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.

项目摘要 鞘内持续注射吗啡用于慢性疼痛患者。一个限制是吗啡 导致脑膜形成炎性细胞团(肉芽肿)。我们重述了这些 在导致肉芽肿的腰椎脑脊液浓度相似的犬模型中的观察 与在人类身上观察到的结果相一致。在这笔赠款的最后两个资助周期中，我们表明肉芽肿是 以浓度依赖的方式被吗啡和其他阿片类药物诱导，而根本不被芬太尼或 阿芬太尼。我们推测肉芽肿源于脑膜肥大细胞(MMC)脱颗粒。 因此：i)在体外使MMC脱颗粒并在皮下(SQ)给药后产生皮肤红斑的阿片类药物 A肉芽肿；ii)脑膜/皮下脱颗粒/红斑和肉芽肿被MC阻断 稳定剂色甘露，但不是阿片类拮抗剂。这种阿片受体非依赖性MC的起源 脱颗粒假设是为了反映非肽和多肽阿片配体的阳离子性质。 通过G蛋白偶联受体家族作用于肥大细胞脱颗粒，如Mas相关基因 受体(MRGX)。这些观察共同导致了对假设的详细描述，以刻画和避免 肉芽肿。假设1：阿片类药物引起的肥大细胞脱颗粒不依赖阿片受体 激活，但可能依赖于阳离子电荷激活的受体(MRGX；HFPR)。假设2. 阿片类肉芽肿不依赖于阿片受体的激活，但与非肽和 使肥大细胞脱颗粒的多肽阿片配体。在假设1中，我们将检验浓度依赖关系 阿片类药物(DAMGO、TAPP、达尔加和DMT-Dalga)和非阿片肽(齐康肽)和非阿片肽的作用 多肽(如巴氯芬、可乐定、新斯的明)对：狗的闪光，人的肥大细胞脱颗粒 肥大细胞培养和小鼠原代细胞培养。使用人类肥大细胞培养，我们将检查 使用shRNA的MgrX-r降低该蛋白表达的作用和确定阳离子受体在 肥大细胞脱颗粒。在假设2中，我们将：1)进行狗的剂量反应曲线 上述MU阿片肽用于定义公正的最大有效镇痛剂量：JMEAD和 最大耐受剂量(如急性副作用限制)，ii)定义选定药物的鞘内PK和 三)确定输注最大等效(止痛剂)剂量的这些多肽是否会导致 肉芽肿。