(692.6) P2Y14 receptor inhibition reverses mechanical sensitivity in a mouse model of chronic neuropathic pain

Poster Board Number: B28

Fatma Mufti (Saint Louis University, Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University), Young-Hwan Jung (National Institute of Diabetes and Digestive and Kidney Diseases), Luigino Giancotti (Saint Louis University, Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University), Jinha Yu (National Institute of Diabetes and Digestive and Kidney Diseases), Zhoumou Chen (Saint Louis University, Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University), Ngan Phung (National Institute of Diabetes and Digestive and Kidney Diseases), Kenneth Jacobson (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health), Daniela Salvemini (Saint Louis University, Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University)

Chronic neuropathic pain is a major health issue and an economic burden that affects large numbers of people. Patients suffering from chronic pain have a significantly lowered quality of life, and to date there are no effective treatments for neuropathic pain. The P2Y14 receptor (P2Y14R) is a purinergic G-protein coupled receptor that binds nucleotide-sugars. P2RY14 is widely expressed in the body and is found in the immune system and nervous tissues. Few studies provide evidence that P2Y14R is involved in pain conditions. In rat traumatic nerve injury-induced pain and post-surgical pain models, P2RY14 transcript levels were found to increase on the same side of the spinal cord as the nerve injury. In addition, P2Y14R expression was elevated in an inflammatory pain model after a complete Freund’s adjuvant injection in the rat trigeminal ganglia. Taken together, we hypothesize that the P2Y14R plays a role in the development and maintenance of neuropathic pain. To test this, we used peripheral nerve injury model of neuropathic pain and tested several novel P2R14R antagonists, which had varying potencies and bioavailabilities. Adult male ICR mice went through unilateral chronic constriction of the sciatic nerve, and on day 7 post injury they received a P2Y14R antagonist intraperitoneally and the mechanical sensitivity in the hind paws was assessed. The antagonists rapidly (≤30 min) attenuated, some even reversed, mechanical sensitivity in the mice, with maximal effects observed typically within 1 h post-injection, in a dose-dependent manner. Overall, our findings provide evidence that the P2Y14R is a potential therapeutic target for treating chronic pain, and its antagonists can be candidate drugs for pain treatment.

NIH Intramural Research Program (NIDDK, ZIADK31116) and Saint Louis University Startup (DS) Funds.