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

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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.

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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

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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.

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Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, 221000, Jiangsu, People’s Republic of China

    Yonghong Ding, Wenhui Shi, Qinghe Wang & Zongwang Zhang

  2. Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, 221000, Jiangsu, People’s Republic of China

    Yonghong Ding, Wenhui Shi, Qinghe Wang & Zongwang Zhang

  3. Department of Anesthesiology, Liaocheng People’s Hospital, No. 67 Dongchang West Road, Liaocheng City, 252000, Shandong, People’s Republic of China

    Yonghong Ding, Guannan Xie, Ailan Yu & Zongwang Zhang

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  1. Yonghong Ding
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  2. Wenhui Shi
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Correspondence to Zongwang Zhang.

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Ding, Y., Shi, W., Xie, G. et al. CX3CR1 Mediates Nicotine Withdrawal-Induced Hyperalgesia via Microglial P38 MAPK Signaling. Neurochem Res 40, 2252–2261 (2015). https://doi.org/10.1007/s11064-015-1715-x

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