Rezende Rafael Machado, Dos Reis Webster Glayser Pimenta, Duarte Igor Dimitri Gama, Lima Patrícia Paiva, Bakhle Yeshwant S, de Francischi Janetti Nogueira
Laboratory of Inflammation and Pain, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, Brazil.
Pain. 2009 Mar;142(1-2):94-100. doi: 10.1016/j.pain.2008.12.005. Epub 2009 Jan 30.
Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) and blocks prostaglandin (PG) biosynthesis associated with inflammatory conditions. In a model of peripherally induced inflammatory pain in rats, celecoxib, given systemically, induced a state of hypoalgesia where the nociceptive threshold was raised above basal values, an effect not observed after treatment with non-selective inhibitors of COX (indomethacin, piroxicam). Here, we have assessed the possibility that these atypical effects of celecoxib could be mediated by action at a site in the CNS. Inflammation and hyperalgesia were induced in one hind paw of rats by intraplantar injection of carrageenan (250microg). Nociceptive thresholds to mechanical stimulation were measured in the inflammed and contralateral paws for 6h after carrageenan injection. Celecoxib, SC236 (selective COX-2 inhibitors), indomethacin (non-selective COX inhibitor), SC560 (selective COX-1 inhibitor) or morphine were given by i.c.v. injection, 30 min before carrageenan. Celecoxib, SC236 or morphine-induced hypoalgesia whereas, after indomethacin or SC 560, the nociceptive threshold only returned to basal values. Naltrexone, also given i.c.v., reversed the hypoalgesia after celecoxib or morphine. Bestatin, an inhibitor of metabolism of endogenous opioid peptides, given i.c.v., potentiated the analgesic effects of a low dose of celecoxib. Taken together, these data indicate that celecoxib could act centrally after systemic administration to produce its characteristic profile of analgesia in this model of peripheral inflammatory pain. Moreover, this atypical analgesia appeared to be mediated by endogenous opioids rather than by inhibition of PG biosynthesis.
塞来昔布是一种环氧化酶-2（COX-2）的选择性抑制剂，可阻断与炎症状态相关的前列腺素（PG）生物合成。在大鼠外周诱导性炎性疼痛模型中，全身给药的塞来昔布可诱导痛觉减退状态，此时伤害性感受阈值高于基础值，而使用COX非选择性抑制剂（吲哚美辛、吡罗昔康）治疗后未观察到这种效果。在此，我们评估了塞来昔布的这些非典型效应可能通过作用于中枢神经系统中的某个部位来介导的可能性。通过足底注射角叉菜胶（250μg）在大鼠的一只后爪诱导炎症和痛觉过敏。在注射角叉菜胶后6小时，测量炎症爪和对侧爪对机械刺激的伤害性感受阈值。在注射角叉菜胶前30分钟，通过脑室内注射给予塞来昔布、SC236（选择性COX-2抑制剂）、吲哚美辛（非选择性COX抑制剂）、SC560（选择性COX-1抑制剂）或吗啡。塞来昔布、SC236或吗啡可诱导痛觉减退，而在给予吲哚美辛或SC560后，伤害性感受阈值仅恢复到基础值。同样通过脑室内注射给予的纳曲酮可逆转塞来昔布或吗啡后的痛觉减退。脑室内注射内源性阿片肽代谢抑制剂贝司他汀可增强低剂量塞来昔布的镇痛作用。综上所述，这些数据表明，在全身给药后，塞来昔布可在中枢发挥作用，在该外周炎性疼痛模型中产生其特征性的镇痛作用。此外，这种非典型镇痛似乎是由内源性阿片类物质介导的，而不是通过抑制PG生物合成。
