It’s intriguing to see the reintegration of pain signaling pathways into obesity therapeutics at a conceptual level.https://pilapharma.com/pilas-trpv1-asset/ PILA PHARMA is developing novel oral drugs for treatment of obesity and diabetes based on TRPV1 inhibition (XEN-D0501 is at a preclinical stage).

TRPV1 (Transient Receptor Potential Vanilloid 1) is a non-selective cation channel, also known as the capsaicin receptor or vanilloid receptor 1. It is expressed in the brain, pancreas, vasculature, vagal and gut neurons, muscle, adipocytes, immune, and other tissues involved in pain, inflammation, and metabolism.

A TRPV1 inhibitor, XEN-DO501, represents a first-in-class agent, which has not been studied in obesity until now.

We are, however, already familiar with CB1-targeting agents in this field. Rimonabant, an early-generation CB1 antagonist, was withdrawn due to central side effects, while new-generation CB1 antagonists with limited blood–brain barrier penetration are now under development.

Obesity is associated with a hyperactive endocannabinoid system.
In human and animal studies, plasma and tissue levels of the main endocannabinoids
• Anandamide
• 2-Arachidonoylglycerol
are significantly elevated in obesity and metabolic syndrome.

What’s particularly interesting is the strong interaction between TRPV1 and the endocannabinoid system:
1. Several endocannabinoids (Anandamide, N-Arachidonoyl-Dopamine, N-Oleoyldopamine) and related lipid mediators can directly activate or sensitize TRPV1.
2. CB1 activation can desensitize or inhibit TRPV1, whereas TRPV1 activation can modulate CB1 signaling through Ca²⁺-dependent pathways.
3. TRPV1 in pancreatic β-cells and adipose tissue is influenced by endocannabinoid tone, linking it to glucose metabolism and obesity.

https://link.springer.com/article/10.1186/s10194-025-02085-1 This study of functional crosstalk between the vanilloid and endocannabinoid systems (ECS) in modulating vascular tone concludes that the interaction between the ECS and vanilloid system may represent promising therapeutic avenues for (neuro)vascular disorders, including migraine, by targeting shared signalling pathways that modulate vascular tone. 

It will be exciting to see whether modulating pain and metabolic pathways together can demonstrate synergistic therapeutic effect in obesity, or other indications.