Validation of Spinal Neurotensin Receptor 2 as an Analgesic Target
脊髓神经降压素受体 2 作为镇痛靶点的验证
基本信息
- 批准号:9976792
- 负责人:
- 金额:$ 16.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2022-07-05
- 项目状态:已结题
- 来源:
- 关键词:AbdomenAbsence of pain sensationAcuteAffectiveAfferent NeuronsAffinityAgonistAmino AcidsAnalgesicsAnimalsArizonaBackBaclofenBindingBlindedBolus InfusionBreakthrough PainCRISPR/Cas technologyCalcium ChannelCaliberCanis familiarisClinicalClinical ResearchClonidineClustered Regularly Interspaced Short Palindromic RepeatsConotoxinDataDevelopmentDissectionDoseDrug Delivery SystemsDrug KineticsElectrophysiology (science)Epidural AnalgesiaFemaleGeneticGranulomaHumanIntractable PainLaboratoriesLeadLocal AnestheticsMalignant NeoplasmsMeasuresMechanicsMediatingMethodsModelingMotorMouse StrainsMulti-Institutional Clinical TrialMusNeuropathyNeurotensinNeurotensin ReceptorsOperative Surgical ProceduresOpioidOpioid AnalgesicsPainPain managementPain qualityParalysedPatientsPeptidesPharmaceutical PreparationsPharmacologyPilot ProjectsPostoperative PainPropertyProtocols documentationPsychotic DisordersRattusResearch DesignResistanceRiskRodentRodent ModelRoleRouteSensorySensory ThresholdsSiteSnail VenomsSpecificitySpinalSpinal GangliaSpinal cord injurySprague-Dawley RatsStimulusTachyphylaxisTestingTherapeuticThoracic Surgical ProceduresUniversitiesUtahValidationVentilatory DepressionViral Vectorbasecancer painchronic neuropathic painclinical effectdorsal horndrug discoveryganglion cellgenetic approachhemodynamicsimprovedin vivoknockout animalmalenon-opioid analgesicnovelpain modelpainful neuropathypower analysispre-clinicalpreferencepresynapticreceptorremote controlresponsesexside effecttherapeutic developmenttooltranscriptomicstranslational studyvoltageziconotide
项目摘要
Project Summary:
Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some
of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative
pain after major abdominal/thoracic surgeries. Despite their profound efficacy, their use is limited primarily because of the side
effects such as tolerance, granuloma, psychosis and motor block. Discovery and validation of new spinal analgesic targets for
development of therapeutics is urgently needed.
Here we propose to validate a novel spinal analgesic target, neurotensin receptor 2 (NTSR2), based upon our mechanistic studies
of Contulakin-G (CGX), that has shown preliminary efficacy in humans suffering from one of the hardest to treat neuropathic
pain condition-spinal cord injury associated pain.
CGX is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans. A
small, pilot Phase1A study demonstrated analgesic effect in some patients with spinal cord injury-associated pain. Although,
CGX does not have favorable pharmacokinetic properties, these studies suggested a possibility of a novel, non-opioid, analgesic
mechanism that is active in humans. Our preliminary studies suggest CGX produces its analgesic actions via activation of spinal
neurotensin receptor 2 (NTSR2) and subsequent inhibition of voltage-gated calcium channels. NTSR2 is highly expressed in
small/medium size sensory neurons in rodents and co-expressed with voltage gated calcium channels. Transcriptomics
confirmed NTSR2 expression in human dorsal root ganglia sensory neurons. Importantly, our pilot studies show that NTSR2
activation by CGX produces profound analgesia and is not associated with unwarranted side effects such as rapid tolerance or
motor blockade. Preliminary data thus support a role of spinal NTSR2 in pain modulation, but validation of this receptor as an
analgesic target has not been done.
In this project, we propose to perform a robust validation of spinal NTSR2 as an analgesic target utilizing three species of both
sexes (rat, mice and human), two models (neuropathic pain and post-surgical pain), pharmacological (SA1) and state of the art
genetic tools such as CRISPR-Cas9 editing (SA2) and assessment of both sensory and affective measures of pain. Moreover, we
propose a rigorous, two-site parallel confirmation study (SA3) designed after multisite clinical trials to further authenticate spinal
NTSR2 as an analgesic target.
If successful, proposed studies could lead to a development of non-opioid spinal analgesic that has high translational potential.
项目总结:
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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Amol M Patwardhan其他文献
Amol M Patwardhan的其他文献
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{{ truncateString('Amol M Patwardhan', 18)}}的其他基金
Mechanism of intrathecal Contulakin-G induced analgesia without motor block
鞘内Contulakin-G诱导无运动阻滞镇痛机制
- 批准号:
10739276 - 财政年份:2022
- 资助金额:
$ 16.41万 - 项目类别:
Mechanism of intrathecal Contulakin-G induced analgesia without motor block
鞘内Contulakin-G诱导无运动阻滞镇痛机制
- 批准号:
10408115 - 财政年份:2018
- 资助金额:
$ 16.41万 - 项目类别:
Mechanism of intrathecal Contulakin-G induced analgesia without motor block
鞘内Contulakin-G诱导无运动阻滞镇痛机制
- 批准号:
9927707 - 财政年份:2018
- 资助金额:
$ 16.41万 - 项目类别: