Stemming the opioid-induced pain cascade via cannabinoid modulation
通过大麻素调节阻止阿片类药物引起的疼痛级联反应
基本信息
- 批准号:10218325
- 负责人:
- 金额:$ 20.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerolAcuteAnalgesicsAnimal ModelAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAttentionAttenuatedBehaviorBehavioralBehavioral ModelBindingBiologicalCNR1 geneCNR2 geneCannabinoidsCannabisChemicalsChronicDataDepressed moodDevelopmentDiseaseDrug TargetingDrug abuseEndocannabinoidsEnzymesExperimental Animal ModelFemaleGeneticGlycerolGoalsGoldHarvestHumanHyperalgesiaImmunologicsIn VitroIncubatedIndividualInflammationInflammatoryInjuryLiteratureMAGL inhibitorMeasuresModelingMonoacylglycerol LipasesMorphineMorphine UsersMotivationMusNeedlestick InjuriesNeuronsOpiate AddictionOpioidPainPainlessPathway interactionsPerceptionPeripheralPharmaceutical PreparationsPharmacologyPhysiologicalPhysiological ProcessesPostoperative PainPostoperative PeriodPropertyQuality of lifeRelapseReportingResearchRiskSpinal CordSplenocyteStimulusSubstance Use DisorderSurfaceSurgical incisionsSurgical suturesTLR4 geneTestingTherapeuticTherapeutic InterventionThermal HyperalgesiasTissuesTranslational ResearchTreatment outcomeWithdrawalWomanallodyniabasecannabinoid receptorcannabinoid receptor antagonistcombatconditioningcytokinedependence relapsedesensitizationdrug relapseeffective therapyendogenous cannabinoid systemexogenous cannabinoidinflammatory painmacrophagemalemarijuana usemechanical allodyniamonocytemorphine administrationmu opioid receptorsneurobehavioralnovel strategiesopioid abuseopioid epidemicopioid exposureopioid sparingopioid useopioid use disorderopioid useropioid withdrawalpain perceptionpain sensitivitypainful neuropathypreclinical studyprescription opioidpreventreceptorrelating to nervous systemresponsesexside effectstemsubstance abuse treatment
项目摘要
Despite their abuse potential, opioids remain a gold standard analgesic. One of the lesser
discussed effects of chronic opioid use is opioid induced hyperalgesia (OIH), or increased pain
sensitivity in some users. OIH persists for a longer duration than opioid withdrawal and may
contribute to drug seeking and relapse in people with substance use disorders. The
physiological causes of OIH are caused by (1) repeated µ opioid activation and desensitization,
and (2) activation of inflammatory pathways by morphine binding to Toll-like receptor 4.
Cannabinoids have well established analgesic and anti-inflammatory properties. Endogenous
cannabinoids (i.e., endocannabinoids) have anti-inflammatory effects with limited intoxicating
effects, as compared with exogenous cannabinoids. The proposed study will use an
experimental animal model of repeated morphine exposure, followed by paw incision injury. Our
goal is to test the hypothesis that inhibition of the endocannabinoid catabolic enzyme
monoacylglycerol lipase (MAGL) decreases pain and inflammation caused by repeated
morphine treatment. Male and female mice will be repeatedly administered morphine or vehicle,
in the presence of increased endocannabinoid tone, for four days. Endocannabinoid tone will be
increased by either chemical inhibition of MAGL, or genetic deletion of MAGL globally or on
neurons only. Then, a small incision will be made and sutured closed in the plantar surface of
one hindpaw, to model postoperative hyperalgesia. Mice will be tested repeatedly for pain-
induced, pain-suppressed, and pain conditioning behavioral models. Endocannabinoid receptor
mechanism will be determined using selective CB1 and CB2 cannabinoid receptor antagonists.
Paw tissue will be collected to quantify proinflammatory cytokine levels, and individual cytokine
levels will be correlated with pain-related behaviors. The anti-inflammatory mechanisms of
endocannabinoid modulation will be further probed in vitro, using isolated
macrophages/monocytes. Extant studies of preclinical OIH models have used male animals
almost exclusively. Because women may be at increased risk for developing OIH, we will
include sufficient numbers of both female and male mice to investigate Sex as a Biological
Variable. In addition to increasing basic understanding of the underlying neural and
immunological mechanisms that contribute to opioid-induced hyperalgesia, our translational
research goal is to develop treatments for substance abuse disorders.
