title: 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.
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, via Balzaretti, 9, Milan, Italy; Department of Drug Discovery and Development, Italian Institute of Technology (IIT), via Morego, 30, Genoa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Magni
authors.forename: Davide
authors.initials: D
authors.lastname: Merli
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.forename: Stefania
authors.initials: S
authors.lastname: Ceruti
mesh_terms: D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy / Q000503:physiopathology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005157:Facial Pain / Q000188:drug therapy* / Q000503:physiopathology; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism; D027161:Satellite Cells, Perineuronal / Q000187:drug effects* / Q000502:physiology; D013704:Temporomandibular Joint; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D018712:Analgesics, Non-Narcotic; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D005620:Freund's Adjuvant
keywords: AR-C118925; P2Y2 receptors; orofacial pain; satellite glial cells; trigeminal pain