Dietary supplementation with grape seed extract prevents development of trigeminal sensitization and inhibits pain signaling in a preclinical chronic temporomandibular disorder model

Abstract

BackgroundThe risk factors neck muscle tension, prolonged jaw opening, and female gender are associated with developing temporomandibular disorders (TMD), which are characterized by persistent sensitization of trigeminal neurons and enhanced pain signaling. Dietary supplementation with a grape seed extract (GSE) can modulate expression of proteins that decrease neuronal excitability and trigeminal sensitization.MethodsMechanical nocifensive thresholds over the masseter were determined using von Frey filaments in male and female adult Sprague Dawley rats. To promote trigeminal sensitization, animals were injected with complete Freund’s adjuvant in the upper trapezius. After 8 days, animals were subjected to near maximal jaw opening and head withdrawal responses were determined for 28 days. Some animals received continuous supplementation with 0.5% GSE in their drinking water two weeks prior to trapezius injections.ResultsProlonged jaw opening increased the average number of nocifensive responses to mechanical stimuli for 14 days in males and females. However, trapezius inflammation prior to jaw opening promoted persistent mechanical sensitivity up to 28 days post‐jaw opening in females, while in males nociceptive levels were still elevated at day 21. Supplementation with GSE, which is enriched in polyphenols and exhibits antioxidant and COX‐2 activity, inhibited trigeminal nociception in response to jaw opening in both male and female sensitized animals.ConclusionsOur findings provide evidence that multiple risk factors contribute to the development of a prolonged state of trigeminal sensitization that is more severe in females and provide preclinical evidence that supplementation with GSE could be beneficial in the management of TMD.

Preclinical models of deep craniofacial nociception and temporomandibular disorder pain

“…Prolonged jaw opening model increases mechanical sensitivity in the face with elevated the level of inflammatory cytokines in the trigeminal root ganglion and upper cervical spinal cord [ 156 ], while repeated jaw openings also increase mechanical sensitivity in the facial region [ 157 ]. Interestingly, the neck inflammation increases mechanical sensitivities in the facial region evoked by prolonged jaw openings [ 158 ], suggesting that chronic tension in the neck and shoulder muscles could involve the nociception in the deep craniofacial tissues.…”

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

“…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.…”

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

“…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 ).…”

“…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 ). The modulatory effects of the neurotransmitter GABA, which is synthesized in neurons by the enzymes glutamate decarboxylase (GAD) 65 and 67, are mediated via activation of the GABA receptors GABAA and GABAB ( Barker and Hines, 2020 , Evenseth et al, 2020 ).…”