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

Chih Peng Lin, Kai Hsiang Kang, Tzu Hung Lin, Ming Yueh Wu, Houng Chi Liou, Woei Jer Chuang, Wei Zen Sun, Wen Mei Fu

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)666-676
Number of pages11
JournalAnesthesiology
Volume122
Issue number3
DOIs
Publication statusPublished - 2015 Mar 4

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Opioid Analgesics
Rodentia
Morphine
Cerebrospinal Fluid
Chemokines
Analgesics
Tail
Neutralizing Antibodies
Intraperitoneal Injections
Neuroglia
Signal Transduction
Neoplasms
Spinal Cord
Tumor Necrosis Factor-alpha
Cytokines
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

Lin, Chih Peng ; Kang, Kai Hsiang ; Lin, Tzu Hung ; Wu, Ming Yueh ; Liou, Houng Chi ; Chuang, Woei Jer ; Sun, Wei Zen ; Fu, Wen Mei. / Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study. In: Anesthesiology. 2015 ; Vol. 122, No. 3. pp. 666-676.
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title = "Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study",
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.",
author = "Lin, {Chih Peng} and Kang, {Kai Hsiang} and Lin, {Tzu Hung} and Wu, {Ming Yueh} and Liou, {Houng Chi} and Chuang, {Woei Jer} and Sun, {Wei Zen} and Fu, {Wen Mei}",
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Lin, CP, Kang, KH, Lin, TH, Wu, MY, Liou, HC, Chuang, WJ, Sun, WZ & Fu, WM 2015, 'Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study', Anesthesiology, vol. 122, no. 3, pp. 666-676. https://doi.org/10.1097/ALN.0000000000000523

Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study. / Lin, Chih Peng; Kang, Kai Hsiang; Lin, Tzu Hung; Wu, Ming Yueh; Liou, Houng Chi; Chuang, Woei Jer; Sun, Wei Zen; Fu, Wen Mei.

In: Anesthesiology, Vol. 122, No. 3, 04.03.2015, p. 666-676.

Research output: Contribution to journalArticle

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T1 - Role of spinal CXCL1 (GROα) in opioid tolerance a human-to-rodent translational study

AU - Lin, Chih Peng

AU - Kang, Kai Hsiang

AU - Lin, Tzu Hung

AU - Wu, Ming Yueh

AU - Liou, Houng Chi

AU - Chuang, Woei Jer

AU - Sun, Wei Zen

AU - Fu, Wen Mei

PY - 2015/3/4

Y1 - 2015/3/4

N2 - 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.

AB - 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.

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