PROJECT SUMMARY Millions of chronic pain patients lack adequate therapeutics to treat their pain. Orphan G-protein coupled receptors could be a new avenue to investigate for the treatment of pain and a variety of other health concerns. One interesting candidate is GPR171 that recently was found to be the receptor of the highly abundant neuropeptide, BigLEN. The purpose of this proposed research is to investigate the neural circuitry of this system, BigLEN-GPR171, and its ability to alleviate chronic pain. Our preliminary data show that a GPR171 agonist has antinociceptive properties in chronic pain. In addition, neuropathic pain downregulates GPR171 expression within a key brain region, periaqueductal gray, that is involved in pain modulation. Our hypothesis is that GPR171 within the periaqueductal gray regulates neuropathic pain. To test this hypothesis, we will use molecular and behavioral pharmacology to investigate a GPR171 agonist on chemotherapy-induced neuropathic pain and decipher which brain areas are mediating these responses. Aim 1 will determine the effectiveness of long-term treatment with a GPR171 agonist on treating chronic neuropathic pain. Alterations in GPR171 expression and signaling within the descending pain circuit following chronic pain will be investigated in Aim 2a by using molecular techniques. Aim 2b will use viral knockdown and local administration of GPR171 compounds to determine the role of the periaqueductal gray in relieving neuropathic pain. Overall, this innovative research has important pain therapeutic implications, as it will enhance our understanding of the physiological functions of this novel neuropeptide system.