An Endocannabinoid Enzyme Inhibitor Lost Pain-Related Activity With Repeated Dosing
An experimental enzyme inhibitor produced a different profile after repeated treatment than after a single dose in mice. The finding shows why an acute cannabinoid-related benefit cannot automatically be projected into chronic therapy.
Raising an endogenous cannabinoid
The investigators blocked monoacylglycerol lipase, or MAGL, using JZL184 and compared pharmacological results with genetic MAGL disruption. MAGL normally helps break down the endocannabinoid 2-AG. This approach differs from administering THC or a retail CBD product.
Acute and repeated treatment diverged
Repeated MAGL blockade lost analgesic activity and produced cross-tolerance to selected effects of cannabinoid-receptor agonists. Brain receptor expression, signaling and synaptic-plasticity findings supported adaptation. Cross-tolerance was not equally strong for every endpoint, including catalepsy.
Another enzyme was not equivalent
Sustained inhibition of FAAH, an enzyme involved in anandamide breakdown, showed a contrasting profile with preserved analgesic activity and less receptor adaptation under the tested conditions. Both pathways involve endogenous cannabinoids, but that common label did not predict identical chronic responses.
From mechanism to treatment
These were mouse, tissue and laboratory experiments, not trials showing that a medicine safely treats chronic pain in patients. The dose, extent and duration of enzyme inhibition matter; partial blockade could behave differently from sustained high-level inhibition. The study supports testing chronic efficacy and dependence-related outcomes directly. It does not establish the long-term performance of cannabis, CBD or every endocannabinoid-targeted drug.
Related analysis: evaluating cannabis tolerance claims.
Primary research
Schlosburg JE; Blankman JL; Long JZ; Nomura DK; Pan B; Kinsey SG; Nguyen PT; Ramesh D; Booker L; Burston JJ; Thomas EA; Selley DE; Sim-Selley LJ; Liu QS; Lichtman AH; Cravatt BF. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nature neuroscience (2010). DOI: 10.1038/nn.2616.
