Resveratrol-induced antinociception is involved in calcium channels and calcium/caffeine-sensitive pools

Xiaoyu Pan,Quan Ma,Ling Chen,Ruochuan Cheng,Lin Wang,Weijie Wang,Meixi Zhang,Gang Wang,Jiechun Chen,Jianbo Zhang,Lichao Chen,Hao Wu

doi:10.18632/oncotarget.14090

Abstract

Resveratrol has been widely investigated for its potential health properties, although little is known about its mechanism in vivo. Previous studies have indicated that resveratrol produces antinociceptive effects in mice. Calcium channels and calcium/caffeine-sensitive pools are reported to be associated with analgesic effect. The present study was to explore the involvement of Ca2+ channel and calcium/caffeine-sensitive pools in the antinociceptive response of resveratrol. Tail-flick test was used to assess antinociception in mice treated with resveratrol or the combinations of resveratrol with MK 801, nimodipine, CaCl2, ryanodine and ethylene glycol tetraacetic acid (EGTA), respectively. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) levels in the spinal cord were also investigated when treated with the above drugs. The results showed that resveratrol increased the tail flick latency in the tail-flick test, in dose-dependent manner. N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK 801 potentiated the antinociceptive effects of sub-threshold dose of resveratrol at 10 mg/kg. Ca2+ channel blocker, however, abolished the antinociceptive effects of resveratrol. In contrast to these results, EGTA or ryanodine treatment (i.c.v.) potentiated resveratrol-induced antinociception. There was a significant decrease in p-CaMKII and an increase in BDNF expression in the spinal cord when combined with MK 801, nimodipine, ryanodine and EGTA. While an increase in p-CaMKII level and a decrease in BDNF expression were observed when high dose of resveratrol combined with CaCl2. These findings suggest that resveratrol exhibits the antinociceptive effects by inhibition of calcium channels and calcium/caffeine-sensitive pools.

Highlights

Resveratrol (3, 4′, 5-trihydroxystilbene), a naturally occurring polyphenol compound naturally present in significant amounts in several plants, has garnered considerable interest given its presence in berries, peanuts, grapes, and red wine [1]
To confirm the analgesic effect of resveratrol and whether NMDA receptor antagonist MK 801 is involved in the effect of resveratrol, we examined antinociceptive response of resveratrol in the tail-flick test in mice treated with resveratrol or combined with MK 801
MK 801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, at the dose of 0.5 mg/kg, increased the latency to nociceptive stimulus when combined with resveratrol it did not induce any behavioral changes when it was used alone (p < 0.01) (Figure 1B), which were consistent with the previous studies [19, 20]

Summary

Introduction

Resveratrol (3, 4′, 5-trihydroxystilbene), a naturally occurring polyphenol compound naturally present in significant amounts in several plants, has garnered considerable interest given its presence in berries, peanuts, grapes, and red wine [1]. Previous study reports that both isoforms possess biological activity [2] and inhibit synthesis of proinflammatory mediators by suppressing cyclooxygenase and lipoxygenase pathways, which suggest that resveratrol may have analgesic activity [3,4,5]. L-type Ca2+ channel antagonists, nimodipine for example, produces analgesic effect after central and peripheral administration [12,13,14,15]. The effects of L-type Ca2+ channel inhibitors on nociception differ depending on the drug, dosage, and route of administration and the algesimeter test used [16]. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain derived neurotrophic factor (BDNF) are involved in the oxaliplatin-induced mechanical allodynia [17], and plays an important role in brain cells when talked about pain [18]

Methods

Results

Conclusion