Updated mechanisms underlying sickle cell disease-associated pain

Abstract

Sickle cell disease (SCD) is one of the most common severe genetic diseases around the world. A majority of SCD patients experience intense pain, leading to hospitalization, and poor quality of life. Opioids form the bedrock of pain management, but their long-term use is associated with severe side effects including hyperalgesia, tolerance and addiction. Recently, excellent research has shown some new potential mechanisms that underlie SCD-associated pain. This review focused on how transient receptor potential vanilloid 1, endothelin-1/endothelin type A receptor, and cannabinoid receptors contributed to the pathophysiology of SCD-associated pain. Understanding these mechanisms may open a new avenue in managing SCD-associated pain and improving quality of life for SCD patients.

Keywords: Cannabinoid receptors; Endothelin type A receptor; Endothelin-1; Pain; Sickle cell disease; TRPV1.

Fig. 1.

The molecular mechanisms that underlies TRPV1-mediated nociceptive hypersensitivity in the dorsal root ganglion (DRG) neurons from a mouse model of sickle cell disease. In the SCD mice, a prolonged increase in plasma adenosine activates ADORA2B on myeloid cells, leading to an elevation in circulating IL-6 and sIL-6R. The IL-6/sIL-6R complex binds to gp130 on DRG neurons, producing STAT3 phosphorylation and consequently inducing neuronal TRPV1 expression. SCD-induced up-regulation of CCL2/CCR2 signaling enhances the sensitivity and expression of TRPV1. In addition, the increased protons caused by SCD directly sensitize and activate the TRPV1 channel. The activated/increased TRPV1 augments nociceptive sensitivity and participates in the induction and maintenance of SCD-associated chronic pain. Ca²⁺ influx through the activated TRPV1 channel increases intracellular Ca²⁺ levels and subsequently activates PKC and CaMKIIα. PKC can also be activated by the ET-1/ETA receptor signaling pathway. Both PKC and CaMKIIα can further activate TRPV1 via phosphorylation of TRPV1. This PKC/CaMKIIα-TRPV1 positive feedback may be one mechanism underlying nociceptive hypersensitivity and chronic pain in SCD. ADORA2B: adenosine A_2B receptor; gp130: glycoprotein 130; STAT3: signal transducer and activator of transcription 3; CCL2: chemokine (C-C motif) ligand 2; CCR2: C-C motif chemokine receptor 2; PKC: protein kinase C; CaMKIIα: Calcium/calmodulin-dependent protein kinase type II alpha; ET-1: endothelin-1; ETA: endothelin-type A.

Fig. 2.

Proposed mechanisms that underlie endothelin-1/endothelin-type A receptor-mediated nociceptive hypersensitivity in dorsal root ganglion (DRG) neurons from a mouse model of sickle cell disease. Endothelin-1 (ET1) released from endothelial cells, macrophages, mast cells, or keratinocytes activated endothelin type A (ETA) receptor on nociceptive terminals. ETA receptor activation triggered a G-protein linked signaling cascade, in which the production of diacyl-glycerol (DAG) activated protein kinase C (PKC). The activated PKC induced the activation of the NF-κB signaling pathway to upregulate Nav1.8 channel expression, resulting in an increase in neuronal excitability in primary sensory neurons of sickle cell mice. The activated PKC might also phosphorylate and activate TRPV1 channels. TRPV1 channel activation increased calcium influx, resting membrane potential depolarization, and neuronal excitability in SCD DRG. PLC: phospholipase C; IP3: inositol trisphosphate; TRPV1: transient receptor potential vanilloid 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells.