Transporter Inhibition vs FAAH Inhibition
There are two primary ways in which manipulation of the endocannabinoid system is currently achieved. One method is to inhibit the enzymes responsible for enzymatic break down of the endocannabinoids such as fatty-acid amide hydrolase (FAAH), the enzyme which deactivates anandamide. FAAH inhibitors or (FAAHI’s) may be the next big thing in cannabinoid pharmacology. We have been utilizing the other method to treat all types of pain for a long time but have only recently come to understand this to be the case. This method is to inhibit the endocannabinoid transporters responsible for removing the endocannabinoids from the intercellular space after they have been released. As it turns out, AM404, one of the main active metabolites of acetaminophen, is an inhibitor of anandamide’s transporter, an agonist at the TRPV1 receptor and a weak agonist at CB1 receptor. [NOTE: Other metabolites of acetaminophen are very toxic to the liver in high doses. DO NOT attempt to take acetaminophen in excess to get high. It will only poison you without producing noticeable psychoactive effects (i.e., you will just get sick and damage your liver).]
So which, if either, of these two methods are useful tools in the fight against neuralgia? So far, it appears that the anandamide transporter inhibitor AM404 is potentially more effective and definitely more reliable at inhibiting the allodynia and hyperalgesia associated with neuralgia. Using rat models of neuropathic pain and inflammation, Mitchell, Greenwood, Jayamanne and Vaughan, 2007, found that one time systemic injections of AM404 reduced evidence of neuralgia associated allodynia but not that produced by neural inflammation. Co-administration of a selective CB1 antagonist completely reversed the affect of AM404 suggesting that CB1 receptor activation was completely responsible for this effect (15). Interestingly, another study published at the same time by Dani, Guindon, Lambert, and Beaulieu, 2007, on local injection of acetaminophen to the site of neuropathic pain (the paw) in a rat model found that acetaminophen inhibited both neuropathic allodynia and hyperalgesia. These antineuralgia effects of local administration of acetaminophen were inhibited by both selective CB1 and CB2 inhibitors. It was unclear from the study if AM404, acetaminophen itself, or one of its other other metabolites were responsible for the apparent CB2 receptor activation (16). This question was answered the year before by Costa and colleagues, 2006. They found a dose- and time-dependant inhibition of allodynia and hyperalgesia following daily administration of AM404 in a rat model of neuralgia. Although this effect was partially inhibited by co-administering a selective CB1 antagonist, a selective CB2 antagonist, or a TRPV1 receptor antagonist, it was only with co-administration of all three together that complete reversal of the effect was observed. This lead Costa, et al., to conclude that the antineuralgia properties of AM404 resulted from activation of multiple endocannabinoid related pathways through the CB1, CB2 and TRPV1 receptors (12). Clearly anandamide transporter inhibition, at least with AM404, is a viable route to helping control neuropathic pain. In light of this, it would be worthwhile to further investigate the use of AM404 to specifically treat TN.