Anandamide in primary sensory neurons: too much of a good thing?

The quest for possible targets for the development of novel analgesics has identified the activation of the cannabinoid type 1 (CB1) receptor outside the CNS as a potential means of providing relief from persistent pain, which currently constitutes an unmet medical need. Increasing tissue levels of the CB1 receptor endogenous ligand N-arachidonoylethanolamine (anandamide), by inhibiting anandamide degradation through blocking the anandamide-hydrolysing enzyme fatty acid amide hydrolase, has been suggested to be used to activate the CB1 receptor. However, recent clinical trials revealed that this approach does not deliver the expected relief from pain. Here, we discuss one of the possible reasons, the activation of the transient receptor potential vanilloid type 1 ion channel (TRPV1) on nociceptive primary sensory neurons (PSNs) by anandamide, which may compromise the beneficial effects of increased tissue levels of anandamide. We conclude that better design such as concomitant blocking of anandamide hydrolysis and anandamide uptake into PSNs, to inhibit TRPV1 activation, could overcome these problems.