Sickle cell disease (SCD) is the most common inherited disease.
Pain is a key morbidity of SCD and
opioids are the main treatment but their side effects emphasize the need for new
analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of
pain. Homozygous (HbSS) Berkley mice express >99% human
sickle hemoglobin and several features of clinical SCD including
hyperalgesia. Previously, we reported that the
endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator
prostaglandin E2-glyceryl
ester (PGE2-G) which contributes to
hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in
hyperalgesia in sickle mice.
Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing
enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of
PGE2 and PGE2-G, pronociceptive derivatives of 2-AG. A single
intravenous injection of 2-AG produced
hyperalgesia in non-hyperalgesic HbSS mice, but not in control (
HbAA) mice expressing normal human HbA.
JZL184, an inhibitor of 2-AG hydrolysis, also produced
hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence
hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat
hyperalgesia in HbSS mice. The decrease in
hyperalgesia was accompanied by reductions in 2-AG,
PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat
pain in SCD.