|Title:||Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study||Authors:||Lin C.-P.
|Issue Date:||2015||Journal Volume:||122||Journal Issue:||3||Start page/Pages:||666-676||Source:||Anesthesiology||Abstract:||
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 (r2 = 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. Copyright ? 2014, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/564586||ISSN:||33022||DOI:||10.1097/ALN.0000000000000523||SDG/Keyword:||chemokine receptor CXCR2 antagonist; CXCL1 chemokine; fractalkine; gamma interferon inducible protein 10; messenger RNA; monocyte chemotactic protein 1; morphine; neutralizing antibody; tumor necrosis factor alpha; CXCL1 chemokine; CXCL1 protein, human; Cxcl1 protein, rat; narcotic analgesic agent; adult; analgesia; animal experiment; animal model; Article; cancer patient; clinical article; continuous infusion; controlled study; drug efficacy; human; latent period; male; middle aged; morphine tolerance; mouse; nonhuman; priority journal; protein cerebrospinal fluid level; rat; tail flick test; upregulation; aged; animal; cerebrospinal fluid; drug effects; drug tolerance; female; intraspinal drug administration; pain measurement; physiology; procedures; Sprague Dawley rat; translational research; Adult; Aged; Analgesics, Opioid; Animals; Chemokine CXCL1; Drug Tolerance; Female; Humans; Injections, Spinal; Male; Middle Aged; Pain Measurement; Rats; Rats, Sprague-Dawley; Translational Medical Research
|Appears in Collections:||藥理學科所|
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