Apr 25, 2020

Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain

BioRxiv : the Preprint Server for Biology
Saurabh AggarwalS. Matalon


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, {beta}-endorphin ({beta}-END), within their endoplasmic reticulum (ER). When released into plasma, {beta}-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 {beta}-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 {beta}-END compared to PWH without CWP and HIV-negative individuals with or without pain. In vitro heme exposure decreased {beta}-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 {beta}-END levels and hindpaw mechanical sensitivity thresholds. ...Continue Reading

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Mentioned in this Paper

Genetic Drift
CFC1 gene
CFC1 wt Allele

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