News Brief: Substrate-Selective COX-2 Inhibitor Elevates Brain Endocannabinoids
Pharmacological strategies to increase endocannabinoids (ECs) could provide new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders. A study published in the August 4 Nature Neuroscience describes a new compound that boosts brain levels of ECs in mice by inhibiting cyclooxygenase-2 (COX-2). In the study, elevation of ECs was associated with reduced anxiety behaviors in mice. The work, from Lawrence Marnett, Sachin Patel, and colleagues at Vanderbilt University School of Medicine, Nashville, Tennessee, US, provides the best evidence to date that COX-2 is an important regulator of endogenous ECs in vivo and should spur testing of EC-boosting COX-2 inhibitors in animal models of pain.
COX-2 is well known to contribute to inflammatory pain by catalyzing the transformation of arachidonic acid into prostaglandins, but the enzyme also oxygenates and inactivates the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), endogenous lipid activators of cannabinoid receptors and physiological modulators of pain signaling. Marnett’s group previously discovered that “inactive” enantiomers of profen-family COX-2 inhibitors, which do not inhibit the production of prostaglandins, could block the breakdown of ECs (see PRF related news story on Duggan et al., 2011). Others have shown that such substrate-selective inhibitors are analgesic in animal models of neuropathic pain (Bishay et al., 2010), offering a new opportunity to target COX-2, and elevate ECs, for analgesia.
First author Daniel Hermanson and colleagues identified the new candidate compound LM-4131 by designing and screening derivatives of the COX-2 inhibitor indomethacin to identify those that inhibited oxygenation of ECs but not arachidonic acid. When given to mice, LM-4131 produced a significant increase in whole-brain levels of anandamide (139 percent) and a small increase in 2-AG (109 percent), but had no effect on arachidonic acid or prostaglandin levels. That gave LM-4131 a unique profile compared to traditional COX-2 inhibitors, which affected arachidonic acid and prostaglandin levels as well.
The increase in anandamide had behavioral effects: The investigators found that under conditions in which LM-4131 increased brain EC levels in mice, it reduced anxiety behaviors. Overall, the authors wrote, the effects of LM-4131 closely mirrored the behavioral effects of inhibitors of other anandamide-degrading enzymes, including fatty acid acyl hydrolase (FAAH). FAAH inhibitors are a hot area of research for new analgesics (reviewed in Roques et al., 2012).
In an initial test of pain behavior in mice, however, LM-4131 did not alter acute heat pain sensitivity on a hot plate. But that simple measure may not be a good indication of other forms of pain, Patel said. “Inflammatory or neuropathic pain may be very different,” he noted.
“It’s just a matter of time,” Patel said, before the compound will be tested in other pain models.
Image credit: Daniel Hermanson, Vanderbilt University School of Medicine
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