title: Involvement of CCL3/CCR5 Signaling in Dorsal Root Ganglion in Remifentanil-induced Hyperalgesia in Rats.
abstract: Several mechanisms of remifentanil-induced hyperalgesia in spinal cord mainly have been explained such as N-methyl-D-aspartate receptors activation, but the mechanism in dorsal root ganglion (DRG) is poorly understood. It has been reported that CCL3 may be a regulator in both inflammatory pain and hyperalgesia. In this paper we explored whether CCL3 and CCR5, the mainly receptor of CCL3, play a role in the remifentanil-induced hyperalgesia in DRG by using a rat model with remifentanil administration.
  
  
  
  The von Frey test and hot plate test were performed to measure the different threshold to evaluate mechanical and thermal hyperalgesia. Real-time polymerase chain reaction and Western blot analysis were used to evaluate time course of CCL3 and CCR5 expression in DRG after remifentanil infusion. The changes of glial cells and the expression of CCL3 and CCR5 were detected by immunofluorescence assay. Finally, intrathecal injection of CCL3-neutralizing antibody and maraviroc, the CCR5 antagonists, were used sevoflurane to confirm the role of CCL3/CCR5 signaling in the rat model of remifentanil-induced hyperalgesia.
  
  
  
  Remifentanil infusion profoundly increased thermal and mechanical hyperalgesia from 2 to 48 hours according to paw withdrawal latency (PWL) and paw withdrawal thresholds (PWT) (mean±SD, hyperalgesia vs. control, 17.4±0.91 vs. 8.5±1.46 s; 20.1±0.32 vs. 9.6±0.5 g, n=8). Moreover, the expression of mRNAs and proteins of CCL3 and its receptor CCR5 in DRG were dramatically increased after remifentanil infusion as compared with the normal saline group. We also found that CCL3 and CCR5 were colocalized with glial cells or neurons. Furthermore, intrathecal injection of CCL3-neutralizing antibody (mean±SD, hyperalgesia vs. control, 17.4±0.91 vs. 8.5±1.46 s; 20.1±0.32 vs. 9.6±0.5 g, n=5) and maraviroc(mean±SD, hyperalgesia vs. control, 17.4±0.91 vs. 8.5±1.46 s; 20.1±0.32 vs. 9.6±0.5 g, n=5) were able to suppress remifentanil-related thermal and mechanical hyperalgesia according to behavioral test.
  
  
  
  The results highlighted the fact that CCL3 and its receptor CCR5 in DRG might contribute to remifentanil-induced hyperalgesia. Thus CCL3/CCR5 signaling may be further considered in the development of new therapeutic strategies.
authors.affiliation: *Department of Anesthesiology, Tianjin Medical University General Hospital †Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.forename: Ruichen
authors.initials: R
authors.lastname: Shu
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.forename: Zhifen
authors.initials: Z
authors.lastname: Wang
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3 / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000077592:Maraviroc; D010880:Piperidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000378:metabolism*; D000077208:Remifentanil; D014110:Touch; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D003510:Cyclohexanes; D010880:Piperidines; D012333:RNA, Messenger; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc; D000077208:Remifentanil