UC Irvine

Sickle cell disease (SCD) is the most common inherited disease, characterized by severe organ damage, often life-long pain, and a shortened lifespan. A hallmark of SCD is vaso-occlussive crisis (VOC), the blockage of small blood vessels by rigid and sticky sickled red blood cells which results in intense and unpredictable episodes of acute pain requiring hospitalization, reduced survival, and treatment with high-dose opioids. Cannabidiol (CBD) is one of the major non psychotropic constituents of cannabis and is generally considered safe and non-toxic. CBD has recently been approved by the Food and Drug Administration (FDA) for the treatment of certain types of epilepsy. Preclinical studies have shown CBD may have many benefits including for pain, inflammation, neuroinflammation, oxidative stress, ischemia/reperfusion injury, and asthma. All of these conditions occur in SCD, and so we considered using CBD for the treatment of SCD to support FDA-led translational studies for clinical translation. In this dissertation, I show the effects of CBD treatment in a humanized HbSS-BERK mouse model of SCD, which recapitulates the pathobiology and characteristic features of pain observed in persons with SCD. We found that treating both male and female sickle mice with CBD led to significant reduction in chronic pain-like behaviors, oxidative stress, and inflammation, which was sustained for more than a week after discontinuation of CBD suggesting a disease-modifying effect in the treatment of SCD. Pre-treatment with CBD for two-weeks also prevented acute hyperalgesia from occurring in sickle mice following the incitement of hypoxia/reoxygenation to simulate VOCs. CBD decreased IL-5 in both spinal cords and skin releasate, suggesting that CBD’s anti-hyperalgesic action in SCD acute pain may be due to attenuation of pro-nociceptive and/or anti-inflammatory activity in the periphery and the central nervous system (CNS). Furthermore, long-term CBD use did not result in impairment of motor coordination or negatively affect memory in sickle or non-sickle control mice, providing further evidence that long term CBD use may be without major side effects. While more investigation is required, our data provide support for clinical trials to evaluate the effect of CBD for the treatment of pain in SCD and other painful conditions such as cancer.