title: CX3CR1 Mediates Nicotine Withdrawal-Induced Hyperalgesia via Microglial P38 MAPK Signaling.
abstract: Previously, we reported that nicotine withdrawal (NT) significantly increased pain sensitivity in rats. Recent reports suggest that fractalkine is involved in the spinal cord neuron-to-microglia activation via CX3CR1 signaling. However, its contribution to NT-induced hyperalgesia and the underlying mechanisms have yet to be elucidated. In the present study, a rat model of NT was used to test the changes in CX3CR1 expression in the spinal cord. We also evaluated the effect of the CX3CR1 neutralizing antibody on spinal microglial activity, the expression of phosphorylated p38-mitogen-activated protein kinase (p-p38-MAPK) and heat-induced pain responses. We established a NT model via subcutaneous injection of pure nicotine (3 mg/kg), three times daily for 7 days. The expression of CX3CR1 was studied by Western blot and immunofluorescence staining. Following NT, the rats received daily intrathecal injections of CX3CR1 neutralizing antibody for 3 days. The change in paw withdrawal latency (PWL) was observed. The activation of microglia and the expression of p-p38-MAPK were investigated by Western blot and immunofluorescence staining. The expression of CX3CR1 was significantly increased after NT and co-localized with IBA-1. NT rats treated with CX3CR1 neutralizing antibody showed significantly increased PWL on day 4 after NT. Furthermore, the activation of microglia and the expression of p-p38-MAPK in the spinal cord were suppressed. These results indicate that microglial CX3CR1/p38MAPK pathway is critical for the development of pain hypersensitivity after NT.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, 221000, Jiangsu, People's Republic of China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, 221000, Jiangsu, People's Republic of China.|Department of Anesthesiology, Liaocheng People's Hospital, No. 67 Dongchang West Road, Liaocheng City, 252000, Shandong, People's Republic of China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, 221000, Jiangsu, People's Republic of China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, 221000, Jiangsu, People's Republic of China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Liaocheng People's Hospital, No. 67 Dongchang West Road, Liaocheng City, 252000, Shandong, People's Republic of China.
authors.forename: Guannan
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Liaocheng People's Hospital, No. 67 Dongchang West Road, Liaocheng City, 252000, Shandong, People's Republic of China.
authors.forename: Ailan
authors.initials: A
authors.lastname: Yu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, 221000, Jiangsu, People's Republic of China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, 221000, Jiangsu, People's Republic of China.
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, 221000, Jiangsu, People's Republic of China. zhangzongwang@hotmail.com.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, 221000, Jiangsu, People's Republic of China. zhangzongwang@hotmail.com.|Department of Anesthesiology, Liaocheng People's Hospital, No. 67 Dongchang West Road, Liaocheng City, 252000, Shandong, People's Republic of China. zhangzongwang@hotmail.com.
authors.forename: Zongwang
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D007278:Injections, Spinal; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D017628:Microglia / Q000187:drug effects; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C100745:Aif1 protein, rat; D057134:Antibodies, Neutralizing; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D018722:Nicotinic Agonists; D019707:Receptors, Chemokine; D009538:Nicotine; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CX3CR1; Hyperalgesia; Microglia; Nicotine withdrawal; p38 MAP kinase