大麻素受体 1 拮抗剂 AM251 减轻烧伤后机械性痛觉过敏和热痛觉过敏。
Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury.
机构信息
From the Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospitals for Children®, Boston, Massachusetts; and Harvard Medical School, Boston, Massachusetts (M.U., H.I., S.W., E.M., K.Y.T.P, J.M., J.A.J.M.); and Department of Anesthesiology, Fukui University, Fukui, Japan (E.M.).
出版信息
Anesthesiology. 2014 Dec;121(6):1311-9. doi: 10.1097/ALN.0000000000000422.
BACKGROUND
Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain.
METHODS
Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 μg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry.
RESULTS
Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251.
CONCLUSIONS
AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.
背景
烧伤会引起伤害性感受行为，炎症相关的病理性疼痛会导致神经胶质细胞激活。本研究旨在验证以下假说，即烧伤会激活神经胶质细胞，而大麻素受体 1（CB1R）拮抗剂 AM251 可减轻烧伤疼痛。
方法
将麻醉大鼠的背部后爪造成 0.75 厘米的三度烧伤。鞘内给予载体或 AM251（30μg；老年大鼠，每组 6 只）或给予载体、0.1 或 1.0mg/kg 腹腔内注射（年轻大鼠，每组 6 只），于烧伤后即刻开始给药，连续给药 7 天。在伤后 14 天内通过检测腹侧爪来测试机械性痛觉过敏和热痛觉过敏。通过免疫细胞化学评估小胶质细胞和星形胶质细胞的活性。
结果
从伤后第 1 天到第 14 天，在烧伤侧观察到的痛觉过敏（P<0.05）在鞘内和腹腔内给予 AM251（1mg/kg）后从第 3 天到第 14 天明显减轻。从第 3 天到第 12 天观察到的痛觉过敏完全（P<0.05）被鞘内和腹腔内给予 AM251（1mg/kg）逆转。AM251（0.1mg/kg）无作用。小胶质细胞活性（n=3 个时间点）分别增加了 18.5±7.5 和 12.3±1.6（均值±标准差）倍，分别在第 7 天和第 14 天。星形胶质细胞活性（n=4 个时间点）仅在第 7 天增加了 2.9±0.3 倍。AM251 未改变神经胶质细胞的活性。
结论
即使在给药超过 7 天的时间后，AM251 也能抑制烧伤后的伤害性感受行为。尽管许多研究已经证明了 CB1R 激动剂的实用性，但本研究表明，内源性大麻素在烧伤疼痛发展过程中可能具有意外的致痛作用，这可以解释为什么 CB1R 拮抗剂 AM251 可以改善伤害性感受行为。AM251 没有改变神经胶质细胞的活性，但降低了伤害性感受，表明 AM251 作用于激活的神经胶质细胞的下游。
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