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

• 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
• 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

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 化疗诱导的周围神经病变（CIPN）在近70%的接受抗肿瘤药物治疗的患者中表现出来。 肿瘤药物，并在治疗停止后持续存在，从而影响患者的生活质量。反- 阿度洛西汀（5-羟色胺和去甲肾上腺素摄取的选择性抑制剂）提供有限的疼痛缓解， 长期使用类阿片治疗慢性疼痛存在安全风险。因此，需要新的非阿片类镇痛药， 癌症患者的疼痛管理。我们的研究结果表明，脊髓上（在大脑中）输送可卡因和 苯丙胺调节转录肽II（CART II）逆转男性和女性的疼痛样行为（触觉） CIPN小鼠多个行为输出将提供临床表面有效性和支持翻译的一个 因此，在慢性疼痛期间CART II抗痛觉过敏作用的全面剂量评价 在两种性别的慢性疼痛的多个终点，两种性别的CART II状态是有道理的。以前的研究 已经揭示了CART II的更广泛的药理学作用和神经肽的全身给药 可能会带来挑战，因此确定CART II的神经化学信号传导机制至关重要 在CIPN。虽然缺乏已知的CART II受体阻碍了这种机制研究，但我们发现， 溶血磷脂酸受体2（LPAR 2）是大脑中CART II的高亲和力受体。我们用手机- 基于分析和体内药理学工具，以显示脊髓上的LPAR 2是CART II诱导的必需的。 急性镇痛然而，LPAR 2在慢性疼痛状态中的作用尚未得到评估。我们的研究结果还 表明治疗剂量的脊髓上CART II增加腹外侧区谷氨酸释放， 在幼稚小鼠中脑导水管周围灰质（vlPAG）和延髓核（NAcc），以前的工作表明兴奋性 输入到这些脑部位可以缓解神经性疼痛状态。然而，在CIPN期间， vlPAG和NAcc尚未完全建立。该建议的中心假设是CART II产生 其通过激活LPAR 2和增加谷氨酸释放的抗痛觉过敏作用。因此，我们建议充分 通过两种方法检查该信号通路在男性和女性vlPAG和NAcc中的抗痛觉过敏作用。 相互独立又相互关联的目标。目的1全面评价剂量依赖性抗痛觉过敏药物 脊髓上CART II对4种不同行为输出测量（触觉、寒冷、焦虑、抑郁）的影响， 询问CIPC治疗潜力的任何性别差异。掺入正变构调节剂 并且敲除小鼠将揭示LPAR 2对于CART II的抗痛觉过敏作用是否是必需的和足够的。 目的2将研究CART II介导的神经传递作为其抗痛觉过敏的作用机制。 在CIPN的影响。总体而言，预期成果将解决在理解《公约》方面存在的重大差距。 神经病理性疼痛状态的脊髓上机制，并询问CART II/LPAR 2轴作为一种新的 逆转已经建立的CIPN的治疗策略。