Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

Abstract

Sickle cell disease (SCD), a hemoglobinopathy, causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. A vast majority of SCD patients experience pain on a chronic basis, and many turn to opioids to provide limited relief. The side effects that come with chronic opioid use push for research into understanding the specific mechanisms of SCD-associated chronic pain. Current advances in SCD-associated pain have focused on alterations in the pain pathway including nociceptor sensitization and endogenous pain inducers. This article reviews the underlying pathophysiology of SCD, potential pain mechanisms, current treatments and their mechanism of action, and future directions of SCD-associated pain management. The information provided could help propel research in SCD-associated chronic pain and uncover novel treatment options for clinicians.

Keywords: Mechanisms; Pain; Sickle cell disease; Treatment.

Figure 1

Vaso-occlusive events lead to acute painful episodes in SCD patients. Deoxygenation of red blood cells harboring sickle beta globin causes polymerization of hemoglobin and morphological changes in the red blood cell. The cell adheres with greater affinity to endothelial cells lining blood vessel walls, creating a blockage (A). Endothelial cells then become activated releasing cytokines (B) and allowing for increased extravasation of monocytes (C). The increase of inflammatory cells in the surrounding tissue further contributes to the release of cytokines surrounding nociceptor terminals. This inflammatory soup then activates the nociceptor to allow the release of substance P or CGRP from nociceptor terminals, resulting in a feed-forward mechanism contributing to nociceptor sensitization (D). CGRP: calcitonin gene related peptide; TRPV1: transient receptor potential vanilloid channel 1.

Figure 2

Proposed mechanism that underlies ET-1-induced sensitization of transient receptor potential vanilloid 1 (TRPV1) channels. Endothelin-1 (ET1) released from endothelial cells, macrophages, mast cells, or keratinocytes can activate endothelin type A receptors (ETA) on nociceptive terminals. ETA receptor activation initiates a G-protein linked signaling cascade, in which the production of diacyl-glycerol (DAG) activates protein kinase C (PKC) ε. The latter phosphorylates TRPV1 channels. TRPV1 channel phosphorylation results in its activation, an influx of calcium, the depolarization of the resting membrane potential, and an increase in cell excitability and vesicle release of substance P. PLC: phospholipase C; IP3: inositol trisphosphate.