Inhibiting FAAH and MAGL, the enzymes that break down the body's own cannabinoids, reduced neuropathic pain in mice through distinct cannabinoid receptor mechanisms and without behavioral side effects.
Read this if you are interested in pain treatments that work through the endocannabinoid system without producing a high.
Both FAAH and MAGL inhibitors reduced neuropathic pain without behavioral side effects
What the researchers found
Researchers tested whether blocking the enzymes that degrade endocannabinoids could reduce neuropathic pain in mice with sciatic nerve injury.
FAAH inhibitors (URB597 and OL-135), which increase anandamide levels, reduced both mechanical and cold allodynia. This effect required both CB1 and CB2 receptors but not TRPV1 or opioid receptors.
The MAGL inhibitor JZL184, which increases 2-AG levels, also reduced allodynia but only through CB1 receptors, not CB2.
Critically, neither FAAH nor MAGL inhibition produced the behavioral side effects typically associated with direct cannabinoid receptor agonists (like THC).
Brain and spinal cord measurements confirmed that URB597 increased anandamide while JZL184 increased 2-AG in these tissues, but endocannabinoid levels did not differ between nerve-injured and control mice.
Why it matters
This study demonstrated that boosting the body's own cannabinoids through enzyme inhibition could reduce neuropathic pain without the psychoactive and behavioral side effects of THC, providing a promising therapeutic strategy.
The numbers in context
FAAH inhibition increased brain and spinal cord anandamide. MAGL inhibition increased 2-AG. FAAH anti-allodynic effects required both CB1 and CB2. MAGL effects required CB1 only. Neither opioid nor TRPV1 receptors were involved.
How the study worked
Mice underwent chronic constriction injury of the sciatic nerve to model neuropathic pain. FAAH inhibitors (URB597, OL-135) and the MAGL inhibitor (JZL184) were administered acutely. Mechanical and cold allodynia were measured. Receptor involvement was tested using selective antagonists. FAAH knockout mice and endocannabinoid tissue levels were used to confirm specificity.
What this study cannot tell us
Animal model of neuropathic pain may not fully represent human conditions. Acute dosing was tested; chronic treatment effects and potential tolerance were not examined. The precipitating nerve injury model is only one type of neuropathic pain.
How to read the evidence
Rigorous preclinical study with appropriate controls (knockout mice, selective antagonists) demonstrating clear mechanisms, but still an animal model.
When this study was published
Published in 2009. FAAH inhibitors have since entered clinical trials for pain (with mixed results), while MAGL inhibitor development continues.
The bigger picture
Neuropathic pain is notoriously difficult to treat, and existing medications often have significant side effects. Enhancing endocannabinoid signaling by blocking degradation enzymes represents a fundamentally different approach than administering plant-derived or synthetic cannabinoids directly.
Questions still open
- Will FAAH and MAGL inhibitors prove effective for neuropathic pain in humans? Does tolerance develop with chronic use of these inhibitors? Could combined FAAH and MAGL inhibition provide greater relief than either alone?
Common questions
What are FAAH and MAGL?
Why is this approach different from using THC or CBD?
Read the original research
Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.
The Journal of pharmacology and experimental therapeutics, 330(3), 902-10
Citation
Kinsey, S G; Long, J Z; O'Neal, S T; Abdullah, R A; Poklis, J L; Boger, D L; Cravatt, B F; Lichtman, A H. (2009). Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.. The Journal of pharmacology and experimental therapeutics, 330(3), 902-10. https://doi.org/10.1124/jpet.109.155465
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