Anti-nociceptive actions of CART II in chemotherapy-induced peripheral neuropathy

CART II 在化疗引起的周围神经病变中的抗伤害作用

基本信息

批准号：
10719026
负责人：
Matthew Wallace Buczynski
金额：
$ 35.77万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2023-06-09 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719026
关键词：
Absence of pain sensation Acute Acute Pain Affect Affinity Aftercare Analgesics Antidepressive Agents Antineoplastic Agents Anxiety Behavior Behavior Control Behavioral Biological Assay Brain CARTPT gene Cancer Patient Cells Chemicals Chemotherapy-induced peripheral neuropathy Clinical DNQX Data Dose Evaluation Excitatory Amino Acid Antagonists Exhibits Face Female Genetic Glutamates Hyperalgesia Hypersensitivity Impairment Knockout Mice Lysophosphatidic Acid Receptors Mass Spectrum Analysis Measures Mediating Mental Depression Microdialysis Molecular Mood Disorders Mus Neuropeptides Neurotransmitters Nociception Norepinephrine Nucleus Accumbens Opioid Opioid Peptide Output Paclitaxel Pain Pain management Patients Peptides Pharmacologic Actions Pharmacology Pilot Projects Quality of life Risk Role Safety Serotonin Sex Differences Signal Pathway Signal Transduction Site System Tactile Testing Therapeutic Work allodynia antagonist antinociception chronic pain drug candidate duloxetine experimental study extracellular in vivo inhibitor male midbrain central gray substance neurochemistry neurotransmission non-opioid analgesic novel novel therapeutic intervention novel therapeutics pain relief painful neuropathy positive allosteric modulator prevent receptor response sex tool treatment response uptake

项目摘要

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) manifests in nearly 70% of patients treated with anti- neoplastic drugs and persists after treatment discontinuation, thereby impacting patient quality of life. The anti- depressant duloxetine (selective inhibitor of serotonin and norepinephrine uptake) offers limited pain relief, while long-term use of opioids for chronic pain carries safety risks. Thus, novel non-opioid analgesics are needed for pain management in cancer patients. Our findings show that supraspinal (in the brain) delivery of cocaine and amphetamine-regulated transcript peptide II (CART II) reverses pain-like behaviors (tactile) in male and female mice with CIPN. Multiple behavioral outputs would provide clinical face validity and bolster translatability of a given target, thus a comprehensive dose-evaluation of CART II anti-hyperalgesic effects during chronic pain states of CART II in both sexes at multiple endpoints of chronic pain in both sexes is warranted. Previous studies have uncovered broader pharmacological actions of CART II and systemic administration of a neuropeptide likely will impose a challenge, so it is critical to determine the neurochemical signaling mechanisms of CART II in CIPN. While the lack of a known receptor for CART II has prevented such mechanistic studies, we discovered that Lysophosphatidic Acid Receptor 2 (LPAR2) is a high affinity receptor for CART II in the brain. We used cell- based assays and in vivo pharmacology tools to show that supraspinal LPAR2 is necessary CART II-induced acute analgesia. However, the role of LPAR2 in chronic pain states has not been evaluated. Our findings also demonstrate that therapeutic doses of supraspinal CART II increase glutamate release in ventrolateral periaqueductal gray (vlPAG) and nucleus accumbens (NAcc) in naïve mice, and previous work shows excitatory inputs into these brain sites can relieve neuropathic pain states. However, neurotransmission during CIPN in the vlPAG and NAcc has not been fully established. The central hypothesis in this proposal is that CART II produces its anti-hyperalgesic effects via activation of LPAR2 and increased glutamate release. Thus, we propose to fully examine anti-hyperalgesic actions of this signaling pathway in vlPAG and NAcc in males and females via two independent yet interconnected aims. Aim 1 will comprehensively evaluate dose-dependent anti-hyperalgesic effects of supraspinal CART II in 4 different behavioral output measures (tactile, cold, anxiety, depression) to interrogate any sex differences in therapeutic potential for CIPN. Incorporation of a positive allosteric modulator and knockout mice will reveal if LPAR2 is necessary and sufficient for the anti-hyperalgesic actions of CART II. Aim 2 will examine CART II-mediated neurotransmission as a mechanism of action for its anti-hyperalgesic effects in CIPN. Collectively, the expected results will address significant gaps in understanding of the supraspinal mechanisms underlying neuropathic pain states and interrogate the CART II/LPAR2 axis as a novel therapeutic strategy in reversing already established CIPN.

项目摘要化学疗法诱导的周围神经病（CIPN）表现出近70％的抗治疗患者治疗后，肿瘤药物和持续存在，从而影响患者的生活质量。反 - 抑制剂杜洛西汀（5-羟色胺和去甲肾上腺素摄取的选择性抑制剂）可提供有限的疼痛缓解，而长期使用阿片类药物用于慢性疼痛会带来安全风险。这是需要新颖的非阿片类镇痛药的癌症患者的疼痛管理。我们的发现表明，可卡因和苯丙胺调节的转录肽II（CART II）逆转男性和女性的疼痛样行为（触觉）带有CIPN的小鼠。多重行为输出将提供临床面部有效性和辅助的翻译性给定目标，因此在慢性疼痛期间对CART II抗透明效应的全面剂量评估有必要在两个性别的多个终点的两性中的CART II状态。先前的研究发现了CART II和全身给药神经肽的更广泛的药物作用可能会引起挑战，因此确定CART II的神经化学信号传导机制至关重要在CIPN。虽然缺乏CART II的已知受体已经阻止了此类机械研究，但我们发现了溶物磷酸受体2（LPAR2）是大脑中CART II的高亲和力受体。我们使用了细胞基于基于的测定和体内药理学工具，以表明上脊柱上lpar2是必要的购物车II引起的急性镇痛。但是，尚未评估LPAR2在慢性疼痛状态中的作用。我们的发现也是如此证明脊柱上cart的治疗剂量会增加腹外侧的谷氨酸释放幼稚小鼠中的灰灰色（VLPAG）和伏隔核（NACC），以前的工作显示出兴奋性这些大脑部位的输入可以挽救神经性疼痛状态。但是，在CIPN期间的神经传递 VLPAG和NACC尚未完全确定。该提议中的中心假设是CART II产生通过激活LPAR2并增加谷氨酸释放，其抗透明效应。那我们建议完全通过两个在VLPAG和NACC中检查男性和女性的抗高温作用独立但相互联系的目标。 AIM 1将全面评估剂量依赖性的抗高疗法 4种不同行为输出措施（触觉，冷，焦虑，抑郁）中脊柱上车II的影响询问CIPN理论潜力的任何性别差异。掺入阳性变构调节剂敲除小鼠将揭示LPAR2是否需要且足以满足CART II的抗透视作用。 AIM 2将检查CART II介导的神经传递，作为其抗高质量的作用机理 CIPN的影响。总的来说，预期的结果将解决理解的巨大差距神经性疼痛状态下的脊柱上方机制，并将CART II/LPAR2轴作为新颖逆转已经建立的CIPN的治疗策略。