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

Abstract

Migraine is associated with peripheral and central sensitization of the trigeminal system and dysfunction of descending pain modulation pathways. Recently, dietary inclusion of grape seed extract (GSE) was shown to inhibit mechanical nociception in a preclinical model of chronic temporomandibular joint disorder, a condition often comorbid with migraine, with the antinociceptive effect mediated, in part, by activation of 5-HT3/7 and GABAB receptors. This study further investigated the mechanisms by which GSE inhibits mechanical nociception in a preclinical model of episodic migraine. Hyperalgesic priming of female and male Sprague Dawley rats was induced by three consecutive daily two-hour episodes of restraint stress. Seven days after the final restraint stress, rats were exposed to pungent odors from an oil extract that contains the compound umbellulone, which stimulates CGRP release and induces migraine-like pain. Some animals received dietary supplementation of GSE in their drinking water beginning one week prior to restraint stress. Changes in mechanical sensitivity in the orofacial region and hindpaw were determined using von Frey filaments. To investigate the role of the endocannabinoid receptors in the effect of GSE, some animals were injected intracisternally with the CB1 antagonist AM 251 or the CB2 antagonist AM 630 prior to odor inhalation. Changes in CGRP expression in the spinal trigeminal nucleus (STN) in response to stress, odor and GSE supplementation were studied using immunohistochemistry. Exposure of stress-primed animals to the odor caused a significant increase in the average number of withdrawal responses to mechanical stimulation in both the orofacial region and hindpaw, and the effect was significantly suppressed by daily supplementation with GSE. The anti-nociceptive effect of GSE was inhibited by intracisternal administration of antagonists of CB1 and CB2 receptors. GSE supplementation inhibited odor-mediated stimulation of CGRP expression in the STN in sensitized animals. These results demonstrate that GSE supplementation inhibits trigeminal pain signaling in an injury-free model of migraine-like pain via activation of endocannabinoid receptors and repression of CGRP expression centrally. Hence, we propose that GSE may be beneficial as a complementary migraine therapeutic.

Grape seed extract suppresses calcitonin gene-related peptide secretion and upregulates expression of GAD 65/67 and GABAB receptor in primary trigeminal ganglion cultures

“…Thus, the GSE-mediated increase in the functional expression of the GABAB receptor via upregulation of GABAB1 in trigeminal neurons could directly oppose the cellular effects of stimulatory agents such as nitric oxide and cytokines that facilitate CGRP release ( Bowen et al, 2006 , Durham et al, 2006 ). This change in neuronal receptor expression would allow for more GABA binding, which could partially explain some of the inhibitory effects of GSE observed in preclinical orofacial pain models ( Cady et al, 2010 , Cornelison et al, 2020 , Cornelison et al, 2021 , Woodman et al, 2022 ). Increased activation of the GABAB receptors is known to promote potassium efflux, inhibition of calcium influx, and a decrease in cyclic AMP levels in the neurons, resulting in a lower neuronal excitability state ( Padgett and Slesinger, 2010 , Evenseth et al, 2020 ).…”

“…8 ). Previously, we demonstrated that dietary inclusion of GSE functions to enhance descending inhibitory pain signaling in preclinical models of migraine and TMD via activation of serotonergic, GABAergic, and endocannabinoid receptors to suppress central sensitization ( Cornelison et al, 2021 , Woodman et al, 2022 ). Further, the cellular effects of GSE were shown to involve upregulation of basal levels of the enzyme MKP-1, which inactivates the pro-inflammatory MAP kinases, and the glutamate transport proteins GLAST and GLT-1 to lower the extracellular concentrations of this stimulatory neurotransmitter ( Cady, Hirst et al 2010 ).…”

“…Previous findings from our laboratory have provided evidence that the addition of a commercially available grape seed extract (GSE) as a daily supplement to the drinking water of Sprague-Dawley rats inhibits pain signaling in preclinical models of TMD and migraine ( Cornelison et al, 2020 , Cornelison et al, 2021 , Woodman et al, 2022 ). Furthermore, GSE inhibited the development of central sensitization within the spinal cord and peripheral sensitization in the trigeminal ganglion by modulating the excitability state of neurons and glia ( Cady et al, 2010 , Cornelison et al, 2020 , Cornelison et al, 2021 , Woodman et al, 2022 ). The inhibitory effect of GSE involves repression of basal CGRP expression in the spinal cord and involved in part, activation of gamma-aminobutyric acid (GABA) receptors within the spinal cord ( Cornelison et al, 2020 ).…”

Pharmacotherapeutic potential of Vitis vinifera (grape) in age-related neurological diseases

“…Migraine Woodman et al (2022), further investigated how GSE inhibits mechanical nociception in a preclinical model of episodic migraine. In an injury-free paradigm of migraine-like pain, GSE supplementation decreases trigeminal pain signals by activating endocannabinoids and inhibiting the production of CGRP centrally.…”

“…In an injury-free paradigm of migraine-like pain, GSE supplementation decreases trigeminal pain signals by activating endocannabinoids and inhibiting the production of CGRP centrally. GSE may therefore be helpful as an additional migraine therapy (Woodman et al, 2022). The authors of a study by Slavin et al called their investigation Using spice and grape pomace extracts to affect migraine-related indicators in vitro.…”