Sickle Cell Disease represents a major cause of morbidity and mortality worldwide, and affects more than 100,000 people in the US. This genetic diseased results in recurrent vaso-occlusive pain crises that are not only the primary cause of hospitalization but also cause a debilitating chronic pain. Although opioids remain the standard of care for chronic pain in sickle cell patients, their adverse side effects (e.g., constipation, respiratory depression, abuse liability, tolerance, and dependence) limit their effectiveness. Thus, an urgent need exists to identify effective non-opioid analgesic strategies to reduce chronic pain in sickle cell patients. Here we use a humanized mouse model of sickle cell disease to compare the antinociceptive effects of oxycodone to an inhibitor of the endocannabinoid regulating enzyme monoacylglycerol lipase (MAGL) in a battery of stimulus-evoked nociceptive and functional behavioral assays.  Male and female HbSS-BERK (sickle) and HbAA-BERK (control) mice served as subjects in these experiments. Subjects were administered oxycodone or the MAGL inhibitor MJN110 and tested for stimulus-evoked nociceptive behaviors (i.e., von Frey assay for mechanical allodynia and hotplate test for thermal nociception), and in functional behavioral assays (grip strength, nesting, and inverted screen assays. Oxycodone fully attenuated mechanical allodynia in sickle mice but significantly elevated von Frey paw withdrawal thresholds in control mice. It also produced full antinociceptive effects in the hotplate assay regardless of genotype. However, oxycodone either had no effect or worsened performance in the functional assays. In contrast, MJN110 fully reversed mechanical allodynia and partially reversed thermal hyperalgesia and grip strength deficits, but did not affect performance in the nesting or inverted screen assays in sickle cell mice. Ongoing research is examining whether MJN110 maintains its antinociceptive effects in the von Frey, hotplate, and grip strength assays, as well as possibly enhances performance in nesting and inverted screen assays upon repeated MJN110 administration. The present findings suggest that MAGL represents a potential target to treat sickle cell pain and may offer some advantages over opioids, though neither oxycodone nor MJN110 normalized performance in all functional behavioral assays. 

Acknowledgements: P30 DA033934, Southern Regional Education Board Doctoral Scholars Program and KUH Training Grant; VCU School of Pharmacy, and VCU School of Medicine