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Characterization of Toxicity with Spinal Opiates

脊髓阿片类药物的毒性表征

基本信息

批准号：
9300886
负责人：
TONY L. YAKSH
金额：
$ 52.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300886
关键词：
Acute Adenosine Adverse effects Alfentanil Analgesics Appearance Arachnoid mater Baclofen Bupivacaine Canis familiaris Cations Cell Culture Techniques Cell Degranulation Cells Charge Chronic Clonidine Collection Cromoglicic Acid Cutaneous Data Development Dose Dura Mater Family Fentanyl Flare Funding 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 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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：连续鞘内（IT）吗啡输注用于慢性疼痛患者。一个限制是吗啡会导致脑膜产生炎症细胞团（肉芽肿）。我们在犬模型中重现了这些观察结果，其中导致肉芽肿的腰椎脑脊液浓度与在人类中观察到的相当。在这项资助的最后两个资助周期中，我们证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发的，而不是由芬太尼或阿芬太尼诱发的。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) 阿片类药物可使 MMC 离体脱颗粒，并在皮下 (SQ) 递送后引起皮肤耀斑，产生肉芽肿； ii) 脑膜/皮下脱颗粒/耀斑和肉芽肿被 MC 稳定剂色甘酸阻断，但不能被阿片类拮抗剂阻断。这种不依赖于阿片受体的 MC 脱颗粒的起源被假设反映了非肽和肽阿片配体的阳离子特性，这些配体通过 G 蛋白偶联受体家族（例如 Mas 相关基因样受体 (MrgX)）使肥大细胞脱颗粒。这些观察结果共同导致了对表征和避免肉芽肿的假设的阐述。假设 1：阿片类药物对肥大细胞的脱颗粒作用与阿片受体激活无关，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，但会随着非肽和肽阿片配体使肥大细胞脱颗粒的能力而变化。在假设 1 中，我们将检查阿片类药物（DAMGO、TAPP、DALGA 和 DMT-DALGA）和非阿片肽（齐考诺肽）和非肽（例如巴氯芬、可乐定、新斯的明）对以下方面的浓度依赖性影响：狗的耀斑、人原代肥大细胞培养物和小鼠原代细胞培养物中的肥大细胞脱颗粒。使用人类肥大细胞培养物，我们将使用 shRNA 检查 MgrX-r 的作用，以减少该蛋白质表达，并确定该阳离子受体对肥大细胞脱颗粒的作用。在假设 2 中，我们将 i) 在狗中进行 IT 输注上述 mu 阿片肽的剂量反应曲线，以确定最大有效镇痛剂量：JMEAD 和最大可耐受（例如急性副作用有限）剂量 (MTD)，ii) 定义所选药物的鞘内 PK，以及 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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity.

DOI：
10.1213/ane.0b013e3182501a09
发表时间：
2012-08
期刊：
Anesthesia and analgesia
影响因子：
5.7
作者：
Walker SM;Grafe M;Yaksh TL
通讯作者：
Yaksh TL

Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

DOI：
10.2174/1570159x14666160307145542
发表时间：
2017
期刊：
Current neuropharmacology
影响因子：
5.3
作者：
Yaksh TL;Fisher CJ;Hockman TM;Wiese AJ
通讯作者：
Wiese AJ

Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog.

DOI：
10.1111/j.1525-1403.2012.00479.x
发表时间：
2012-11
期刊：
Neuromodulation : journal of the International Neuromodulation Society
影响因子：
0
作者：
Yaksh TL;de Kater A;Dean R;Best BM;Miljanich GP
通讯作者：
Miljanich GP

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.

DOI：
10.1213/ane.0b013e31826253f2
发表时间：
2012-09
期刊：
Anesthesia and analgesia
影响因子：
5.7
作者：
Walker SM;Yaksh TL
通讯作者：
Yaksh TL

Evaluation of spinal toxicity and long-term spinal reflex function after intrathecal levobupivaciane in the neonatal rat.

DOI：
10.1097/aln.0b013e31828fc7e7
发表时间：
2013-07
期刊：
Anesthesiology
影响因子：
8.8
作者：
Hamurtekin E;Fitzsimmons BL;Shubayev VI;Grafe MR;Deumens R;Yaksh TL;Walker SM
通讯作者：
Walker SM