New kid on the block: hemorphins in sickle cell disease
Year: 2025
Type: article
Abstract: Sickle cell disease (SCD) is the most common inherited blood disorder. A single point mutation causes substitution of valine for glutamic acid at position 6 of the beta-globin chain of hemoglobin (Hb), leading to sickle Hb (HbS) polymerization under low oxygen. This results in red blood cell (RBC) sickling and lysis that releases free heme and Hb into circulation and nearby tissues.11 Pain is one of the leading comorbidities of SCD that can start during infancy and continue throughout life, leading to opioid dependency, hospitalization, poor quality of life, and reduced survival.2 It is characterized by severe chronic pain and, unique to SCD, unpredictable, episodes of acute pain, which are believed to arise from vascular log-jamming by sickling RBCs and other cells impairing oxygen supply to tissues.11 Mechanisms of SCD pain are a work in progress. Hemolysis, oxidative stress, and inflammation have been shown to drive pain, blood–brain barrier dysfunction, and cognitive impairment in preclinical models and persons with SCD.6,9,13 Tan et al.,17 have shed new light on the dynamic interplay between hemolysis and SCD pain by evaluating the role of hemorphins, a class of atypical endogenous opioid peptides derived from the enzymatic degradation of Hb's beta, kappa, and delta chains that produce antinociceptive effects in other pain models.16 Hemoglobin is cleaved by lysosomal proteases, pepsin, and chymotrypsin-like proteases, among several other proteases to produce hemorphins.16 The hemorphins most involved in antinociception, LVV-hemorphin 7 and VV-hemorphin 7, may act at the brain and spinal levels to reduce pain perception through the descending inhibitory pain pathway.4,5,10 Hemorphins produce antinociception by targeting opioid receptors, angiotensin-converting enzyme receptors, and angiotensin IV receptors; however, they interact with protease systems in complex ways to form their functional subunits.1 Proteases, such as trypsin, thrombin, tryptase, and calpains, which contribute to worsening pain and tissue damage are increased in SCD.8 Increased protease content may drive hemorphin biosynthesis.1 Therefore, the cause and/or consequence of increased hemorphin in SCD remains to be understood. In the humanized, Townes mouse model of SCD, the murine alpha- and beta-globin genes have been replaced with human alpha- and beta-sickle globin, which causes mice to spontaneously develop chronic hyperalgesia similar to pain in persons with SCD.12 This humanized mouse model allowed for discrete measurement of hemorphin subtypes in the plasma, dorsal root ganglia (DRG), and brain regions in ascending and descending pain circuits. The liquid chromatography–tandem mass spectrometry approach used by the authors allowed for precise, accurate quantitation of hemorphins that were normalized to Hb and albumin levels in their respective tissues. LVV-hemorphin 7 and VV-hemorphin 7 were both significantly higher in the plasma of SCD mice compared with healthy mice expressing normal human HbA. These hemorphins were also increased in the DRG, which transmit nociceptive inputs from tissues to the spinal cord; the central nuclei of the right amygdala (AMG) and anterior cingulate cortex (ACC), which mediate the affective/emotional component of pain; and the periaqueductal grey (PAG), which is responsible for top-down mechanisms of pain autoinhibition. Notably, only VV-hemorphin 7 was significantly increased in the left AMG of SCD mice, which suggests that hemorphin levels in the brain may be driven by nonuniform injury to the blood–brain barrier, a known feature of SCD,18 thus creating asymmetrical routes of entry for circulating hemorphins, in addition to their on-demand production.1,15 Hemolysis leading to excess cell-free heme is a known complication in SCD, and reduced lactate dehydrogenase levels corresponding to less hemolysis are concomitant with reduced SCD pain and inflammation.7 Greater hemorphin concentrations are associated with reduced nociceptive pain, but paradoxically, hemorphin levels and pain were higher in SCD than healthy control mice. This increase in circulating hemorphins suggests a potential compensatory mechanism, which the authors provide evidence for through association studies looking at circulating hemorphin and hyperalgesia. Using the assessment of mechanical and thermal (heat) hyperalgesia, they observed a negative correlation between circulating hemorphins and hyperalgesia in SCD mice suggestive of an antinociceptive role for hemorphins. Similar to circulating hemorphins, LVV-hemorphin 7 and VV- hemorphin 7 concentrations in the DRG, PAG, ACC, and right AMG were inversely correlated with hyperalgesia, further suggesting a compensatory mechanism in SCD intended to use hemorphins to modulate pain. While opioid signaling is a major contributor to pain modulation, especially in the regions with identified hemorphin upregulation in SCD mice, this may not fully explain the associations observed herein. The work by Tan et al., provides a novel view of hemorphins in SCD pain that may involve opioid receptor signaling; however, hemorphins play myriad roles in cognition and regulating blood pressure.3 Hemorphins may act through multiple nonopioid pathways of antinociception, such as upstream regulation of oxytocin, vasopressin, or angiotensin IV by competitive inhibition of insulin-regulated aminopeptidase suggesting roles in advanced diabetes and SARs-CoV-19 infection.14 Hemorphins acted through these signaling pathways to reduce blood pressure and heart rate in preclinical hypertension, which is promising for addressing ischemia/reperfusion injury that partially characterizes SCD; however, to date, no studies have examined the role for hemorphins in the prevention or treatment of vaso-occlusion in SCD.16 In addition, evidence suggests that LVV-hemorphin 7 may have a beneficial role in addressing anxiety and depression-like behavior that may arise from prior SARs-CoV-19 infection through oxytocin signaling.16 As noted by the authors, future investigations into hemorphin targets will help to elucidate their specific antinociceptive mechanisms, but these studies may also consider the neuropsychiatric complications involved with hemorphin signaling through opioid and nonopioid pathways. Owing to the wide berth of hemorphin subtypes, including some which may have pronociceptive effects, and potential differences between men and women, careful scrutiny is needed for its role in SCD. This work provides a launchpad for future studies to probe hemorphins as a pathway that may or may not involve opioid signaling during the process of pain regulation. Given the reliance on high and frequent doses of opioids as the standard-of-care for SCD pain management, hemorphins provide a novel target to understand the mechanisms and targeting of pain in SCD. Conflict of interest statement The authors have no conflict of interest to declare.
Source: Pain
Authors: Donovan A. Argueta, Kalpna Gupta
Institution: University of California, Irvine
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4416654494