Trigeminal (TG)
pain often lacks a satisfactory pharmacological control. A better understanding of the molecular cross-talk between TG neurons and surrounding satellite glial cells (SGCs) could help identifying innovative targets for the development of more effective
analgesics. We have previously demonstrated that neuronal pro-algogenic mediators upregulate
G protein-coupled
nucleotide P2Y receptors (P2YRs) expressed by TG SGCs in vitro. Here, we have identified the specific P2YR subtypes involved (i.e., the
ADP-sensitive P2Y1 R and the
UTP-responsive P2Y2 R subtypes), and demonstrated the contribution of neuron-derived
prostaglandins to their upregulation. Next, we have translated these data to an in vivo model of TG
pain (namely, rats injected with Complete
Freund's adjuvant in the temporomandibular joint), by demonstrating activation of SGCs and upregulation of P2Y1 R and P2Y2 R in the ipsi-lateral TG. To unequivocally link P2YRs to the development of facial
allodynia, we treated animals with various
purinergic antagonists. The selective P2Y2 R antagonist
AR-C118925 completely inhibited SGCs activation, exerted a potent anti-allodynic effect that lasted over time, and was still effective when administration was started 6-days post induction of
allodynia, i.e. under subchronic
pain conditions. Conversely, the selective P2Y1 R antagonist
MRS2179 was completely ineffective. Moreover, similarly to the anti-inflammatory
drug acetylsalicylic acid and the known anti-
migraine agent
sumatriptan, the P2X/P2Y nonselective antagonist
PPADS was only partially effective, and completely lost its activity under sub-
chronic conditions. Taken together, our results highlight glial P2Y2 Rs as potential "druggable" targets for the successful management of TG-related
pain.