The transient receptor potential melastatin subtype 8 (TRPM8) channel is inhibited by the prostacyclin receptor in a Gq/11-dependent manner

The Transient receptor Receptor potential Potential melastatin Melastatin family member subtype 8 (TRPM8) receptor-channel is involved in mammalian innocuous cold perception and is also known to mediate anti-inflammatory effects, reversing nociceptive hypersensitivity and reducing chronic pain. Besides the well-characterized effects of prostacyclin (PGI2) in the vasculature, there is a general recognition that PGI2 is also involved in nociception, as it induces pain sensitivity and increase inflammatory responses. These biological effects are mediated by the prostacyclin receptor (IP-R) expressed in platelets, smooth muscle cells of arteries, neurons of the dorsal root ganglia (DRGs), and macrophages. Given the critical roles of TRPM8 and IP-R in the regulation of pain and inflammation, and taking into account the overlapping expression of TRPM and IP-R, we analyzed the functional interaction between human TRPM8 and IP-R. Our results indicate that the activation of IP-R by selective agonists, including cicaprost but also others, inhibits TRPM8 independently of the Gs-cAMP pathway. Interestingly, the potent inhibition of TRPM8 by IP-R involves Gq/11 coupling of IP-R. These effects were also observed in neurons isolated from mouse DRGs. Our results may contribute to a better understanding of the roles of TRPM8 and IP-R in the regulation of pain and inflammation.