Role of spinal CXCL1 (GROα) in opioid tolerance: a human-to-rodent translational study.
BACKGROUND
The 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.


METHODS
Cerebrospinal 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.


RESULTS
CXCL1 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.


CONCLUSIONS
CXCL1 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.
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.
Chih-Peng
CP
Lin
Kai-Hsiang
KH
Kang
Tzu-Hung
TH
Lin
Ming-Yueh
MY
Wu
Houng-Chi
HC
Liou
Woei-Jer
WJ
Chuang
Wei-Zen
WZ
Sun
Wen-Mei
WM
Fu
D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D054360:Chemokine CXCL1 / Q000134:cerebrospinal fluid*; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D057170:Translational Research, Biomedical / Q000379:methods*
D000701:Analgesics, Opioid; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat