The role of delta opioid receptors in trigeminovascular pain
δ阿片受体在三叉血管疼痛中的作用
基本信息
- 批准号:10608549
- 负责人:
- 金额:$ 47.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-15 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:Absence of pain sensationAbstinenceAcuteAdenylate CyclaseAffectAgonistAnalgesic Overuse HeadachesAurasBehavioralBindingBiochemicalBiological AssayBrain regionCellsCephalicChronicClinicalClinical TrialsComplexDataDiseaseEffectivenessElectrophysiology (science)EmotionalFundingGTP-Binding ProteinsGeneticGoalsGrantHeadacheHeadache DisordersHot SpotImmunohistochemistryIn Situ HybridizationIndividualKnock-outLinkMapsMigraineModelingOpioidOpioid ReceptorOpioid agonistPACAPR-1 proteinPainPatientsPeripheralPharmaceutical PreparationsPharmacotherapyPopulationPost-Traumatic HeadachesPrevalenceQuality of lifeReceptor ActivationRefractoryRoleSeveritiesSignal TransductionSiteSourceStructure of trigeminal ganglionSystemTestingTherapeuticTrigeminal NucleiTrigeminal SystemViralWorkabuse liabilityallodyniaassociated symptomchronic painconditional knockoutdelta opioid receptordisabilitydrug developmentefficacy evaluationevidence baseexperimental studygamma-Aminobutyric Acidinhibitorinnovationinsightinterdisciplinary approachmidbrain central gray substancemigraine treatmentnovelnovel therapeutic interventionpain processingpain sensitivitypituitary adenylate cyclase activating polypeptidepresynapticreceptorreceptor expressionreturn to usetargeted treatmenttherapeutic targettranslational modeltriptans
项目摘要
Chronic use of commonly used migraine therapies can lead to medication overuse headache (MOH). This is a
paradoxical increase in severity of migraine-associated symptoms and headaches which are refractory to other
treatments. Currently, the first-line treatment for MOH is drug cessation. However, during this abstinence period,
patients continue to suffer from severe migraine, and a majority of MOH patients return to these medications
within the first year. Targeted therapies specifically for MOH would result in better headache management and
increased patient quality of life. One of the accomplishments of the previous funding cycle of this grant was to
test δ opioid receptor (δOR) agonists in multiple headache models, including models of MOH. We found that
δOR activation completely reversed cephalic allodynia induced by chronic medication treatment, revealing δOR
agonists as a novel therapeutic strategy for MOH. In the previous funding cycle, we also performed a large scale
unbiased peptidomic screen to identify overlapping mechanisms between chronic migraine and MOH. We
identified pituitary adenylate cyclase activating polypeptide (PACAP) binding through PAC1 receptor as a
potential link between these two disorders; and that the PACAPergic system may be distinctly involved in pain
facilitation by chronic medication exposure. Upon further analysis we also found that there is high co-expression
between δOR and PACAP or PAC1 in pain-processing regions, including in the periaqueductal grey (PAG) and
trigeminal complex. The overall goal of this renewal is to build upon these exciting findings and determine if δOR
agonists relieve migraine and MOH through inhibition of the PACAPergic system. In Aim 1, we will test G protein
biased δOR agonists in novel translationally significant models of cephalic MOH and determine if they cause
tolerance in this model. These studies will strengthen the evidence for drug development of δOR for MOH. In
Aim 2 we will map the co-expression of δOR with PACAP and PAC1 and use biochemical and
electrophysiological assays to investigate how δOR modulates PACAPergic signaling. Finally, in Aim 3 we will
generate conditional knockouts of δOR in PACAP and PAC1 expressing cells, which will reveal if the behavioral
effects of δOR agonists are regulated through PACAPergic signaling. The experiments proposed in this
application are highly innovative and use a multidisciplinary approach. They will provide important insight on the effectiveness of δOR agonist as a therapeutic target for MOH and headache disorders more broadly and will
determine if δOR agonists work through inhibition of the PACAPergic system. Further, the modulation of the
PACAPergic system by δOR may be fundamental to other δOR behavioral effects, including emotional
modulation and peripheral analgesia.
