osition of the first double bond present in their structures \[[@B47-ijms-21-03421],[@B48-ijms-21-03421]\].

In the body, specifically in the hepatocyte's endoplasmic reticulum, they are transformed (elongated and desaturated) and form long-chain polyunsaturated fatty acids, starting from reactions orchestrated by malonyl CoA. In this way, linoleic acid (LA 18:2) serves as a precursor to several other molecules such as arachidonic acid (AA 20:4) \[[@B47-ijms-21-03421]\]. Then, this is followed by hydroxylation or epoxidation reactions catalyzed by cytochrome P450 (CYP450) enzymes, resulting in the generation of hydroxyeicosatetraenoic acids (HETEs), such as 20-hydroxyeicosatetraenoic acid (20-HETE), or epoxieicosatrienoic acids (EETs) \[[@B49-ijms-21-03421],[@B50-ijms-21-03421]\] ([Figure 2](#ijms-21-03421-f002){ref-type="fig"}).

α-linolenic acid (ALA 18:3) produces eicosapentaenoic acid (EPA 20:5) and docosahexaenoic acid (DHA 22:6) \[[@B47-ijms-21-03421]\], which are precursors of 20-hydroxyeicosapentaenoic acid (20-HEPE) and 22-hydroxyeicosapentaenoic acid (22-HDoHE) \[[@B50-ijms-21-03421]\] ([Figure 3](#ijms-21-03421-f003){ref-type="fig"}).

In 2000, Hwang and collaborators proved that hydroxyeicosapentaenoic acid (12 (S)-HPETE, the (S)-enantiomer of 12-HPETE derived from AA, [Figure 2](#ijms-21-03421-f002){ref-type="fig"}) is capable of activating the TRPV1 channel \[[@B53-ijms-21-03421]\] and this discovery led to further studies which investigated the effects of other PUFA-derived molecules on the activation of TRPV1, as mentioned below.

It has also been shown that hepoxylin (HXA3 and HXB3; [Figure 2](#ijms-21-03421-f002){ref-type="fig"}), a product of arachidonic acid and 12(S)-HPETE, has the ability of triggering Ca^2+^ mobilization in a heterologous expression system (HEK cells) that stably expresses the TRPV1 and Transient Receptor Potential Ankyrin 1 (TRPA1) channels as well as in rat sensory neurons. It is worth mentioning that TRPA1 channels are also noxious stimuli-sensing proteins that are coex