Painful Neuron-Microglia Interactions in the Trigeminal Sensory System

Abstract

Abstract:The trigeminal sensory system is unique in its innervation of structures specific to the orofacial area. Nociceptive trigeminal afferents are known to synapse with second-order neurons in the trigeminal subnucleus caudalis (Sp5C) in the brain stem. The activity of neurons within the Sp5C is responsible for the relay of nociceptive signals to higher brain centers. Recent evidence suggests that central sensitization may be fundamental to many trigeminal-specific painful neuropathies, including trigeminal neuralgia and migraine.Glia within the Sp5C are emerging as prime suspects in trigeminal central sensitization. In particular, microglial activation has been implicated in the development of neuropathic pain. It is possible that activated microglia release factors that alter the activity of second-order neurons or the synaptic activity of peripheral terminals within the Sp5C.Microglial activation has been characterized by changes in morphology, expression of membrane receptors and ion channels, as well as alterations to cytokine and chemokine release. In addition, microglia have been studied in brain slice and dissociated culture where activation is characterized by changes to P2X receptor and potassium channel membrane currents. However, little is known about resting and activated microglial membrane properties in the Sp5C and, furthermore, how these properties are affected following trigeminal nerve injury. This review summarizes the anatomical and pathophysiological importance of the Sp5C and focuses on recent studies on neurons and microglia in the trigeminal sensory system. The final part of the review aims to link important aspects of microglial membrane physiology with their potential role in chronic trigeminal pain conditions.

Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons

“…Elevated CGRP levels in the spinal cord are implicated in the development of central sensitization by mediating changes in the expression of ion channels, receptors, and inflammatory genes in second order neurons and glial cells including astrocytes and microglia. Activation of astrocytes and microglia results in a prolonged inflammatory response that helps to sustain central sensitization and promotes a pathological pain state (Xie, 2008, Davies et al, 2010, Ikeda et al, 2012). …”

Lectin from Abelmoschus esculentus reduces zymosan-induced temporomandibular joint inflammatory hypernociception in rats via heme oxygenase-1 pathway integrity and tnf-α and il-1β suppression

“…It is already known that the perception of pain in the orofacial region involves peripheral and central mechanisms [34]. The trigeminal ganglion transmits impulses to the brainstem at the bridge region, making synapse with second-order neurons in the trigeminal nucleus [35,36]. In this process, nociceptors are sensitized by pro-inflammatory mediators such as prostaglandins (PGE2), serotonin, substance P, tumor necrosis factor (TNF), and interleukins [37].…”

The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells

“…Several other reports confirmed the potential role of HCY in migraine (Lea et al 2009;Oterino et al 2010) although there is still controversy on this issue (Hering-Hanit et al 2001). Recent data indicated an important contribution of neuron-glia crosstalk in many chronic pain states (Ceruti et al 2008;Davies et al 2010;Durham and Garrett 2010;Gu et al 2010;Jasmin et al 2010;Suadicani et al 2010). Notably, homocysteic acid, the close endogenous analog of HCY, could be released from glial cells by glutamate activation of respective ionotropic and metabotropic receptors (Benz et al 2004).…”

“…Many neurodegenerative diseases and chronic pain states are based on neuroglial interactions (Tsuda et al 2013). In the trigeminal ganglia, increased signaling between neuronal cell bodies and satellite glia cells play a supporting factor for chronic pain (Ceruti et al 2008;Davies et al 2010;Durham and Garrett 2010;Suadicani et al 2010). Similar to cortical neurons, trigeminal cells express NR1, NR2A and NR2B subunits of NMDA receptor (Abushik et al 2013), while out of various group I metabotropic glutamate receptors the mGluR5 subtype is mostly expressed (Lee and Ro 2007).…”