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）：慢性疼痛患者使用了连续鞘内（IT）吗啡输注。一个局限性是吗啡会导致脑膜引起的炎性细胞肿块（肉芽肿）。我们在犬类模型中概括了这些观察结果，其中导致肉芽肿的腰CSF浓度与在人类中观察到的浓度相当。在这笔赠款的最后两个资金周期中，我们表明颗粒瘤是由吗啡和其他阿片类药物以浓度依赖的方式诱导的，而不是芬太尼或阿芬太尼诱导的。我们假设肉芽瘤是由脑膜肥大细胞（MMC）的脱粒引起的。因此：i）鸦片皮下脱脂MMC在皮下（平方英尺）递送后的皮肤耀斑会产生肉芽肿； ii）脑膜/皮下脱粒/耀斑和颗粒瘤被MC稳定器Cromolyn阻塞，但不能被鸦片拮抗作用。假设该阿片类药物不依赖的MC脱粒的起源是反映了作用于G蛋白偶联受体家族（例如Mass相关基因喜欢受体（MRGX））的非肽和肽阿片化配体的阳离子特性。这些观察结果共同导致对假设的阐述，以表征和避免肉芽瘤。假设1：阿片类药物对肥大细胞的脱粒化与阿片受体的激活无关，但可能取决于阳离子电荷激活的受体（MRGX； HFPR）。假设2。阿片类肉芽肿与阿片受体的激活无关，但将与非肽和肽阿片类药物配体脱脂肥大细胞的能力相关。在假设1中，我们将研究阿片类药物（Damgo，Tapp，Dalga和Dmt-Dalga）和非阿片类肽（Ziconotide）和非肽（例如Baclofen，Clonidine，Neostigmine，Neostigmine）的浓度依赖性作用：狗的细胞中的细胞中的细胞培养物中的原始细胞培养物，以及在人类原始细胞中的Flare。使用人类肥大细胞培养物，我们将使用SHRNA检查MGRX-R的作用，以降低该蛋白质表达并定义该阳离子受体在肥大细胞脱粒化中的作用。 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肉芽瘤。

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