NMDAR and JNK Activation in the Spinal Trigeminal Nucleus Caudalis Contributes to Masseter Hyperalgesia Induced by Stress.

Wenqing Lin,Baixiang Cheng,Yajuan Zhao,Yongjin Chen,Min Zhang,Li Miao,Qiang Li,Haidan Zhao

doi:10.3389/fncel.2019.00495

Wenqing Lin, Baixiang Cheng + Show 6 more

Open Access

https://doi.org/10.3389/fncel.2019.00495

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Abstract

It is commonly accepted that psychological stress is closely associated with the occurrence and development of chronic orofacial pain. However, the pathogenesis underlying this process has not been fully elucidated. In the present study, we explored the role of N-methyl-D-aspartate receptors (NMDARs) and Jun N-terminal kinase (JNK) mediated intercellular communication between neurons and astrocytes in the spinal trigeminal nucleus caudalis (Vc) in the induction of masseter hyperalgesia by psychological stress in rats. We found that subjecting rats to 14 days of restraint stress (8 h/d) caused a significant decrease in body weight gain, behavioral changes and marked masseter hyperalgesia in the rats. We also found that exposure to restraint stress for 14 days caused the expression of pJNK in astrocytes in the Vc to significantly increase, and intrathecally infusing a JNK inhibitor significantly prevented restraint stress-induced masseter hyperalgesia in the rats. In addition, after exposure to restraint stress for 14 days, the stressed group exhibited a noticeably increased expression level of pNR2B in neurons in the Vc. Then, we intrathecally injected MK-801 (an NMDAR inhibitor) and ifenprodil (a selective NR2B subunit antagonist) and observed that the two types of inhibitors not only alleviated masseter hyperalgesia but also significantly inhibited the phosphorylation of JNK in the Vc after restraint stress; this indicates that the effect of NMDAR antagonists may influence the activation of astrocytic JNK. Furthermore, inhibitors of neuronal nitric oxide synthase (nNOS) activation and guanylate cyclase (GC) inhibitor could not only inhibit the expression of pJNK in the Vc, but also effectively alleviate masseter hyperalgesia induced by restraint stress. Taken together, our results suggest that NMDAR activation could increase JNK phosphorylation in astrocytes after restraint stress, which may depend on the nNOS-GC pathway. The intercellular communication between neurons and astrocytes in the Vc may play a key role in the induction of masseter muscle hyperalgesia by psychological stress in rats.

Highlights

With the development of modern society and the formation of an increasingly fast-paced lifestyle, increasing attention has been drawn to the importance of psychological factors in people’s health
The intrathecal administration of MK-801 or ifenprodil effectively down-regulated the stressinduced increase in pJNK1 (Figure 4B). These results suggested that NMDA and its receptors (NMDARs), NR2Bcontaining NMDARs, are highly expressed in Vc neurons and play a pivotal role in the induction of masseter muscle hyperalgesia and astrocytic Jun N-terminal kinase (JNK) activation by restraint stress in rats
The results suggested that NMDA receptor activation could increase JNK phosphorylation in astrocytes after restraint stress, which may depend on the neuronal nitric oxide synthase (nNOS)-guanylate cyclase (GC) pathway

Summary

Introduction

With the development of modern society and the formation of an increasingly fast-paced lifestyle, increasing attention has been drawn to the importance of psychological factors in people’s health. Studies (Guo et al, 2010; Park et al, 2011; Yang et al, 2018) have indicated that the neurons in the Vc are activated following orofacial nociceptive stimulation, and N-methyl-Daspartate (NMDA), a glutamate neurotransmitter, is involved in signal transmission between astrocytes and neurons, which plays an important role in synaptic transmission. It is not clear how neurons mediate the activation of astrocytes through NMDA and its receptors (NMDARs) in chronic orofacial pain

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