Morphine is the common analgesic
treatment but also remains a major challenge due to its side effects and
ability to activate mast cells. We, therefore, examined cannabinoid receptor-
specific mechanisms to mitigate mast cell activation, neurogenic
inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid
receptor-2-deleted sickle mice. We show that cannabinoids mitigate
mast cell activation, inflammation and neurogenic inflammation in sickle
mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence
systemic and neural mechanisms, ameliorating the disease pathobiology
and hyperalgesia in sickle mice. This study provides ‘proof of principle’
for the potential of cannabinoid/cannabinoid receptor-based therapeutics
to treat several manifestations of sickle cell anemia.