• Chih-Peng Lin, Kai-Hsiang Kang, Tzu-Hung Lin, Ming-Yueh Wu, Houng-Chi Liou, Woei-Jer Chuang, Wei-Zen Sun, and Wen-Mei Fu.
• From the Department of Anesthesiology (C.-P.L., W.-Z.S.) and Department of Oncology (C.-P.L.), National Taiwan University Hospital, Taipei, Taiwan; Department of Pharmacology (C.-P.L., K.-H.K., T.-H.L., M.-Y.W., H.-C.L., W.-M.F.), College of Medicine, National Taiwan University, Taipei, Taiwan; and Institute of Basic Medical Sciences (W.-J.C.), College of Medicine, National Cheng Kung University, Tainan, Taiwan.
• Anesthesiology. 2015 Mar 1; 122 (3): 666-76.

BackgroundThe pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats.MethodsCerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance.ResultsCXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r = 0.49, P < 0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist.ConclusionsCXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.

23 keywords...

hide…