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Neurochemical Research

, Volume 40, Issue 11, pp 2252–2261 | Cite as

CX3CR1 Mediates Nicotine Withdrawal-Induced Hyperalgesia via Microglial P38 MAPK Signaling

  • Yonghong Ding
  • Wenhui Shi
  • Guannan Xie
  • Ailan Yu
  • Qinghe Wang
  • Zongwang ZhangEmail author
Original Paper

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.

Keywords

Nicotine withdrawal Hyperalgesia CX3CR1 Microglia p38 MAP kinase 

Abbreviations

NT

Nicotine withdrawal

CX3CR1

Chemokine CX3C motif receptor

SD

Sprague–Dawley

p-p38-MAPK

Phosphorylation of p38-mitogen-activated protein kinase

CPT

Cold pressor test

PKA

Protein kinase A

PKC

Protein kinase C

CaMKII

Calcium/calmodulin-dependent protein kinase II

p38 MAPK

p38-mitogen-activated protein kinase

IBA1

Ionized calcium binding adapter molecule-1

NeuN

Neuronal nucle

GFAP

Glial fibrillary acidic protein

PWL

Paw withdrawal latency

PBS

Phosphate-buffered saline

PFA

Paraformaldehyde

PVDF

Polyvinylidene fluoride membrane

SNI

Spared nerve injury

FKN

Fractalkine

TLR4

Toll-like receptor 4

Notes

Acknowledgments

This work was supported by grants from National Natural Science of China (81471134). Our great thanks also go to the critical scientific opinions of Prof. Li-Cai Zhang from Xuzhou Medical College.

Authors’ Contributions

ZWZ conceived and designed the study. YHD performed the animal surgery, behavioral testing and data analysis. WHS carried out the immunohistochemistry and Western blot. GNX, ALY and QHW participated in behavioral testing and immunohistochemistry experiments. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors report no financial or other conflict of interest relevant to the subject of this manuscript.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yonghong Ding
    • 1
    • 2
    • 3
  • Wenhui Shi
    • 1
    • 2
  • Guannan Xie
    • 3
  • Ailan Yu
    • 3
  • Qinghe Wang
    • 1
    • 2
  • Zongwang Zhang
    • 1
    • 2
    • 3
    Email author
  1. 1.Jiangsu Province Key Laboratory of AnesthesiologyXuzhouPeople’s Republic of China
  2. 2.Jiangsu Key Laboratory of Anesthesia and Analgesia Application TechnologyXuzhouPeople’s Republic of China
  3. 3.Department of AnesthesiologyLiaocheng People’s HospitalLiaocheng CityPeople’s Republic of China

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