Behavioral and Transcriptional Effects of Age in HbSS-BERK Humanized Sickle Cell Disease Mice

Objectives Sickle cell disease (SCD) is associated with morbidity, mortality and severe pain that is well modeled in humanized Berkeley SCD (HbSS) mice. Here, we conducted a comprehensive study to evaluate the effects of age on the development of the HbSS hyper-nociceptive phenotype. We also examined the antinociceptive effects of oxycodone, a commonly used analgesics to manage SCD-related pain, in both genotypes. Methods Mixed sex, 2-, 5-, and 10-month HbSS and HbAA control mice were assessed in cadre of stimulus-evoked and non-evoked functional assays. The dose-response relationship of oxycodone was evaluated in 10-month mice from both genotypes in a subset of in vivo assays. Finally, qRT-PCR was used to quantify the relative mRNA levels of opioid receptors and ligand precursors, and pro-inflammatory cytokines, from spinal cord and dorsal root ganglia. Results HbSS mice displayed augmented responses in stimulus-evoked assays and deficits in non-evoked functional behaviors that overall worsened in severity over age, compared with controls. Oxycodone dose-dependently attenuated mechanical hypersensitivity and produced thermal antinociception but failed to normalize (or worsened) functional behavior. Finally, HbSS mice exhibited overall or age-dependent differences in mRNA amounts of mu and kappa opioid receptors, POMC, IL-1β, and IL-6. Conclusions This study offers a comprehensive approach to investigate candidate drugs to treat SCD pain and explores biomarkers associated with the HbSS SCD mouse model. Although oxycodone ameliorated the hyper-nociceptive phenotype of HbSS mice, it failed to restore functional behavior, underscoring the need to identify novel therapeutic strategies that effectively reduce pain and restore functional behavior.