Behavioral and transcriptional effects of age in HbSS-BERK humanized SCD mice.

Objectives: 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.