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.

中文翻译：

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血红素减弱具有慢性广泛性疼痛的HIV阳性个体白细胞中的内源性阿片样物质水平

HIV感染者（PWH）的慢性广泛性疼痛（CWP）患病率很高，但其潜在机制尚不清楚。白细胞在其内质网（ER）内合成内源性阿片样物质β-内啡肽（β-END）。当释放到血浆中时，β-END通过与感觉神经元上的阿片受体结合而抑制伤害性传递。在本研究中，我们假设血红素诱导的内质网应激可减轻白细胞水平/β-END的释放，从而增加PWH的疼痛敏感性。结果表明，带有CWP的PWH具有脆弱的红细胞，高血浆水平的无细胞血红素和受损的血红素代谢。与没有CWP的PWH以及有或没有疼痛的HIV阴性个体相比，具有CWP的PWH的白细胞也具有较高的ER应激和低的β-END。体外血红素暴露降低了鼠单核细胞/巨噬细胞中的β-END水平/分泌，这是通过用ER应激抑制剂4-苯基丁酸钠进行治疗所预防的。为了在体内临床前模型中模拟溶血作用，给C57BL / 6小鼠注射了苯肼盐酸盐（PHZ）。PHZ增加无细胞血红素和内质网应激，降低白细胞β-END水平和后爪机械敏感性阈值。用血红素清除剂，血红素对PHZ注射的小鼠进行治疗可阻止这些作用，表明血红素诱导的内质网应激和随后白细胞β-END的降低可能有助于PWH中的CWP。