Neuropharmacology
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Lamiophlomis rotata (L. rotata, Duyiwei) is an orally available Tibetan analgesic herb widely prescribed in China. Shanzhiside methylester (SM) is a principle effective iridoid glycoside of L. rotata and serves as a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. This study aims to evaluate the signal mechanisms underlying SM anti-allodynia, determine the ability of SM to induce anti-allodynic tolerance, and illustrate the interactions between SM and morphine, or SM and β-endorphin, in anti-allodynia and anti-allodynic tolerance. ⋯ SM and exenatide specifically activated spinal p38 MAPK phosphorylation. These results indicate that SM reduces neuropathic pain by activating spinal GLP-1 receptors and subsequently stimulating microglial β-endorphin expression via the p38 MAPK signaling. Stimulation of the endogenous β-endorphin expression may be a novel and effective strategy for the discovery and development of analgesics for the long-term treatment of chronic pain.
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Targeting peripheral neuropathic pain at its origin may prevent the development of hypersensitivity. Recently we showed this can be mediated by opioid receptors at the injured nerve trunk. Here, we searched for the most relevant peripheral site to block transient receptor potential vanilloid 1 (TRPV1), and investigated analgesic interactions between TRPV1 and opioids in neuropathy. ⋯ Together, the identification of the primary action site in damaged nerves is crucial for effective pain control. Contrary to opioids, the TRPV1 blockade in the injured nerve peripheral terminals, rather than at the nerve trunk, appears promising against heat pain. Opioid/TRPV1 antagonist combinations at both locations partially reduced neuropathy-triggered heat and mechanical pain.
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Benzonatate was FDA-approved in 1958 as an antitussive. Its mechanism of action is thought to be anesthesia of vagal sensory nerve fibers that mediate cough. Vagal sensory neurons highly express the Nav1.7 subtype of voltage-gated sodium channels, and inhibition of this channel inhibits the cough reflex. ⋯ We found that Na(+) currents are inhibited most potently by a benzonatate fraction containing the 9-ethoxy component. Detectable effects of benzonatate occur at concentrations as low as 0.3 μM, which has been reported in humans. We conclude that benzonatate has local anesthetic-like effects on voltage-gated sodium channels, including Nav1.7, which is a possible mechanism for cough suppression by the drug.