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Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic.

ABSTRACT: Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel stimulus cocktail, consisting of the SSTR2 agonist L-054,264 and the S1PR3 agonist CYM5541, that elicits calcium responses in mouse primary sensory neurons in vitro as well as pain and thermal hypersensitivity in mice in vivo. We screened a library of 906 bioactive compounds and identified 24 hits that reduced calcium flux elicited by L-054,264/CYM5541. Among these hits, silymarin, a natural product derived from milk thistle, strongly reduced activation by the stimulation cocktail, as well as by a distinct inflammatory cocktail containing bradykinin and prostaglandin E2. Silymarin had no effect on sensory neuron excitability at baseline, but reduced calcium flux via Orai channels and downstream mediators of phospholipase C signaling. In vivo, silymarin pretreatment blocked development of adjuvant-mediated thermal hypersensitivity, indicating potential use as an anti-inflammatory analgesic.

SUBMITTER: DuBreuil DM

PROVIDER: S-EPMC9893088 | biostudies-literature | 2023 Jan-Dec

REPOSITORIES: biostudies-literature

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Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic.

DuBreuil Daniel M DM Lai Xiaofan X Zhu Kevin K Chahyadinata Gracesenia G Perner Caroline C Chiang Brenda M BM Battenberg Ashley A Sokol Caroline L CL Wainger Brian J BJ

Molecular pain 20230101

Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel st ...[more]

PMID: 36526437

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Dataset Information

Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic.

Publications

Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic.

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