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

The P2Y₁₂ receptor expressed in satellite cells of the trigeminal ganglion is thought to contribute to neuropathic pain. The functional interaction between neurons and satellite cells via P2Y₁₂ receptors and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) underlying neuropathic pain in the tongue was evaluated in this study. Expression of P2Y₁₂ receptor was enhanced in pERK1/2-immunoreactive cells encircling trigeminal ganglion neurons after lingual nerve crush. The administration to lingual nerve crush rats of a selective P2Y₁₂ receptor antagonist, MRS2395, attenuated tongue hypersensitivity to mechanical and heat stimulation and suppressed the increase in the relative numbers of calcitonin gene-related peptide (CGRP)-immunoreactive neurons and neurons encircled by pERK1/2-immunoreactive cells. Administration of the P2Y_1,12,13 receptor agonist, 2-(methylthio)adenosine 5′-diphosphate trisodium salt hydrate (2-MeSADP), to naïve rats induced neuropathic pain in the tongue, as in lingual nerve crush rats. Co-administration of 2-MeSADP + MRS2395 to naïve rats did not result in hypersensitivity of the tongue. The relative number of CGRP-immunoreactive neurons increased following this co-administration, but to a lesser degree than observed in 2-MeSADP-administrated naïve rats, and the relative number of neurons encircled by pERK1/2-immunoreactive cells did not change. These results suggest that the interaction between activated satellite cells and CGRP-immunoreactive neurons via P2Y₁₂ receptors contributes to neuropathic pain in the tongue associated with lingual nerve injury.