Abstract
(−)-Naringenin 4′,7-dimethyl ether ((−)-NRG-DM) was isolated for the first time by our lab from Nardostachys jatamansi DC, a traditional medicinal plant frequently used to attenuate pain in Asia. As a natural derivative of analgesic, the current study was designed to test the potential analgesic activity of (−)-NRG-DM and its implicated mechanism. The analgesic activity of (−)-NRG-DM was assessed in a formalin-induced mouse inflammatory pain model and mustard oil-induced mouse colorectal pain model, in which the mice were intraperitoneally administrated with vehicle or (−)-NRG-DM (30 or 50 mg/kg) (n = 10 for each group). Our data showed that (−)-NRG-DM can dose dependently (30~50 mg/kg) relieve the pain behaviors. Notably, (−)-NRG-DM did not affect motor coordination in mice evaluated by the rotarod test, in which the animals were intraperitoneally injected with vehicle or (−)-NRG-DM (100, 200, or 400 mg/kg) (n = 10 for each group). In acutely isolated mouse dorsal root ganglion neurons, (−)-NRG-DM (1~30 μM) potently dampened the stimulated firing, reduced the action potential threshold and amplitude. In addition, the neuronal delayed rectifier potassium currents (IK) and voltage-gated sodium currents (INa) were significantly suppressed. Consistently, (−)-NRG-DM dramatically inhibited heterologously expressed Kv2.1 and Nav1.8 channels which represent the major components of the endogenous IK and INa. A pharmacokinetic study revealed the plasma concentration of (−)-NRG-DM is around 7 µM, which was higher than the effective concentrations for the IK and INa. Taken together, our study showed that (−)-NRG-DM is a potential analgesic candidate with inhibition of multiple neuronal channels (mediating IK and INa).
Highlights
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage [1]. It can be subdivided into somatic pain and visceral pain according to the originating tissue, while it can be categorized into acute and chronic pain based on the ongoing time [2]
RWGh-iDleMat stihgendifoicseanotfly30amttegn/ukagt,e(d−p)-aNinRfGu-lDbMehaviors sihnoartednoesde-tdheepleicnkdinegnttimmeanannedrpdauinrisncgorpehoafsteheI tawnod bpehhaasveioIrIal(Fsitgaguerse, 2b)u.tAotnltyhehaddoase of 50 smiggn/ikfigca, n(−t)i-nNflRueGn-cDe Min spihgansiefiIc.antly attenuated painful behaviors, including the licking time and Tooveexracllul dpeaipnosscsiobrlee innonb-ostphecpihfiacsmesusincleforremlaaxlainnt-ionrjescetdeadtimveiceef.feWctsh,ilteheateftfheectsdoosfe of 30 (−)-NRG-DM on motor performance were evaluated in the rotarod test. (−)-NRG-DM wmags/wkge,ll(t−o)l-eNraRteGd-DinMtheshrootratreondedtestth, ewiltihckninogsigtinmifiecaanntdefpfeacitns osncotrhee aobfiltihtye ttowroembaeihnavioral osntatghees,robtuattionnglyrohdaadftaersiingtnriafpicearnittoinnefalluaednmceininistprhataiosen Io. f (−)-NRG-DM at 100 mg/kg, 200 mg/kg, or even 400 mg/kg (Table 1)
The current study showed that the analgesic (−)-NRG-DM directly dampens neuron excitability in acutely isolated mouse small-diameter dorsal root ganglia (DRG) neurons with a reduced threshold and amplitude of action potential firing (Figure 4A)
Summary
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage [1]. The Kv2.1 channels are thought to represent a major component of IK, which helps to set the resting membrane potential and shape the action potentials [18–20]. Modulation of these channels underlies multiple analgesics. Flavonoids are polyphenolic structures naturally distributed in most plants and consumed daily They have been widely used for analgesic, anti-inflammatory, and antioxidant effects along with safe preclinical and clinical profiles [28,29]. As a flavonoid originating from a widely used folk medicine for pain relief, we hypothesized that (−)-NRG-DM might have analgesic activity similar to its naringenin prototype which has been reported to alleviate pain in multiple models [32].
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