尽管存在滥用的可能性,阿片类药物仍然是镇痛的黄金标准。较小的之一
讨论的长期使用阿片类药物的影响是阿片类药物引起的痛觉过敏 (OIH) 或疼痛增加
某些用户的敏感性。 OIH 比阿片类药物戒断持续时间更长,并且可能
导致药物滥用障碍患者寻求药物并导致复吸。这
OIH 的生理原因是由 (1) 反复μ阿片类药物激活和脱敏引起的,
(2)吗啡与 Toll 样受体 4 结合激活炎症通路。
大麻素具有良好的镇痛和抗炎特性。内源性
大麻素(即内源性大麻素)具有抗炎作用,但中毒作用有限
与外源性大麻素相比的效果。拟议的研究将使用
重复吗啡暴露,随后爪子切口损伤的实验动物模型。我们的
目的是检验抑制内源性大麻素分解代谢酶的假设
单酰基甘油脂肪酶 (MAGL) 可减轻反复发作引起的疼痛和炎症
吗啡治疗。雄性和雌性小鼠将被重复施用吗啡或媒介物,
在内源性大麻素浓度增加的情况下,持续四天。内源性大麻素音调将是
通过 MAGL 的化学抑制或 MAGL 的全局或局部基因删除而增加
仅神经元。然后,在足底表面切一个小切口并缝合。
一只后爪,模拟术后痛觉过敏。小鼠将被反复测试疼痛-
诱发、疼痛抑制和疼痛调节行为模型。内源性大麻素受体
机制将使用选择性 CB1 和 CB2 大麻素受体拮抗剂来确定。
将收集爪组织以量化促炎细胞因子水平和个体细胞因子
水平将与疼痛相关行为相关。抗炎机制
内源性大麻素的调节将在体外进一步探讨,使用分离的
巨噬细胞/单核细胞。现有的临床前 OIH 模型研究使用雄性动物
几乎完全。由于女性患 OIH 的风险可能更高,我们将
包括足够数量的雌性和雄性小鼠来研究性别作为生物
多变的。除了增加对底层神经和
导致阿片类药物引起的痛觉过敏的免疫机制,我们的翻译
研究目标是开发药物滥用障碍的治疗方法。
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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Steven G. Kinsey其他文献
#74 Steroid resistance and anxiety-like behaviors develop in aged, socially defeated CD-1 mice
- DOI:
10.1016/j.bbi.2005.10.080 - 发表时间:
2005-07-01 - 期刊:
- 影响因子:
- 作者:
Steven G. Kinsey;Michael T. Bailey;John F. Sheridan;David A. Padgett - 通讯作者:
David A. Padgett
Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation
- DOI:
10.1208/s12248-008-9075-y - 发表时间:
2009-01-29 - 期刊:
- 影响因子:3.700
- 作者:
Joel E. Schlosburg;Steven G. Kinsey;Aron H. Lichtman - 通讯作者:
Aron H. Lichtman
The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB<sub>2</sub> receptor activation
- DOI:
10.1016/j.neuropharm.2024.110216 - 发表时间:
2025-02-15 - 期刊:
- 影响因子:
- 作者:
Antonio Matt Reck;David P. Siderovski;Steven G. Kinsey - 通讯作者:
Steven G. Kinsey
Steven G. Kinsey的其他文献
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{{ truncateString('Steven G. Kinsey', 18)}}的其他基金
Stemming the opioid-induced pain cascade via cannabinoid modulation
通过大麻素调节阻止阿片类药物引起的疼痛级联反应
- 批准号:
10435486 - 财政年份:2021
- 资助金额:
$ 20.13万 - 项目类别:
Reducing the deleterious effects of synthetic cannabinoid withdrawal on emotionality and motivation
减少合成大麻素戒断对情绪和动机的有害影响
- 批准号:
10134039 - 财政年份:2020
- 资助金额:
$ 20.13万 - 项目类别:
Endocannabinoid modulation of affective signs of cannabinoid withdrawal
内源性大麻素对大麻素戒断情感体征的调节
- 批准号:
8806670 - 财政年份:2015
- 资助金额:
$ 20.13万 - 项目类别:
Targeting multiple enzyme systems to reduce arthritic pain and inflammation
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- 批准号:
8878443 - 财政年份:2015
- 资助金额:
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