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.

项目概要 化疗引起的周围神经病变 (CIPN) 出现在接受抗肿瘤药物治疗的患者中，近 70% 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 镇静剂度洛西汀（血清素和去甲肾上腺素摄取的选择性抑制剂）只能有限地缓解疼痛，而 长期使用阿片类药物治疗慢性疼痛存在安全风险。因此，需要新型非阿片类镇痛药 癌症患者的疼痛管理。我们的研究结果表明，脊髓上（大脑中）输送可卡因和 安非他明调节转录肽 II (CART II) 可逆转男性和女性的疼痛样行为（触觉） 患有 CIPN 的小鼠。多种行为输出将提供临床有效性并增强临床的可翻译性 给定目标，从而对慢性疼痛期间 CART II 抗痛觉过敏作用进行全面的剂量评估 两性慢性疼痛多个终点的 CART II 状态是有必要的。之前的研究 发现了 CART II 更广泛的药理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 中。虽然缺乏已知的 CART II 受体阻碍了此类机制研究，但我们发现 溶血磷脂酸受体 2 (LPAR2) 是大脑中 CART II 的高亲和力受体。我们使用细胞- 基于测定和体内药理学工具表明脊髓上 LPAR2 对于 CART II 诱导是必需的 急性镇痛。然而，LPAR2 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 证明治疗剂量的脊髓上 CART II 会增加腹外侧谷氨酸的释放 幼鼠的导水管周围灰质（vlPAG）和伏隔核（NAcc），之前的工作表明兴奋性 对这些大脑部位的输入可以缓解神经性疼痛状态。然而，CIPN 期间的神经传递 vlPAG 和 NAcc 尚未完全建立。该提案的中心假设是 CART II 产生 它通过激活 LPAR2 和增加谷氨酸释放来发挥抗痛觉过敏作用。因此，我们建议充分 通过两种方法检查男性和女性 vlPAG 和 NAcc 中该信号通路的抗痛觉过敏作用 独立但相互关联的目标。目标1将全面评价剂量依赖性抗痛觉过敏药 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 CIPN 治疗潜力的性别差异。掺入正变构调节剂 敲除小鼠将揭示 LPAR2 对于 CART II 的抗痛觉过敏作用是否是必要和充分的。 目标 2 将检查 CART II 介导的神经传递作为其抗痛觉过敏的作用机制 CIPN 中的影响。总的来说，预期的结果将解决人们在理解方面的重大差距。 神经性疼痛状态下的脊髓上机制，并探讨 CA​​RT II/LPAR2 轴作为一种新的机制 逆转已经建立的 CIPN 的治疗策略。