Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal‐regulated kinase phosphorylation is involved in lingual neuropathic pain

Abstract

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats. The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large-sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs, and neurons encircled with GFAP-IR SGCs was decreased following CGRP receptor blocker CGRP or mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.

Interaction between calcitonin gene‐related peptide‐immunoreactive neurons and satellite cells via P2Y12R in the trigeminal ganglion is involved in neuropathic tongue pain in rats

“…We have previously observed that P2Y 12 receptors regulate satellite cell activation (16). The expression of CGRP, pERK1/2, and GFAP was increased in trigeminal ganglion following lingual nerve crush and this expression was attenuated by administration of a CGRP receptor antagonist and MEK 1/2 inhibitor into the trigeminal ganglion (28). Together with these data, the present results suggest that CGRP is released from trigeminal ganglion neurons, and associated ERK1/2 phosphorylation occurs in satellite cells, leading to satellite cell activation.…”

“…Activated satellite cells also release various cytokines that may further enhance neuronal excitability, leading to neuronal sensitization . Moreover, CGRP is known to be involved in ERK1/2 phosphorylation in trigeminal ganglion neurons , and it is also known that stimulation of bradykinin receptors in neurons causes CGRP to be released from somata to activate P2Y receptors via ERK1/2 signaling in satellite cells, resulting in an increase in cytokine release and satellite cell activation . We have previously observed that P2Y 12 receptors regulate satellite cell activation .…”

“…Phosphorylated ERK1/2-immunoreactive satellite cells were observed following nerve ligation (25), and several lines of evidence suggest that activation of the MAPK pathway in satellite cells affects expression of calcitonin gene-related peptide (CGRP) (26)(27)(28). The neuronal excitability of trigeminal ganglion neurons expressing CGRP is altered (29,30) and these neurons have a fundamental role in the development and maintenance of neuropathic pain in the orofacial region (31).…”

Intrinsic mechanisms of neuronal axon regeneration

“…Recent studies have provided evidence that distant nerve injury induces morphological and molecular changes in SGCs, suggesting that SGCs can recognize and respond to this stimulus. These changes include an increase in GFAP expression 231–236 , extracellular-signal-related kinase (ERK) phosphorylation 237,238 , an increase in SGC coupling via gap junctions 239–241 , downregulation of the ATP-dependent inwardly rectifying potassium channel Kir4.1 (REF. 242 ) and proliferation 231 ’ 243,244 .…”

Etiology and Pharmacology of Neuropathic Pain

“…In addition to the obvious importance of neurons and the accepted role of microglia in the initiation of neuropathic pain (Coull et al, 2005;Lu et al, 2009;Salter, 2012b, 2013), the role of other immunocompetent cells, such as astrocytes, endothelial cells, perivascular macrophages, infiltrating T cells, and Drugs for Neuropathic Pain satellite glial cells of DRG neurons, must not be overlooked (DeLeo et al, 2007;Scholz and Woolf, 2007;Costigan et al, 2009a;Beggs et al, 2010;Calvo et al, 2012;Grace et al, 2014;Vicuna et al, 2015;Dodds et al, 2016;Ji et al, 2016;Lim et al, 2017;Mikuzuki et al, 2017). This follows the recognition that immune cells express many of the receptors and transduction mechanisms that are activated by injury to neurons (Chiu et al, 2012).…”