Inhibition of pain and itch by a naturally occurring omega-9 fatty acid

Inhibition of pain and itch by a naturally occurring omega-9 fatty acid

The two primary strategies targeted to control and treat pain have concentrated on preventing the propagation of action potentials in peripheral nociceptors from reaching the central nervous system, and identifying and then inhibiting the receptors whose activation will result in the generation of said action potentials.

One such protein is the transient receptor potential vanilloid 1 (TRPV1), whose role in inflammatory and neuropathic states is well established.

TRPV1 is a non-selective cation channel that is activated by diverse stimuli including capsaicin, noxious temperatures (near 42 °C), extracellular acidic pH and bioactive lipids such as lysophosphatidic acid (LPA), all of which have been shown to activate nociceptors.

In investigating the structure–activity profile of LPA on TRPV1, previously showed that lysophospholipids that activated the channel exhibited specific structural requirements regarding their head group and acyl chain composition. In this process, authors found that oleic acid (OA; cis-9-octadecenoic acid), a naturally occurring long-chain monounsaturated fatty acid, which resembles LPA in both acyl chain composition and being negatively charged, does not activate TRPV1 but rather acts as a naturally occurring inhibitor of this channel.

Although many synthetic antagonists have been developed, only a few natural inhibitors have been identified. Given TRPV1’s role in pain and inflammation, a clinically relevant goal has been to identify natural antagonists of the TRPV1 channel. Moreover, it is important to understand how similar molecules could lead to either the activation or inhibition of this channel and thus affect physiological processes such as pain, inflammation and itch.

Authors in this study published in the Nature Communications show that the inhibition of TRPV1 by OA through a direct interaction with the vanilloid-binding pocket (VBP) also results in the inhibition of TRPV1-dependent pain and itch, and that inhibition arises from the stabilization of a closed state of the channel and thereby precludes its activation in response to several stimuli.

Moreover, authors describe a novel endogenously present itch response inducer, cyclic phosphatidic acid (cPA), which activates TRPV1 and show that this physiological response, as well as itch produced by histamine, are also inhibited by OA.

These findings provide insights not only into the molecular basis of OA inhibition of TRPV1, but a novel way of reducing the pathophysiological effects of pain and itch resulting from its activation.