Characterization of Toxicity with Spinal Opiates

脊髓阿片类药物的毒性表征

• 批准号: 8631713
• 负责人: TONY L. YAKSH
• 金额: $ 53.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631713
• 关键词: Accounting; Acute; Adenosine; Adverse effects; Alfentanil; Analgesics; Appearance; Arachnoid mater; Attenuated; Baclofen; Bupivacaine; Canis familiaris; Cell Culture Techniques; Cell Degranulation; Cells; Charge; Chronic; Clonidine; Collection; Cromoglicic Acid; Cutaneous; Data; Development; Dose; Dose-Limiting; Dura Mater; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Family; Fentanyl; Flare; Funding; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Genes; Grant; Granuloma; Human; Hydromorphone; Incidence; Inflammatory; Infusion procedures; Intrathecal Space; Ketamine; Ketorolac; Lead; Ligands; Mast Cell Stabilizer; Mediating; Meningeal; Meninges; Methadone; Modeling; Morphine; Mus; Naloxone; Naltrexone; Neostigmine; Opiates; Opioid; Opioid Peptide; Opioid Receptor; Pain management; Patients; Peptides; Pharmacology; Plasma; Play; Primary Cell Cultures; Property; Receptor Activation; Relative (related person); Risk; Role; Skin; Spinal; Therapeutic; Toxic effect; Work; chronic pain; clinically relevant; mast cell; non-opioid analgesic; prevent; protein expression; public health relevance; receptor; response; small hairpin RNA; subcutaneous; tetra-4-amidinophenoxypropane; tyrosyl-arginyl-phenylalanyl-lysinamide; ziconotide

Project Summary Continuous intrathecal (IT) morphine infusion is used in chronic pain patients. A limitation is that morphine results in an inflammatory cell mass (granuloma) arising from the meninges. We recapitulated these observations in a canine model wherein lumbar CSF concentrations leading to granulomas were comparable to those observed in humans. In the last two funding cycles of this grant, we showed that granulomas are induced in a concentration dependent fashion by morphine and other opiates and not at all by fentanyl or alfentanil. We hypothesized that the granuloma arises from the degranulation of meningeal mast cells (MMC). Thus: i) opiates that degranulate MMCs ex vivo and cutaneous flare after subcutaneous (SQ) delivery produce a granuloma; ii) the meningeal/subcutaneous degranulation/flare and the granuloma are blocked by the MC stabilizer cromolyn, but not by opiate antagonism. The origin of this opiate receptor-independent MC degranulation is hypothesized to reflect the cationic properties of the nonpeptide and peptide opioid ligands acting to degranulate mast cells through G protein coupled receptor families, such as the Mas-related gene like receptors (MrgX). These observations jointly lead to an elaboration of hypotheses to characterize and avoid the granuloma. Hypothesis 1: Degranulation of mast cells by opioid agents is independent of opiate receptor activation but potentially depend upon receptors activated by cationic charge (MrgX; HFPR). Hypothesis 2. The opiate granuloma is independent of opiate receptor activation but will covary with ability of the nonpeptide and peptide opioid ligands to degranulate mast cells. In hypothesis 1, we will examine concentration dependent effects of opioid (DAMGO, TAPP, DALGA, and DMT- DALGA) and nonopioid peptides (ziconotide) and non- peptides (e.g. baclofen, clonidine, neostigmine) on: flare in the dog, mast cell degranulation in human primary mast cell cultures and on murine primary cell cultures. Using the human mast cell cultures, we will examine the role of MgrX-r using shRNA to reduce that protein expression and define the role of that cationic receptor on mast cell degranulation. In hypothesis 2, we will i) undertake dose response curves in dogs with IT infusion of the above mentioned mu opioid peptides to define the just maximally effective analgesic dose: JMEAD and the maximum tolerable (e.g. acute side effect limited) dose (MTD), ii) define intrathecal PK of selected agent and iii) determine if infusion of the maximum equi-effective (analgesic) doses of these peptides lead to a granuloma.

项目概要 持续鞘内（IT）吗啡输注用于慢性疼痛患者。一个限制是吗啡 导致脑膜产生炎症细胞团（肉芽肿）。我们概括了这些 在犬模型中的观察结果，其中导致肉芽肿的腰椎脑脊液浓度具有可比性 对于在人类中观察到的那些。在本次资助的最后两个资助周期中，我们表明肉芽肿是 由吗啡和其他阿片类药物以浓度依赖性方式诱导，而不是由芬太尼或芬太尼诱导 阿芬太尼。我们假设肉芽肿是由脑膜肥大细胞（MMC）脱颗粒引起的。 因此：i) 使 MMC 离体脱粒的阿片类药物和皮下 (SQ) 递送后的皮肤耀斑产生 肉芽肿； ii) 脑膜/皮下脱颗粒/耀斑和肉芽肿被 MC 阻断 稳定剂色甘酸，但不受鸦片拮抗作用。这种不依赖阿片受体的 MC 的起源 假设脱颗粒反映了非肽和肽阿片配体的阳离子特性 通过 G 蛋白偶联受体家族（例如 Mas 相关基因）使肥大细胞脱粒 受体（MrgX）。这些观察结果共同导致了对假设的阐述，以描述和避免 肉芽肿。假设 1：阿片类药物对肥大细胞的脱粒作用与阿片受体无关 激活，但可能取决于阳离子电荷激活的受体（MrgX；HFPR）。假设 2. 阿片肉芽肿与阿片受体激活无关，但会随着非肽和阿片受体的能力而变化。 肽阿片配体使肥大细胞脱粒。在假设 1 中，我们将检验浓度依赖性 阿片类药物（DAMGO、TAPP、DALGA 和 DMT-DALGA）和非阿片肽（齐考诺肽）和非阿片类药物的作用 肽（例如巴氯芬、可乐定、新斯的明）对：狗的耀斑、人类原发性肥大细胞脱颗粒 肥大细胞培养物和小鼠原代细胞培养物。使用人类肥大细胞培养物，我们将检查 MgrX-r 使用 shRNA 减少该蛋白质表达的作用并定义该阳离子受体的作用 肥大细胞脱颗粒。在假设 2 中，我们将 i) 绘制 IT 输注狗的剂量反应曲线 上述μ阿片肽来定义最大有效镇痛剂量：JMEAD和 最大耐受（例如急性副作用有限）剂量 (MTD)，ii) 定义所选药物的鞘内 PK 和 iii) 确定输注这些肽的最大等效（镇痛）剂量是否会导致 肉芽肿。