TRPV1 blockers as potential new treatments for psychiatric disorders

Abstract

The transient receptor potential vanilloid-1 channel (TRPV1) is responsible for decoding physical and chemical stimuli. TRPV1 is activated by capsaicin (a compound from chili peppers), heat (above 43°C) and acid environment, playing a major role in pain, inflammation and body temperature. Molecular and histological studies have suggested TRPV1 expression in specific brain regions, where it can be activated primarily by the endocannabinoid anandamide, fostering studies on its potential role in psychiatric disorders. TRPV1 blockers are effective in various animal models predictive of anxiolytic and antipanic activities, in addition to reducing conditioned fear. In models of antidepressant activity, these compounds reduce behavioral despair and promote active stress-coping behavior. TRPV1 blockers also reduce the effects of certain drugs of abuse and revert behavioral changes in animal models of neurodevelopmental disorders. The main limiting factor in developing TRPV1 blockers as therapeutic agents concerns their effects on body temperature, particularly hyperthermia. New compounds, which block specific states of the channel, could represent an alternative. Moreover, compounds blocking both TRPV1 and the anandamide-hydrolyzing enzyme, fatty acid amide hydrolase (FAAH), termed dual TRPV1/FAAH blockers, have been investigated with promising results. Overall, preclinical studies yield favorable results with TRPV1 blockers in animal models of psychiatric disorders. Behavioural Pharmacology 33: 2-14

Human TRPV1 structure and inhibition by the analgesic SB-366791

“…Altogether, brain TRPV1 channels act as detectors of harmful stimuli and key players of the microglia to neuron communication 8 . Beyond chronic pain (including nociception and neuropathic pain) 9 and thermoregulation disorders, selective high-affinity inhibitors of human TRPV1 are urgently needed in view of the channel’s rapidly emerging role in various psychiatric diseases, such as depression, anxiety, fear, emotional stress, and drug abuse 10 – 14 .…”

The FAAH inhibitor URB597 reduces cocaine seeking during conditioned punishment and withdrawal

“…Consistent with this hypothesis, a recent study found that local blockade of TRPV1 in CA1 of hippocampus prevented the retrieval of contextual fear memories (measured by freezing behaviour) of mice exposed to foot shocks and reported a positive correlation between the levels of AEA and the freezing behaviour [62]. The authors propose opposite roles of CB1R and TRPV1 in the modulation of conditioned fear [63,64], in which activation of TRPV1 by AEA would lead to the strengthening of aversive memories. Another possible explanation could be related to a URB597-induced improvement in properly assigning value to aversive outcomes that occur as a consequence of compulsive drug seeking [65].…”

Selective activation of AKAP150/TRPV1 in ventrolateral periaqueductal gray GABAergic neurons facilitates conditioned place aversion in male mice

“…These findings indicate that the development mechanisms of different CPA models are not the same, and the role of the vlPAG in CPA is complicated. Transient receptor potential vanilloid 1 (TRPV1), a calcium permeable ion channel, can work as a biomarker for neuropathic pain triggered by several chemicals and heat (>42 °C) and then integrate into nociceptive signals 16 , 17 . TRPV1 knockout mice showed that TRPV1 may take part in the development process of aversive behavior, such as facilitating conditioned or unconditioned fear and regulating long-term depression 18 .…”