Chronic pain in sickle cell disease: a role for lysophosphatidic acid

Blood. 2026 Apr 1:blood.2025031738. doi: 10.1182/blood.2025031738. Online ahead of print.

ABSTRACT

Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by persistent pain. The mechanisms underlying pain in SCD are poorly understood and opioids remain the primary treatment, despite their severe side effects. Here we investigated the contribution of lysophosphatidic acid (LPA), an endogenous pronociceptive lipid mediator, to chronic pain in SCD using humanized transgenic homozygous Berkeley mice that express >99% human sickle hemoglobin (HbSS mice) and control HbAA mice that express normal human hemoglobin A. Hyperalgesia in HbSS mice was associated with an increase in both plasma level of LPA and expression of LPAR1 mRNA in L1-L5 dorsal root ganglion (DRG). Blocking LPA synthesis with BI-2545 or blocking LPA1 receptor (LPA1R) function with siRNA or the LPA1R antagonist, AM966, reversed mechanical and heat hyperalgesia in HbSS mice. LPA also produced acute mechanical and heat hyperalgesia in HbAA mice, which resulted from the sensitization of C-fiber nociceptors. In HbSS mice, hyperalgesia was associated with sensitization of nociceptive DRG neurons. Nociceptors from hyperalgesic HbSS mice had lower rheobase, more positive resting membrane potential and higher frequency of action potential. Although no changes were found in the values of inward currents in nociceptors of HbSS mice compared to HbAA mice, outward-inactivating and non-inactivating currents were reduced, indicating the importance of potassium channels to sensitization in SCD. All these parameters were normalized by pretreatment of HbSS mice with LPA1R siRNA. Our results suggest that LPA signaling may be a promising target for treating pain in SCD.

PMID:42126980 | DOI:10.1182/blood.2025031738