Satellite Glial Cell P2Y₁₂ Receptor in the Trigeminal Ganglion is Involved in Lingual Neuropathic Pain Mechanisms in Rats

Abstract

BackgroundIt has been reported that the P2Y12 receptor (P2Y12R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y12R in SGC in lingual neuropathic pain.ResultsThe head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.ConclusionsThe present findings provide the first evidence that the activation of P2Y12R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.

P2Y1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells

“…Activated microglia can also release ATP, triggering astrocyte-mediated modulation of excitatory neurotransmission and neuroprotective effects via P2Y 1 (70,71). Within sensory ganglia, P2X 7 , P2Y 1 , P2Y 2 , and P2Y 12 receptors have been identified in SGCs (19,26,27). Furthermore, P2Y receptor signaling in SGCs of rat trigeminal ganglia can be potentiated by nociceptive or pro-algogenic mediators from neurons, including calcitonin gene-related peptide and prostaglandin E 2 (20).…”

“…Purines contribute to nociceptive pathways by activating primary sensory neurons and SGCs (19,20,26,27). We investigated whether purinergic signaling is a mechanism of receptoroperated TRPV4 activation in SGCs.…”

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…More importantly, administration of the P2Y 12 antagonist MRS2395 significantly decreased the number of TG neurons encircled with activated (GFAP-positive) SGCs, and reverted the lowered threshold for the head-withdrawal reflex in response to mechanical and heat stimulation of the tongue [86]. Thus, data show that activation of TG SGCs following induction of neuropathic pain leads to the expression of P2Y 12 receptor, which is causally involved in the enhancement of TG neuron activity and nocifensive reflex behavior, contributing to the development of neuropathic pain.…”

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

“…ATP signals of sensory inputs can activate ionotropic P2X receptors and metabotropic P2Y receptors in the DRG. The P2Y 12 receptor is expressed in DRG SGCs [19,20]. However, the effects of the P2Y 12 receptor on HIV added with combination antiretroviral therapyassociated neuropathic pain in rats are unclear.…”