5-HT3/7 and GABA_B receptors mediate inhibition of trigeminal nociception by dietary supplementation of grape seed extract

Inhibition of Nociception in a Preclinical Episodic Migraine Model by Dietary Supplementation of Grape Seed Extract Involves Activation of Endocannabinoid Receptors

“…The inhibitory effects observed in this migraine model agree with our prior findings that dietary inclusion of GSE can suppress trigeminal sensitization and nociception in preclinical models of temporomandibular joint disorder (13), a prevalent orofacial pain condition comorbid with migraine (47,48). In addition to GSE's ability to prevent development of a primed state, we previously reported that its inclusion as a daily supplement after establishment of prolonged trigeminal sensitization could suppress ongoing allodynia and prevent trigeminal neuron activation in a chronic orofacial pain model (13). Thus, dietary inclusion of GSE can prevent and suppress the development of trigeminal sensitization and hence functions differently than several commonly used anti-migraine therapeutics.…”

“…Results from our study provide evidence that GSE contains biologically active molecules that can inhibit trigeminal nociception via activation of CB1 and CB2 receptors within the upper spinal cord. GSE's effects involving CB1 and CB2 receptors provide further support that this nutraceutical can act centrally to modulate pain signaling since we had previously shown that the inhibitory effect on trigeminal pain signaling involves activation of 5-HT3/5-HT7 and GABAB receptors in the STN (13). Furthermore, supplementation with GSE may protect against the development of a persistent pain state characteristic of chronic migraine since GSE was shown to inhibit sustained nociception in a chronic TMD model (13).…”

“…The GSE used in this study and our prior studies (MegaNatural®-BP GSE) is a highly purified extract from Vitis vinifera seeds containing >90% polyphenols that exhibit anti-inflammatory properties and function as antioxidants ( 13 , 37 , 46 ). The inhibitory effects observed in this migraine model agree with our prior findings that dietary inclusion of GSE can suppress trigeminal sensitization and nociception in preclinical models of temporomandibular joint disorder ( 13 ), a prevalent orofacial pain condition comorbid with migraine ( 47 , 48 ).…”

“…Following basal nociceptive testing, animals designated to receive daily supplementation with GSE had their normal drinking water replaced with a 0.5% solid solution of MegaNatural®-BP GSE (Healthy Origins, Pittsburgh, PA) dissolved in water ( 13 , 37 ). The animals consumed on average 800 mL of 0.5% GSE/kg/week which is equivalent to 114.3 mL/kg/day.…”

“…The descending inhibitory pain modulation pathway involves activation of serotonergic, GABAergic, and endocannabinoid receptors to modulate the excitability state of neurons and glial cells within the STN ( 12 ). In a recent study, dietary inclusion of GSE was shown to inhibit trigeminal pain signaling via involvement of 5-HT3, 5-HT7, and GABAB receptors in animals with a sensitized trigeminal system mediated by neck muscle inflammation ( 13 ). The goal of this study was to test the hypothesis that activation of endocannabinoid receptors and cellular changes in the STN are also involved to mediate the inhibitory effects of GSE in a preclinical episodic migraine model involving restraint stress and exposure to a pungent compound ( 14 ).…”