Resveratrol attenuates inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis neurons associated with hyperalgesia in rats

Abstract

Background: Resveratrol, a component of red wine, has been reported to decrease prostaglandin E2 production by inhibiting the cyclooxygenase-2 cascade and to modulate various voltage-dependent ion channels, suggesting that resveratrol could attenuate inflammatory hyperalgesia. However, the effects of resveratrol on inflammation-induced hyperexcitability of nociceptive neurons in vivo remain to be determined. Thus, the aim of the present study was to determine whether daily systemic administration of resveratrol to rats attenuates the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis wide-dynamic range neurons associated with hyperalgesia.

Results: Inflammation was induced by injection of complete Freund's adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to whisker pad in inflamed rats was significantly lower than in control rats. The decreased mechanical threshold in inflamed rats was restored to control levels by daily systemic administration of resveratrol (2 mg/kg, i.p.). The mean discharge frequency of spinal trigeminal nucleus caudalis wide-dynamic range neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after resveratrol administration. In addition, the increased mean spontaneous discharge of spinal trigeminal nucleus caudalis wide-dynamic range neurons in inflamed rats was significantly decreased after resveratrol administration. Similarly, resveratrol significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, resveratrol restored the expanded mean size of the receptive field in inflamed rats to control levels.

Conclusion: These results suggest that chronic administration of resveratrol attenuates inflammation-induced mechanical inflammatory hyperalgesia and that this effect is due primarily to the suppression of spinal trigeminal nucleus caudalis wide dynamic range neuron hyperexcitability via inhibition of both peripheral and central cyclooxygenase-2 cascade signaling pathways. These findings support the idea of resveratrol as a potential complementary and alternative medicine for the treatment of trigeminal inflammatory hyperalgesia without side effects.

Keywords: Inflammation; cyclooxygenase; hyperalgesia; resveratrol; single unit recording; trigeminal system.

Figure 1.

Comparison of changes in the escape threshold among naïve (control), inflamed, and resveratrol-treated inflamed rats. Mechanical stimulation using von Frey hairs was applied to the ipsilateral whisker pad of naïve (saline injected; n = 7), inflamed rats (injection of CFA into the whisker pad; n = 8) and resveratrol-treated inflamed (2 mg/kg, i.p.; n = 10) rats to assess hyperalgesia. Data are the mean ± SEM. *p < 0.05 compared with inflamed rats; ^#p < 0.05 compared with Day 1. CFA: complete Freund’s adjuvant.

Figure 2.

General characteristics of SpVc WDR neuronal activity in the whisker pad. (a) Receptive field of the whisker pad in the facial skin. (b) Distribution of SpVc WDR neurons responding to nonnoxious and noxious mechanical stimulation of the facial skin (n = 25). Numbers below each drawing indicate the frontal plane in relation to the obex. (c) Examples of SpVc WDR neuronal firing in response to nonnoxious and noxious mechanical stimuli. SpVc: spinal trigeminal nucleus caudalis; WDR: wide-dynamic range.

Figure 3.

Reversal by chronic resveratrol of SpVc WDR neuronal hyperactivity after induction of orofacial inflammation. Examples of discharges from SpVc WDR neurons in response to nonnoxious and noxious mechanical stimulation in (a) naïve (control), (b) inflamed, and (c) resveratrol-treated inflamed rats (2 mg/kg, i.p.). Note that resveratrol administration restored the inflammation-induced decreases in the mechanical stimulation threshold to evoke neuronal firing, increases in spontaneous discharge and the size of the receptive field, and the occurrence of noxious pinch-evoked discharges in inflamed rats to control levels. SpVc: spinal trigeminal nucleus caudalis; WDR: wide-dynamic range.

Figure 4.

Summary of resveratrol reversal of the augmented discharge frequency of SpVc WDR neurons after induction of orofacial inflammation. (a) Mean discharge frequencies of SpVc WDR neurons evoked by mechanical stimulation (nonnoxious and noxious) of the whisker pad in naïve (control), inflamed, and resveratrol-treated inflamed rats (2 mg/kg, i.p.). *p < 0.05 compared with inflamed rats. SpVc: spinal trigeminal nucleus caudalis; WDR: wide-dynamic range.

Figure 5.

Summary of resveratrol reversal of SpVc WDR neuron hyperexcitability after induction of orofacial inflammation. (a) Mean mechanical threshold, (b) mean spontaneous discharge, (c) mean noxious pinch-evoked after discharge frequency, and (d) mean size of the receptive field of SpVc WDR neurons in naïve (control), inflamed, and resveratrol-treated inflamed rats (2 mg/kg, i.p.). *p < 0.05 compared with inflamed rats. SpVc: spinal trigeminal nucleus caudalis; WDR: wide-dynamic range.