P2Y₂ receptor antagonists as anti‐allodynic agents in acute and sub‐chronic trigeminal sensitization: Role of satellite glial cells

Abstract

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.

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

“…Unlike ATP, responses of neurons or SGCs to 100 μM ADP were not sensitive to A839977 application (Fig. 9e, f) consistent with previous data from in mouse SGCs that ADP operates mainly via metabotropic P2Y receptors [27,40].…”

“…Our functional tests providing a rationale for this finding showed that this is because in the rat trigeminal nociceptive system ADP could be an agonist as efficient as ATP. Specifically, ADP generated large Ca 2+ transients not only in neuron but also in glial cells consistent with previous observations obtained in mouse trigeminal cells [27,40,42]. In glial cells, ADP was even more effective likely due to activation of ADP sensitive P2Y receptors [27,34,35].…”

“…Both meninges and trigeminal ganglia contain, in peptidergic neurons, the main migraine mediator neuropeptide CGRP, which could be released in Ca 2+ dependent manner to sensitize ATP-gated P2X receptors, in particular P2X3 subtype [21]. In the trigeminal ganglia, ATP can activate also P2X7 receptors in surrounding glia whereas ADP is a full agonist of metabotropic P2Y1 and P2Y2 receptors in satellite glial cells [40]. Activation of various P2 receptors along with pro-inflammatory action of CGRP initiates neurogenic inflammation.…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…Using a TgCRND8 mouse model of AD, Ajit, et al (2014) demonstrated both that P2Y 2 expression is enhanced in concert with the AD phenotype, and that genetic deletion of P2Y 2 enhances early AD pathology. In addition P2Y 2 receptors expressed on satellite glia participate in the sensitization leading to trigeminal pain (Magni et al, 2015).…”

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

“…55,56 There is a need to develop drug-like P2Y2R antagonists which would further validate the therapeutic potential of P2Y2R antagonism in many disease states. Abbreviations Used: ADME absorption, distribution, metabolism, and excretion;…”