长期使用常用的偏头痛疗法可导致药物过度使用头痛(MOH)。这是一个
偏头痛相关症状和头痛的严重程度矛盾地增加,这些症状和头痛对其他
治疗。目前,MOH的一线治疗是停药。然而,在这段禁欲时期,
患者继续遭受严重偏头痛的折磨,大多数MOH患者重新使用这些药物
在第一年内。专门针对MOH的靶向治疗将导致更好的头痛治疗和
提高了患者的生活质量。这笔赠款上一个供资周期的成就之一是
在多种头痛模型中测试δ阿片受体(δOR)激动剂,包括MOH模型。我们发现
δOR激活完全逆转慢性药物治疗所致的头痛症,揭示δOR
激动剂作为治疗MOH的新策略。在之前的融资周期中,我们也进行了大规模的
无偏倚的多肽筛选,以确定慢性偏头痛和MOH之间的重叠机制。我们
鉴定通过PAC1受体结合的垂体腺苷环化酶激活多肽
这两种疾病之间的潜在联系;PACAP能系统可能与疼痛明显相关
通过慢性药物暴露来促进。进一步分析,我们还发现存在高共表达
在疼痛处理区,包括在中脑导水管周围灰质(δ)和
三叉神经复合体。此次更新的总体目标是在这些令人兴奋的发现的基础上,确定δ或
激动剂通过抑制PACAP能系统来缓解偏头痛和MOH。在目标1中,我们将测试G蛋白
有偏倚的δ或激动剂在新的有翻译意义的头面部MOH模型中的作用,并确定它们是否导致
此模型中的容差。这些研究将加强δ或MOH药物开发的证据。在……里面
目的2定位δOR与PACAP和PAC1的共表达,并使用生化AND
电生理实验研究δ或如何调节PACAP能信号。最后,在目标3中,我们将
在PACAP和δ表达细胞中产生PAC1OR的条件敲除,这将揭示是否行为
δ或激动剂的作用是通过PACAP能信号调节的。这项研究中提出的实验
应用是高度创新的,并使用多学科的方法。它们将为δ或激动剂作为更广泛的MOH和头痛障碍的治疗靶点的有效性提供重要的见解,并将
确定δ或激动剂是否通过抑制PACAP能系统起作用。此外,调制
δ的δ或可能是其他PACA或行为影响的基础,包括情绪
调制和外周镇痛。
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)
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Amynah Amir Ali Pradhan其他文献
Amynah Amir Ali Pradhan的其他文献
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{{ truncateString('Amynah Amir Ali Pradhan', 18)}}的其他基金
The development of delta opioid receptor agonists for the treatment of opioid withdrawal associated behaviors
用于治疗阿片戒断相关行为的 δ 阿片受体激动剂的开发
- 批准号:
10730457 - 财政年份:2022
- 资助金额:
$ 47.57万 - 项目类别:
The role of delta opioid receptors in trigeminovascular pain
δ阿片受体在三叉血管疼痛中的作用
- 批准号:
9319659 - 财政年份:2016
- 资助金额:
$ 47.57万 - 项目类别:
In Vivo Implications of Agonist Selective Activation of Delta Opioid Receptor
Delta 阿片受体激动剂选择性激活的体内影响
- 批准号:
8660677 - 财政年份:2013
- 资助金额:
$ 47.57万 - 项目类别:
In Vivo Implications of Agonist Selective Activation of Delta Opioid Receptor
Delta 阿片受体激动剂选择性激活的体内影响
- 批准号:
8609140 - 财政年份:2013
- 资助金额:
$ 47.57万 - 项目类别:
In Vivo Implications of Agonist Selective Activation of Delta Opioid Receptor
Delta 阿片受体激动剂选择性激活的体内影响
- 批准号:
8092465 - 财政年份:2011
- 资助金额:
$ 47.57万 - 项目类别:
In Vivo Implications of Agonist Selective Activation of Delta Opioid Receptor
Delta 阿片受体激动剂选择性激活的体内影响
- 批准号:
8248182 - 财政年份:2011
- 资助金额:
$ 47.57万 - 项目类别:
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