The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1′s actions in the homeostasis of Ca²⁺ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.

Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others. TRP channels are finely modulated by different mechanisms: regulation of their function and/or by control of their expression or cellular/subcellular localization. These mechanisms are subject to being affected by several endogenously-produced compounds, some of which are of a lipidic nature such as steroids. Fascinatingly, steroids and TRP channels closely interplay to modulate several physiological events. Certain TRP channels are affected by the typical genomic long-term effects of steroids but others are also targets for non-genomic actions of some steroids that act as direct ligands of these receptors, as will be reviewed here.

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.

Background: Anandamide (AEA) is a lipid mediator of the endocannabinoid system that plays a key role in pain perception by regulating multiple molecular targets, including transient receptor potential vanilloid type 1 (TRPV1). This vanilloid receptor is abundantly expressed in nociceptive neurons (nociceptors) and plays a crucial role in mediating pain responses. Methods: We used mouse behavioral tests, cell culture, and Western blot assays to test whether AEA regulates acute pain induced by TRPV1 activation and TRPV1 total protein levels. Results: Our results demonstrate that AEA downregulates the capsaicin-evoked pain response and TRPV1 protein levels in nociceptors. Furthermore, in a transiently heterologous TRPV1 expression system, we found that AEA induces ubiquitination of TRPV1 and its degradation via the proteasome pathway, independent of calcium influx. We also found that AEA induced an upregulation of BiP protein levels, a key endoplasmic reticulum chaperone and stress sensor, without changes in other ER stress sensors. Finally, we explored whether the endocannabinoid 2-arachidonoylglycerol (2-AG) and the phytocannabinoid β-caryophyllene (BCP) modulate capsaicin-evoked pain, finding that 2-AG is less effective than AEA in reducing pain behavior, whereas BCP shows effects similar to AEA in reducing capsaicin-evoked pain. Conclusions: These results highlight AEA and BCP as regulators of TRPV1 protein levels and of the painful response mediated by this molecular pain target.