Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

Mohammad Zakir Hossain, Shumpei Unno, Hiroshi Ando, Yuji Masuda, Junichi Kitagawa, Mohammad Zakir Hossain, Shumpei Unno, Hiroshi Ando, Yuji Masuda, Junichi Kitagawa

Abstract

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Keywords: astroglia; microglia; neuropathic orofacial pain; orofacial motor activity; satellite glial cells.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The immune response near the site of a nerve injury sensitizes the nerve terminals. Resident mast cells (MC) are activated and release vasodilators that act on blood vessels, leading to infiltration of immune cells, such as neutrophils, monocytes and T-lymphocytes. Monocytes differentiate into macrophages. These immune cells release inflammatory mediators that sensitize terminals of injured and uninjured nerves. Schwann cells (Sch) that cover the myelinated nerves release cytokines (e.g., TNF-α, IL-15) that also facilitate the recruitment and activation of macrophages. ION: Inferior orbital nerve; IAN: Inferior alveolar nerve; MC: Mast cell; T: T-lymphocyte; N: Neutrophil; MN: Monocyte; MAC: Macrophage; TNF-α: Tumor necrosis factor alpha; IL-15: Interleukin 15.
Figure 2
Figure 2
Satellite glial cells (SGCs) surrounding the cell bodies of neurons in the ganglia play an important role in the development of neuropathic pain. Nerve injury leads to the activation and proliferation of SGCs in the sensory ganglia. They interact with neurons through paracrine signaling. ATP, released from SGCs as well as from injured neurons, acts on purinergic receptors, resulting in the mutual activation of neurons and SGCs (indicated in the diagram by straight arrows). Purinergic receptors, P2Y12 and P2X3, are upregulated in the trigeminal ganglion following nerve injury. SGCs express the inwardly rectifying potassium channel, Kir4.1, which helps to maintain extracellular potassium homeostasis. Following nerve injury, expression of Kir4.1 is downregulated in the trigeminal ganglion, thereby increasing extracellular potassium and neuronal excitability. Communication among the SGCs also increases (indicated in the diagram by solid curved arrows), as evidenced by the increase in expression of the common gap junction protein, connexin 43 (Cx43), in the trigeminal ganglion following nerve injury. This communication spreads to the SGCs of nearby neurons, which in turn sensitizes these cells. ATP: Adenosine triphosphate; P2Y12: Purinergic receptor subtype Y12; P2X3: Purinergic receptor subtype X3; Kir4.1: Inwardly rectifying potassium (Kir) channel 4.1. TG: Trigeminal ganglion.
Figure 3
Figure 3
Glial cell involvement in sensory nuclei participates in the development of neuropathic pain. Microglia and astroglia are activated and proliferated in the brainstem sensory nuclei of the trigeminal nerve. Increased primary afferent input following nerve injury causes the release of neurotransmitters and neural and immune mediators, which increase the sensitivity of postsynaptic secondary neurons and activate glial cells. Upon activation, glial cells release mediators (such as ATP, IL-1β, TNF-α and BDNF) that act on secondary neurons and increase their sensitivity. Glutamate–glutamine shuttle activity between astroglia and neurons is increased following nerve injury, thereby increasing the glutamate supply in the synapses between primary and secondary neurons. Cx43 expression increases in astroglia following trigeminal nerve injury, indicating increased communication among the astroglial cells. ATP: Adenosine triphosphate; CGRP: Calcitonin gene-related peptide; BDNF: Brain derived neurotrophic factor; IL-6: Interleukin 6; CCL2: Chemokine ligand 2; IL-1β: Interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; A: Astroglia; M: Microglia.
Figure 4
Figure 4
Temporal profile of microglial and astroglial activation in the motor nucleus of the trigeminal nerve following peripheral nerve injury (inj-V: injury to the trigeminal nerve). Following nerve injury, the numbers of activated microglial and astroglial cells (counted on day 3 and 14 following nerve injury) were increased significantly compared with sham-operated rats. The highest number of activated microglia was observed on day 3 following injury; however, the highest number of activated astroglia was observed on day 14 following injury. The figure is modified from our previous published papers [118,119]. * p < 0.05.
Figure 5
Figure 5
Schematic showing the involvement of glia in the trigeminal motor nucleus in the change in orofacial motor activity following nerve injury. Activated microglia and astroglia are observed in the motor trigeminal nucleus following nerve injury. Similar to sensory nuclei, pro-inflammatory mediators might be released from hyperactive microglia, and these mediators may alter the sensitivity of motor neurons. The astroglial glutamate–glutamine shuttle might also participate in the modulation of motor neuronal activity. BDNF: Brain derived neurotrophic factor; IL-6: Interleukin 6; IL-1β: Interleukin 1 beta; TNF-α: Tumor necrosis factor alpha; Glut: Glutamate; Gln: Glutamine; Gln sth: glutamine synthetase; ADP: Adenosine Diphosphate; Pi: Inorganic phosphate; A: Astroglia; M: Microglia.

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