Kratom and Cannabinoid Constituents: Mechanisms and Interactive Effects in Neuropathic Pain
Kratom and Cannabinoid Constituents: Mechanisms and Interactive Effects in Neuropathic Pain
批准号:
10745835
负责人:
SCOTT M. RAWLS
金额:
$43.37万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-07 至 2025-07-31
关键词:
Adrenergic AgentsAdrenergic ReceptorAdverse effectsAffinityAlkaloidsAnxietyArrestinsAttenuatedBehaviorBehavioralBindingBiological AssayBlack raceBody TemperatureC57BL/6 MouseCNR1 geneCNR2 geneCannabidiolCannabinoidsCannabisCellsCoffeeComplexCoupledDataDependenceDevelopmentDorsalDoseExploratory/Developmental GrantFaceFemaleFormalinGTP-Binding ProteinsGene ExpressionGene Expression ProfilingGenesHarvestIn VitroLaboratoriesLigandsMarketingMechanicsMediatingMedicalMitragynaMolecular TargetMotivationMusNamesNatural ProductsNatural RemedyNeuropathyOpioidOpioid ReceptorPainPain MeasurementPharmaceutical PreparationsPharmacologic ActionsPharmacologyPlantsPrevalenceRattusReceptor SignalingRegimenReportingRodentRodent ModelSafetySalesSeriesSerotoninSerotonin Receptor 5-HT1ASideSignal TransductionSpecificitySpinal CordSpinal GangliaStatutes and LawsStimulantSurveysSymptomsTherapeutic EffectTimeTissue HarvestingTransfectionWorkantagonistanxiety reductionanxiety-like behaviorattenuationcannabigerolcannabinoid receptorchemotherapychronic paindifferential expressioneffective therapyexperimental studyin vivoinfancyinflammatory paininsightmalemarijuana usemarijuana use disordermechanical allodyniamidbrain central gray substancemouse modelopioid epidemicopioid useoxaliplatinpain modelpain reductionpainful neuropathypharmacologicprescription opioid addictionpreventreceptorrecruitserotonin receptorward
中文摘要
随着美国阿片类药物危机的持续,那些患有慢性疼痛的人希望更安全,更安全
英文摘要
As the opioid crisis continues in the US, those suffering from chronic pain look to perceived safer and more
effective treatment options, including natural remedies. The scientific evidence, practice, and legislation
surrounding the medical use of Cannabis has been steadily on the rise over the last several decades, with pain
reduction and alleviation of anxiety as its top indications. In addition, Kratom, a coffee-like plant containing
compounds that cause opioid and stimulant effects, has also gained popularity for self-treatment of several
symptoms, including chronic pain, prescription opioid dependence, and anxiety. A recent survey of Kratom
users reported that the strongest predictor of Kratom use was Cannabis use, specifically cannabidiol (CBD).
Indeed, the marketing and sale of Kratom and CBD side by side is on the rise, represented by shops such as
CBD Kratom©. To date there are no studies to investigate whether and how Kratom and Cannabis constituents
may interact. Therefore, it is critical to understand 1) the unique and shared pharmacological actions of
Cannabis and Kratom constituents, and 2) whether and how these constituents may act when used together to
impact potential efficacy and adverse effects. The Ward laboratory was the first to report that the non-
psychoactive cannabis constituent CBD significantly attenuated chemotherapy-induced neuropathic pain in
mice, and this effect involved interactions with the serotonin 5-HT1A receptor. Most recently, we have
determined that another Cannabis constituent cannabigerol (CBG) also attenuates mechanical sensitivity in a
mouse model of oxaliplatin associated neuropathic pain, this time through cannabinoid and adrenergic
mechanisms. The Rawls laboratory first reported in 2020 that the bioactive alkaloid of Kratom, mitragynine,
significantly reduced oxaliplatin-induced mechanical allodynia in rats, and this effect involved interactions with
µ-opioid receptors and adrenergic receptors. Therefore, in addition to their potential anti-neuropathic effects,
these Cannabis and Kratom constituents also share a complex and overlapping polypharmacology. For
example, CBG and mitragynine may share direct antagonistic effects on α2 adrenoreceptors, and all three
compounds may interact with cannabinoid and serotonin receptors to in part mediate their behavioral effects.
Understanding of the receptor and molecular targets for mitragynine and CBG is at its infancy, and the extent
to which CBD, CBG, and mitragynine possess unique but overlapping mechanisms of action remains to be
systematically studied. Furthermore, this likelihood of unique and overlapping mechanisms of action strongly
supports that these constituents will work synergistically in combination, whether it be toward potentiating
putative therapeutic effects or exacerbating adverse effects. This R21 application proposes complementary in
vivo, ex vivo, and in vitro experiments to systematically determine receptor, signaling, and gene expression
interactions underlying the effects of CBD, CBG, and mitragynine, and their interactive effects in mouse
models of neuropathic pain, inflammatory pain, anxiety, and body temperature.
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会议论文
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