Harnessing ectonucleotidases to treat chronic pain

利用核酸外切酶治疗慢性疼痛

• 批准号: 8332859
• 负责人: Mark J. Zylka
• 金额: $ 73.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332859
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Adenosine; Adenosine A1 Receptor; Adverse effects; Agonist; American; Analgesics; Animal Model; Area; Aspirin; Behavioral; Behavioral Assay; Binding; Biological Assay; Biomedical Research; Childbirth; Chronic; Constipation; Diabetes Mellitus; Electrophysiology (science); Enzymes; Heart Diseases; Human; Inflammation; Left; Life; Malignant Neoplasms; Measures; Membrane; Microglia; Molecular Target; Morphine; Mus; Neurons; Nociception; Non-Steroidal Anti-Inflammatory Agents; Nucleotides; Operative Surgical Procedures; Opioid; P2X-receptor; Pain; Pain Research; Pain management; Patients; Pharmaceutical Chemistry; Physiological; Prodrugs; Property; Proteins; Pump; Purine Nucleotides; Purinoceptor; Recombinants; Rodent; Serum; Signal Transduction; Spinal Cord; Spinal Ganglia; Spinal Injections; Testing; Time; Tissues; Ventilatory Depression; abstracting; addiction; adenosine monophosphate-adenosine; base; chronic pain; drug development; extracellular; inflammatory neuropathic pain; nerve injury; neural circuit; painful neuropathy; patch clamp; pill; prostatic fraction Acid phosphatase isoenzyme; receptor; research study; small molecule

Project Summary / Abstract More Americans suffer from chronic pain than heart disease, diabetes and cancer combined. Unfortunately, existing analgesics are not completely effective for all pain conditions and have serious side effects. These facts highlight what is undoubtedly a critical challenge for modern biomedical research-the need to provide pain relief without serious side effects. We will directly address this challenge by harnessing ectonucleotidases that are found endogenously in nociceptive (pain-sensing) circuits in dorsal root ganglia (DRG) and spinal cord. Ectonucleotidases degrade purine nucleotides (like ATP and ADP) that cause pain into adenosine-a compound that has analgesic properties in rodents and humans. Adenosine suppresses pain by acting through A1-adenosine receptors. To fully harness ectonucleotidases for the treatment of pain, we will identify all of the ectonucleotidases that metabolize nucleotides to adenosine in nociceptive circuits and then determine if these enzymes can be used alone or in combination to treat acute and chronic pain. We will utilize genetically modified mice that are missing these enzymes, recombinant ectonucleotidase proteins, behavioral assays and patch clamp electrophysiology for these experiments. In addition, we will use medicinal chemistry to synthesize adenosine prodrugs that can be converted into potent A1-adenosine receptor agonists by ectonucleotidases. We will measure the stability of these prodrugs in serum and use behavioral and physiological assays to assess analgesic efficacy and side effects. We will also test ectonucleotidases and prodrugs for efficacy in animal models of chronic inflammatory and neuropathic pain.

项目摘要 /摘要 与心脏病，糖尿病和癌症相比，美国人遭受慢性疼痛的痛苦更多。 不幸的是，现有的镇痛药对于所有疼痛条件都不是完全有效的，并且具有严重的副作用。这些事实突出了什么无疑是现代生物医学研究的关键挑战 - 需要减轻疼痛而没有严重的副作用。我们将通过利用在背根神经节（DRG）和脊髓的伤害性（疼痛）电路中内源性的核苷酸酶来直接解决这一挑战。纤维核苷酸酶降解嘌呤核苷酸（例如ATP和ADP），使疼痛变成腺苷A-A-A化合物，具有镇痛性特性 啮齿动物和人类。腺苷通过通过A1-腺苷受体作用来抑制疼痛。为了完全利用核苷酸酶来治疗疼痛，我们将确定所有将核苷酸代谢核苷酸代谢核苷酸酶中的核苷酸酶中的腺苷中的腺苷，然后确定这些酶是否可以单独或合并用于治疗急性和慢性疼痛。我们将利用缺少这些酶的转基因小鼠，重组核苷酸酶蛋白，行为测定和 这些实验的斑块夹电生理学。此外，我们还将使用药物化学来合成腺苷前药，这些前药可以通过邻核核苷酸酶转化为有效的A1-腺苷受体激动剂。我们将测量这些前药在血清中的稳定性，并使用行为和生理测定法来评估镇痛功效和副作用。我们还将测试核苷酸酶和前药在慢性炎症和神经性疼痛的动物模型中的功效。