Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB1) receptors to induce an intrathecal anti-hyperalgesia

Article

作者: Huang, Eagle Yi-Kung ; Chen, Yuan-Hao ; Chow, Lok-Hi ; Chen, Ying-Jie ; Lin, Pin-Chen

ETHNOPHARMACOLOGICAL RELEVANCEPiper methysticum G. Forst (Piperaceae) is traditionally consumed in Polynesian culture. The roots are used to produce an entheogenic drink and traditional medicine with sedative and anxiolytic properties. There is also evidence that it functions as a pain reliever. Kavalactones, its main active ingredients, exhibit psychoactive effects on the central nervous system. However, the active ingredients and pharmacological mechanisms underlying the analgesic effect of kavalactones are unclear.AIM OF THE STUDYThis study investigated the effects of kavain and yangonin on nociception, inflammatory hyperalgesia, and neuropathic mechanical allodynia at the spinal level.MATERIALS AND METHODSMale Sprague-Dawley rats were administered kavain and yangonin (27.14 and 19.36 nmol/rat) via intrathecal injection. Tail-flick tests were performed to evaluate the anti-nociceptive properties. The efficacy of kavain and yangonin on inflammatory hyperalgesia was examined using a plantar test in rats with carrageenan-induced paw inflammation. The von Frey test was used to assess mechanical allodynia induced by partial sciatic nerve ligation.RESULTSIntrathecal injection of yangonin demonstrated a relatively potent anti-nociceptive effect and attenuated carrageenan-induced hyperalgesia. These effects were completely reversed by the co-administration of PF 514273, a cannabinoid 1 (CB₁) receptor antagonist. However, yangonin did not affect mechanical allodynia at the spinal level. Kavain, another abundant kavalactone, did not affect nociception, hyperalgesia, or mechanical allodynia at the spinal level.CONCLUSIONSOverall, our study demonstrated that yangonin exerts anti-nociception and anti-inflammatory hyperalgesia effects via CB₁ receptors at the spinal level. We identified a single kavalactone, yangonin, extracted from kava as a promising treatment for pain.

2024-04-01·Biomedicine & Pharmacotherapy

Dual effect of anandamide on spinal nociceptive transmission in control and inflammatory conditions

Article

作者: Bhattacharyya, Anirban ; Palecek, Jiri ; Pontearso, Monica ; Spicarova, Diana ; Slepicka, Jakub

Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB₁) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 µM, 10 µM, and 30 µM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB₁ receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 µM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.

2023-01-01·Frontiers in molecular neuroscience

Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions.

Article

作者: Bhattacharyya, Anirban ; Pontearso, Monica ; Muzik, David ; Palecek, Jiri ; Spicarova, Diana ; Nagy, Istvan ; Nerandzic, Vladimir

Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 (CB₁) are essential in the modulation of nociceptive signaling in the spinal cord dorsal horn that underlies different pathological pain states. TRPV1 and CB₁ receptors share the endogenous agonist anandamide (AEA), produced from N-arachidonoylphosphatidylethanolamine (20:4-NAPE). We investigated the effect of the anandamide precursor 20:4-NAPE on synaptic activity in naive and inflammatory conditions. Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) from superficial dorsal horn neurons in rat acute spinal cord slices were used. Peripheral inflammation was induced by subcutaneous injection of carrageenan. Under naive conditions, mEPSCs frequency (0.96 ± 0.11 Hz) was significantly decreased after 20 μM 20:4-NAPE application (55.3 ± 7.4%). This 20:4-NAPE-induced inhibition was blocked by anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. In addition, the inhibition was prevented by the CB₁ receptor antagonist PF 514273 (0.2 μM) but not by the TRPV1 receptor antagonist SB 366791 (10 μM). Under inflammatory conditions, 20:4-NAPE (20 μM) also exhibited a significant inhibitory effect (74.5 ± 8.9%) on the mEPSCs frequency that was prevented by the TRPV1 receptor antagonist SB 366791 but not by PF 514273 application. Our results show that 20:4-NAPE application has a significant modulatory effect on spinal cord nociceptive signaling that is mediated by both TRPV1 and CB₁ presynaptic receptors, whereas peripheral inflammation changes the underlying mechanism. The switch between TRPV1 and CB₁ receptor activation by the AEA precursor 20:4-NAPE during inflammation may play an important role in nociceptive processing, hence the development of pathological pain.

100 项与 PF-514273 相关的药物交易

登录后查看更多信息