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

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.

Neural Pathways of Craniofacial Muscle Pain: Implications for Novel Treatments

“…Multiple preclinical studies have established that sensitization of medullary dorsal horn neurons through NMDA receptors, glial cells, neuropeptides, and multiple cytokines and neurotrophins underpins orofacial hyperalgesia, and recent detailed reviews on this topic are available (Chichorro et al 2017; Shinoda et al 2019). Sensitization of medullary dorsal horn neurons involving NMDA receptor and glial cells within Vc also plays an important role in craniofacial muscle hyperalgesia (Ren and Dubner 2011; Lin et al 2019). In contrast to cutaneous hyperalgesia, muscle hyperalgesia involves sensitization of neurons in not only Vc and upper cervical spinal cord but also the transition zone between Vc and the interpolaris (Vc/Vi; Ren and Dubner 2011).…”

“…Sensitization of TNC neurons also mediates masseter hyperalgesia associated with stress: Forced swim stress increases Fos expression in Vc and Vc/Vi induced by masseter injection of formalin (Nakatani et al 2018). Restraint stress induces masseter mechanical hyperalgesia through the NMDA receptor and neuronal nitric oxide synthase in Vc (Lin et al 2019). Therefore, TNC is a critical relay station in which somatosensory input is integrated with multiple factors to modulate pain from craniofacial muscles.…”

Neuroprotective Effect of Moxibustion on Cerebral Ischemia/Reperfusion Injury in Rats by Downregulating NR2B Expression

“…NR2B antagonists have protective effects on LPS-induced JNK phosphorylation in the frontal lobe and hippocampus [ 48 ]. The activation of NMDAR, especially NMDAR containing NR2B, plays a key role in the phosphorylation of JNK in astrocytes [ 49 ]. In this study, we found that the activation of JNK during a cerebral ischemia-reperfusion injury was related to NR2B.…”

Review of Literatures: Physiology of Orofacial Pain in Dentistry

“…However, repetitive stimulation of c-fibers via the inflammation or nerve injury stimulates a gradual increase of neuron excitability or winds them up, causing central sensitization. Evidence showed that blockading NMDA receptors could attenuate chronic inflammatory or neuropathic pain in animal models ( Wong et al, 2014 ; Lin et al, 2019 ; Neyama et al, 2020 ). Subsequently, its mechanism can drive central hyper excitability by chemical mediators and other peptides that remove the magnesium-ion block of NMDA receptors at the trigeminal nucleus caudalis, which could possibly increase pain perception ( Koichi et al, 2011 ).…”