{"doi":"10.1177/17448069221148351","title":"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.","journal":"Molecular Pain","year":2022,"id":274780,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":757588,"name":"Xiaofan Lai","orcid":"0000-0002-0898-1654","position":1,"is_corresponding":false},{"id":364830,"name":"Kevin Zhu","orcid":"0000-0001-7664-7204","position":2,"is_corresponding":false},{"id":943813,"name":"Gracesenia Chahyadinata","orcid":null,"position":3,"is_corresponding":false},{"id":235424,"name":"Caroline Perner","orcid":"0000-0002-0851-1759","position":4,"is_corresponding":false},{"id":757587,"name":"Brenda M. Chiang","orcid":"0000-0001-9165-8067","position":5,"is_corresponding":false},{"id":943814,"name":"Ashley Battenberg","orcid":null,"position":6,"is_corresponding":false},{"id":943815,"name":"Caroline L Sokol","orcid":null,"position":7,"is_corresponding":false},{"id":262656,"name":"Brian J. Wainger","orcid":"0000-0002-3664-7231","position":8,"is_corresponding":false},{"id":628679,"name":"D Dubreuil","orcid":"0000-0001-6202-4049","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:28:12.324621Z","pmid":"36526437","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}