title: CXCL12/CXCR4 Signaling Contributes to the Pathogenesis of Opioid Tolerance: A Translational Study.
abstract: Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance.
  
  
  
  The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM.
  
  
  
  CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P < .0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P < .0001; 47.6% vs 17.5% on day 2, P < .0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03).
  
  
  
  The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.
authors.affiliation: From the *Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan; †Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; ‡Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan; and §Material and Chemical Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Lin
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Kang
authors.forename: Huang-Ju
authors.initials: HJ
authors.lastname: Tu
authors.forename: Ming-Yueh
authors.initials: MY
authors.lastname: Wu
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Lin
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Sun
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D016022:Case-Control Studies; D054377:Chemokine CXCL12 / Q000134:cerebrospinal fluid*; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D000701:Analgesics, Opioid; D015415:Biomarkers; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D009020:Morphine