Spinal WNT pathway contributes to remifentanil induced hyperalgesia through regulating fractalkine and CX3CR1 in rats.
Tremendous experimental and clinical studies identify that remifentanil anesthesia might elicit postoperative opioid-induced hyperalgesia (OIH) and aggravate nociceptive hypersensitivity, whereas definite mechanisms remain equivocal. WNT signaling and fractalkine pathway have been manifested to participate in varieties of pain pathogenesis, respectively, but no report is on whether they could lead to OIH. This study intended to investigate the effect of WNT3a/β-catenin on fractalkine and its receptor CX3CR1 in OIH in rats model of incision pain.



A WNT scavenger Fz-8/Fc and a neutralizing antibody against CX3CR1 (anti-CX3CR1) were injected intrathecally after remifentanil infusion. Exogenous WNT agonist delivery was utilized in naïve rats. PWT and PWL were documented for postsurgical 48h to assess mechanical and thermal hyperalgesia. Also, expressions of WNT3a, FZ1, FZ8, β-catenin, fractalkine and CX3CR1 in spinal dorsal horn were measured by Western blot and RT-qPCR after nociceptive testing.



We found that postsurgical mechanical and thermal hyperalgesia could be engendered after remifentanil exposure, which was accompanied by a dramatical rise of spinal WNT3a, FZ8, β-catenin, fractalkine and CX3CR1 levels. Moreover, OIH was attenuated by intrathecal application of Fz-8/Fc and anti-CX3CR1. Up-regulation of spinal fractalkine and CX3CR1 expression after remifentanil anesthesia was reversed by Fz-8/Fc. Also, WNT agonist administration could directly generate hypernociception and elevate fractalkine/CX3CR1 level in naïve rats, which was prevented by anti-CX3CR1.



These present findings demonstrated that the involvement of spinal WNT3a/FZ8/β-catenin in OIH through modulating fractalkine/CX3CR1 in rats.
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Gu
G
Gong
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Ling
L
Hu
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Fuen
F
Qin
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Liang
L
Yin
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Xiaobo
X
Yi
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China.
Libang
L
Yuan
Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu 610072, Sichuan, China. Electronic address: wuweichengdu2016@163.com.
Wei
W
Wu
D000701:Analgesics, Opioid / Q000009:adverse effects*; D018686:Anesthetics, Intravenous / Q000009:adverse effects*; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D010149:Postoperative Pain / Q000139:chemically induced / Q000378:metabolism; D010880:Piperidines / Q000009:adverse effects*; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000378:metabolism*; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D051157:Frizzled Receptors; D010880:Piperidines; D019707:Receptors, Chemokine; D060509:Wnt3A Protein; D051176:beta Catenin; D000077208:Remifentanil
Fractalkine; Opioid-induced hyperalgesia; Remifentanil; WNT3a; β-catenin