Suppression of hyperexcitability of trigeminal nociceptive neurons associated with inflammatory hyperalgesia following systemic administration of lutein via inhibition of cyclooxygenase-2 cascade signaling

Abstract

IntroductionLutein is a dietary constituent known to inhibit inflammation; however, its effect on nociceptive neuron-associated hyperalgesia remains to be determined. The present study therefore investigated under in vivo conditions whether administration of lutein attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons that is associated with mechanical hyperalgesia.ResultsComplete Freund’s adjuvant (CFA) was injected into the whisker pads of rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was significantly lower in inflamed rats compared to uninjected naïve rats, and this lowered threshold was returned to control levels by 3 days after administration of lutein (10 mg/Kg, i.p.) Also the lutein administration, inflammation-induced thickness of edema was returned to control levels. The mean increased number of cyclooxygenase-2 (Cox-2)-immunoreactive cells in the whisker pads of inflamed rats was also returned to control levels by administration with lutein. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after lutein administration. In addition, the increased mean spontaneous discharge of SpVc WDR in inflamed rats was significantly decreased after lutein administration. Similarly, lutein significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, lutein restored the expanded mean size of the receptive field in inflamed rats to control levels.ConclusionThese results together suggest that administration of lutein attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons via inhibition of the peripheral Cox-2 signaling cascade. These findings support the proposed potential of lutein as a therapeutic agent in complementary alternative medicine strategies for preventing inflammatory mechanical hyperalgesia.

Effect of lutein on the acute inflammation‐induced c‐Fos expression of rat trigeminal spinal nucleus caudalis and C1 dorsal horn neurons

“…Our present findings also agree with a previous report showing that 6 h after pretreatment with the polyphenol, resveratrol, there is a significant decrease in the mean thickness of inflammation‐induced edema in the whisker pad, compared with untreated, inflamed rats, and also a significant decrease in the number of c‐Fos‐immunoreactive SpVc and C1 neurons in inflamed rats compared with naïve rats . We have also previously observed the following findings in a CFA‐induced chronic inflammatory pain model: (i) the mechanical threshold is significantly lower in inflamed rats than in uninjected naïve rats, and this low threshold returns to control levels by 3 d after administration of lutein; (ii) lutein administration causes the inflammation‐induced edema to return to control levels; and (iii) the increased mean number of COX‐2‐immunoreactive cells in the whisker pads of inflamed rats also returns to control levels after administration of lutein . In this study, the same concentration of lutein (10 mg kg −1 , administered intraperitoneally) that attenuates CFA inflammation‐induced chronic inflammatory hyperalgesia also inhibited acute inflammatory responses.…”

“…We have also previously observed the following findings in a CFA‐induced chronic inflammatory pain model: (i) the mechanical threshold is significantly lower in inflamed rats than in uninjected naïve rats, and this low threshold returns to control levels by 3 d after administration of lutein; (ii) lutein administration causes the inflammation‐induced edema to return to control levels; and (iii) the increased mean number of COX‐2‐immunoreactive cells in the whisker pads of inflamed rats also returns to control levels after administration of lutein . In this study, the same concentration of lutein (10 mg kg −1 , administered intraperitoneally) that attenuates CFA inflammation‐induced chronic inflammatory hyperalgesia also inhibited acute inflammatory responses. Therefore, taken together, these findings suggest that the acute systemic administration of lutein can attenuate the acute inflammation‐induced neuronal activity of trigeminal spatial distribution in the SpVc and C1 dorsal horn via suppression of COX‐2 signaling pathways, in addition to its effects on chronic inflammation.…”

“…This results in the release of a large amount of glutamate into the synaptic cleft, which binds to upregulated postsynaptic glutamate receptors, augmenting excitatory postsynaptic potentials, causing a barrage of action potentials to be conducted to the higher centers involved in pain pathways and creating a state of heightened sensitivity, termed peripheral sensitization . As we observed suppression of acute inflammation‐induced c‐Fos immunoreactivity in the SpVc and C1 neurons following acute systemic administration of lutein, it can be assumed that lutein suppresses the activity of trigeminal nociceptive afferent neurons and the hyperexcitability of SpVc WDR neurons via inhibition of both peripheral and central COX‐2 cascade signaling and TRPA1 .…”

“…Actually, Syoji et al . recently reported that chronic administration of lutein strongly attenuates the suppression of rat SpVc WDR neuronal hyperexcitability associated with chronic CFA‐induced inflammatory hyperalgesia by inhibiting COX‐2 immunoreactivity in inflamed tissue. The chemical irritant mustard oil is an agonist of transient receptor potential ankyrin 1 (TRPA1) and has been known to activate somatosensory neurons, resulting in acute pain and neurogenic inflammation , and TRPA1 modulates mechanotransduction in primary sensory neurons .…”

Modulatory mechanism underlying how dietary constituents attenuate orofacial pain

“…The present authors recently tested the hypothesis that intraperitoneally administered dietary constituents could attenuate SpVc neuronal hypersensitivity related to mechanical hyperalgesia induced by complete Freund's adjuvant (CFA) [62,63]. In addition, the authors showed that resveratrol, DHA, and lutein provided in the diet inhibited inflammatory mechanical hyperalgesia and associated nociceptive neuronal hyperexcitability induced by CFA, possibly by inhibiting the Cox-2 converting enzyme from arachidonic acid to PGE 2 [64][65][66]. This experimental series showed (i) that the lowered escape threshold for mechanical stimulation in inflamed rats returned to control levels with ongoing administration of dietary constituents, (ii) that dietary components also reversed the high-frequency SpVc WDR discharges elicited by mechanical non-noxious and noxious stimuli, (iii) that dietary constituents returned the spontaneous discharges rates of SpVc WDR neurons as well as the noxious pinch-evoked after-discharge frequency in inflamed rats, and (iv) that control levels of receptive field expansion in inflamed rats were attained [64][65][66].…”