:
10721752 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别:
A novel clinically-relevant mouse model of chronic overlapping pain conditions for screening analgesics
用于筛选镇痛药的新型临床相关慢性重叠疼痛小鼠模型
- 批准号:
10821681 - 财政年份:2022
- 资助金额:
$ 52.03万 - 项目类别: