Principal Investigator: Durham, Paul Louis Summary Our long-term goal is to better understand the cellular and molecular changes in neuron-glia communication mediated by a polyphenol-enriched grape seed extract (GSE) to reduce the burden of chronic pain. Based on findings from our prior NIH grant, we discovered that dietary supplementation with the nutraceutical GSE inhibits trigeminal pain signaling in preclinical models of temporomandibular joint disorder (TMD) and migraine. The mechanism involved modulation of the serotonergic/GABAergic descending inhibitory pain pathway, which is activated by endogenous opioids and endocannabinoids. The inhibitory effects of GSE on trigeminal pain signaling involves activation of GABAB receptors in the spinal cord. GABAB receptors are expressed on the central nervous system glial cells, astrocytes, and microglia, and on trigeminal ganglion satellite glial and Schwann cells. GABAB are Gi/o protein-coupled receptors that decrease intracellular cAMP levels and inhibit activation of the pro-inflammatory signaling enzyme protein kinase A (PKA), whose elevated expression is implicated in the development of chronic pain. The chronic pain reported for TMD, and migraine is associated with sustained peripheral and central sensitization and involves enhanced neuron-glia interactions. A significant role for calcitonin-gene related peptide (CGRP) has been established in the underlying pathology of chronic orofacial pain by enhancing neuron-glia communication in the trigeminal ganglia and spinal trigeminal nucleus. The physiological effects of CGRP, which include promoting neurogenic inflammation and enhancing pain signaling, are mediated via activation of CGRP receptors expressed on satellite glia, Schwann cells, astrocytes, and microglia. CGRP binding to its receptor couples to the Gs protein, activation of adenylate cyclase, increased cAMP levels, and enhanced PKA activity that promote cellular changes in peripheral and central nervous system neurons and glial cells. CGRP also increases expression and activity of the pro- inflammatory and pro-nociceptive enzymes inducible nitric oxide synthase (iNOS) and p38 MAP kinase in glial cells. Recently, we published that GSE could suppress basal CGRP secretion, enhance neuronal expression of the glutamate synthesizing enzymes GAD 65/67, and increase basal expression of GABAB in cultured satellite glia and Schwann cells. In our proposed studies, we will test the hypothesis that GSE-mediated increased expression of Gi/o-coupled GABAB receptors on glial cells will inhibit the stimulatory effects of Gs- coupled CGRP receptors that are implicated in the development of peripheral and central sensitization and chronic pain. Given the need for safer and more effective therapeutic options for managing chronic pain, we will test if dietary inclusion of GSE can lower the concentration of the GABABR agonist baclofen (prescription medicine) for inhibiting CGRP activation of glial cells. Henc...