NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

Abstract

Peripheral and central sensitizations of the trigeminal nervous system are the main mechanisms to promote the development and maintenance of chronic orofacial pain characterized by allodynia, hyperalgesia, and ectopic pain after trigeminal nerve injury or inflammation. Although the pathomechanisms of chronic orofacial pain are complex and not well known, sufficient clinical and preclinical evidence supports the contribution of the N-methyl-D-aspartate receptors (NMDARs, a subclass of ionotropic glutamate receptors) to the trigeminal nociceptive signal processing pathway under various pathological conditions. NMDARs not only have been implicated as a potential mediator of pain-related neuroplasticity in the peripheral nervous system (PNS) but also mediate excitatory synaptic transmission and synaptic plasticity in the central nervous system (CNS). In this review, we focus on the pivotal roles and mechanisms of NMDARs in the trigeminal nervous system under orofacial neuropathic and inflammatory pain. In particular, we summarize the types, components, and distribution of NMDARs in the trigeminal nervous system. Besides, we discuss the regulatory roles of neuron-nonneuronal cell/neuron-neuron communication mediated by NMDARs in the peripheral mechanisms of chronic orofacial pain following neuropathic injury and inflammation. Furthermore, we review the functional roles and mechanisms of NMDARs in the ascending and descending circuits under orofacial neuropathic and inflammatory pain conditions, which contribute to the central sensitization. These findings are not only relevant to understanding the underlying mechanisms, but also shed new light on the targeted therapy of chronic orofacial pain.

Effects of stress contagion on anxiogenic‐ and orofacial inflammatory pain‐like behaviors with brain activation in mice

“…A brainstem pain-modulating system, also known as descending pain controls, with its output node in the rostral ventromedial medulla, regulates deep craniofacial nociception through the regulation of neural activities in the C1/C2 regions [44]; changes in neural activities in the rostral ventromedial medulla could facilitate nociception in various psychological stress models [45][46][47]. The rostral ventromedial medulla, including nucleus raphe magnus and LPGi, has descending 5-HT fibers to the C1/C2 region [13,48].…”

Deciphering migraine pain mechanisms through electrophysiological insights of trigeminal ganglion neurons

“…Additionally, this process can trigger the release of other ions and chemicals, including potassium, proton, and prostaglandin, further amplifying the peripheral sensitization 3 , 38 . CSD-induced NMDA receptor stimulation may also contribute to the peripheral sensitization process 39 . We hypothesize that the higher excitability of SM-sized nociceptive trigeminal ganglion neurons, along with the elevated level of protein expression and the adaptation of relevant receptors, contribute to migrainous aura and also an extreme sensitivity to pain (allodynia) in migraineurs during migrainous attack 40 – 43 .…”

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“…Moreover, the TG system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, 87 TG neuralgia, 88 , 89 and other orofacial pains, 90 as well as ocular pain. 91 …”