Up-regulation of CXCL1 and CXCR2 contributes to remifentanil-induced hypernociception via modulating spinal NMDA receptor expression and phosphorylation in rats

Neurosci Lett. 2016 Jul 28;626:135-41. doi: 10.1016/j.neulet.2015.12.044. Epub 2015 Dec 24.


Background: It is commonly known that remifentanil exposure during anesthesia might cause postoperative hyperalgesia and promote nociceptive sensitization, but specific mechanisms remain elusive. Recently, chemokine CXCL1 is considered to be involved in inflammatory and neuropathic pain, simultaneously, CXCL1 might facilitate nociceptive process by increasing of NMDA receptor activity. Several studies have also reported that NMDA receptor activation has been associated with development of remifentanil-induce hypernociception (RIH). However, whether CXCL1 could contribute to RIH in rats remains not understood.

Methods: To investigate effect of CXCL1 and its primary receptor CXCR2 on RIH, a selective CXCR2 antagonist SB225002 was administrated intrathecally after remifentanil exposure in rats. PWT and PWL were evaluated and recorded for 48 post-infusion hours to measure mechanical and thermal hyperalgesia. Then expression and phosphorylation of NMDA receptor, CXCL1 and CXCR2 levels in dorsal horn were analyzed by Western blotting and RT-qPCR after nociceptive testing.

Results: We discovered that remifentanil infusion could induce postoperative mechanical and thermal hypernociception, which was effectively reversed by intrathecal delivery of SB225002. Furthermore, spinal CXCL1and CXCR2 mRNA and protein expressions were elevated after remifentanil exposure. It was also found that remifentanil infusion could up-regulate NR2B-containing NMDA receptor expression and phosphorylation in spinal cord, which was markedly inhibited by SB225002.

Conclusion: These findings indicated that up-regulation of CXCL1 and CXCR2 might contribute to RIH via modulating spinal NR2B-containing NMDA receptor expression and phosphorylation in rats.

Keywords: CXCL1; CXCR2; NMDA receptor; Remifentanil-induced hypernociception.

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Animals
  • Chemokine CXCL1 / metabolism*
  • Hyperalgesia / chemically induced
  • Hyperalgesia / metabolism*
  • Male
  • Nociception / drug effects
  • Nociception / physiology*
  • Phenylurea Compounds / administration & dosage
  • Phosphorylation
  • Piperidines / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-8B / antagonists & inhibitors
  • Receptors, Interleukin-8B / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Remifentanil
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Up-Regulation


  • Analgesics, Opioid
  • Chemokine CXCL1
  • Cxcl1 protein, rat
  • Phenylurea Compounds
  • Piperidines
  • Receptors, Interleukin-8B
  • Receptors, N-Methyl-D-Aspartate
  • SB 225002
  • Remifentanil