Melanocortin Receptors as Anti-Inflammatory and Analgesic Targets in Sickle Cell Disease: A Comparative Study in Congolese Patients

Abstract

Introduction : Sickle cell disease is an autosomal recessive inherited hemoglobinopathy, leading to the formation of an abnormal hemoglobin, hemoglobin S (HbS). CVO is the most frequent and disabling clinical manifestation of sickle cell disease, representing the main cause of hospitalization, school or work absenteeism, and reduced quality of life in SS homozygous patients. These painful attacks are the result of a complex pathogenic process combining HbS polymerization, systemic inflammation, vascular endothelial activation and tissue ischemia. Despite therapeutic advances, management of CVO-related pain remains limited and unsatisfactory, particularly in sub-Saharan Africa. Commonly used treatments include opioids (such as morphine), which are effective in the short term but associated with significant side effects, including tolerance, constipation, sedation, and above all the risk of dependence and abuse. These therapeutic limitations underline the pressing need to develop new, targeted approaches that are more effective and better tolerated, based on a thorough understanding of the pathophysiological mechanisms of sickle cell pain. MCRs, activated by pro-opiomelanocortin (POMC) peptides such as melanotropic hormone ( α -MSH) and corticotropic hormone (ACTH), are involved in a variety of biological processes including regulation of immunity, stress response, energy homeostasis and nociception. The MC3R, MC4R and MC5R receptors appear to be strategic biological targets in the study of sickle cell pain, due to their shared involvement in inflammatory and nociceptive signaling pathways, their potential as biomarkers of severity, and their suitability as pharmacological targets in the development of new treatments. For the first time in the Congolese context, this study examines the correlations between MC3R, MC4R and MC5R receptor expression levels and CVO clinical parameters in homozygous sickle cell patients followed in Brazzaville. Methodology : A prospective observational study was carried out on 85 patients (2 - 62 years). Pain intensity was assessed using a validated scale. Biomarkers (haemogram, CRP, IL-6, MC3R, MCR4R and MC5R) were measured by turbidimetry and ELISA. Data were statistically analyzed using specific tools. Results : 45.88% or 39 of patients were in CVO, while severe pain was reported frequently in more than 14 patients during attacks. WBC, CRP and MC5R showed significantly higher concentrations during CVO (p = 0.018 for WBC; p < 0.0001 for CRP and p < 0.003 for MC5R), while the other markers measured (GR, PLT, IL6, MC3R, MC4R) showed no statistically significant difference. Although a weak positive correlation was observed between CRP levels and MC5R expression (r = 0.23, p = 0.07), this did not reach statistical significance. Conclusion : These results suggest that MC5R may be considered a promising biomarker for assessing inflammatory pain during CVO and its potential usefulness in therapeutic pain monitoring in sickle cell crisis patients, although further studies are needed to confirm its clinical role. Also, CRP/MC5R correlation results may suggest a complex regulatory mechanism of melanocortin receptors during sickle cell inflammation.