Schmidt-Rondon Eric, Wang Zhenping, Malkmus Shelle A, Di Nardo Anna, Hildebrand Keith, Page Linda, Yaksh Tony L
Department of Anesthesiology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States.
Department of Dermatology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States.
Toxicol Appl Pharmacol. 2018 Jan 1;338:54-64. doi: 10.1016/j.taap.2017.10.017. Epub 2017 Oct 27.
Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures.
Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50μL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34/CD45 cells) were employed and β-hexosaminidase in cell-free supernatants were measured to assess degranulation.
A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of β-hexosaminidase. The rank order of drug-induced hMC β-hexosaminidase release was similar to that for flares.
A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.
肥大细胞（MC）脱颗粒与多种临床常用药物的副作用有关。因此，鞘内给药后，占位性、源于脑膜的肿块的形成可能与局部MC脱颗粒有关。我们系统地研究了阿片类和非阿片类镇痛药对犬皮肤潮红以及原代人MC（hMC）培养物的脱颗粒作用。
犬静脉注射丙泊酚麻醉后，进行皮内（ID）注射（50μL）。30分钟时测量潮红直径。对显示出潮红反应的药物，在肌肉注射（IM）MC稳定剂色甘酸（10mg/kg）后进行测试。使用人原代MC（人脐带血CD34/CD45细胞），并测量无细胞上清液中的β-己糖胺酶以评估脱颗粒情况。
观察到几类药物会引起明显的皮肤潮红，包括阿片类药物、齐考诺肽、氯胺酮、ST-91、新斯的明、腺苷、布比卡因、利多卡因、MK-801和48/80。替扎尼定、芬太尼、阿芬太尼、加巴喷丁和巴氯芬未引起潮红。除腺苷、布比卡因和利多卡因外，所有ID药物引起的潮红均被色甘酸减轻。纳洛酮对阿片类药物或48/80引起的潮红无影响。在hMC研究中，48/80导致β-己糖胺酶浓度依赖性释放。药物诱导hMCβ-己糖胺酶释放的顺序与潮红的顺序相似。
多种治疗用药物可使MC脱颗粒。这种作用可能解释了诸如鞘内注射阿片类药物导致的鞘内肉芽肿等副作用。这种脱颗粒作用可能有助于预测新型药物开发中的潜在鞘内毒性。
