{"doi":"10.1101/2020.04.24.059790","title":"Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain","abstract":"ABSTRACT The prevalence of chronic widespread pain (CWP) in people with HIV (PWH) is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin (β-END), within their endoplasmic reticulum (ER). When released into plasma, β-END dampens nociceptive transmission by binding to opioid receptors on sensory neurons. In the present study, we hypothesized that heme-induced ER stress attenuates leukocyte levels/release of β-END, thereby increasing pain sensitivity in PWH. Results demonstrate that PWH with CWP have fragile erythrocytes, high plasma levels of cell-free heme, and impaired heme metabolism. Leukocytes from PWH with CWP also had high ER stress and low β-END compared to PWH without CWP and HIV-negative individuals with or without pain. In vitro heme exposure decreased β-END levels/secretion in murine monocytes/macrophages, which was prevented by treatment with sodium 4-phenylbutyrate, an ER stress inhibitor. To mimic hemolytic effects in a preclinical model in vivo , C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-END levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with the heme scavenger, hemopexin, blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-END may contribute to CWP in PWH.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126566,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":351729,"name":"Jennifer J. DeBerry","orcid":"0000-0002-6613-2909","position":1,"is_corresponding":false},{"id":382561,"name":"Israr Ahmad","orcid":"0000-0002-6164-9247","position":2,"is_corresponding":false},{"id":431175,"name":"Prichard Lynn","orcid":null,"position":3,"is_corresponding":false},{"id":431176,"name":"Cary DeWitte","orcid":null,"position":4,"is_corresponding":false},{"id":430079,"name":"Simran Malik","orcid":"0000-0003-0839-1299","position":5,"is_corresponding":false},{"id":430080,"name":"Jessica S. Merlin","orcid":"0000-0003-3207-4875","position":6,"is_corresponding":false},{"id":430081,"name":"Burel R. Goodin","orcid":"0000-0002-8159-1310","position":7,"is_corresponding":false},{"id":385134,"name":"Sonya L. Heath","orcid":"0000-0002-3826-0954","position":8,"is_corresponding":false},{"id":382562,"name":"Sadis Matalon","orcid":"0000-0003-0683-3700","position":9,"is_corresponding":false},{"id":351730,"name":"Saurabh Aggarwal","orcid":"0000-0001-7192-1569","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"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":[]}