TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

Abstract

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

Partners in Crime: Towards New Ways of Targeting Calcium Channels

“…Upon application of progesterone, the interaction of Sig-1R with the channel is disrupted, resulting in the downregulation of plasma membrane TRPV1 expression and, consequently, in a decrease in capsaicin-induced nociceptive responses of sensory neurons. These results were confirmed in vivo for both males treated with a synthetic antagonist of Sig-1R and pregnant females where progesterone levels were elevated [56]. In line with these results Sig-1R knockout mice exhibited endurance to pain and mechanical allodynia induced by formalin and capsaicin, respectively [64,65].…”

“…Many factors among which steroids act on the Sig-1R resulting in negative or positive effects on the function and plasma membrane expression of potassium, calcium, and TRP channels [54]. Sig-1R was described to interact with TRPV1, TRPA1, TRPM8 in calcium and ligand-dependent ways [55,56]. Sig-1R and calmodulin were shown to bind directly to cytosolic regions of these three TRPs, and that this binding increasing in the presence of calcium.…”

“…Since Sig-1R is implicated in essential physiological processes, exploiting such interactions may represent a means to develop more selective and efficacious pharmacological interventions. In this context, it was recently shown that Sig-1R interaction with TRPV1 may reduce pain under physiological conditions such as pregnancy [56]. TRPV1 is considered as a key player in the transduction of noxious stimuli [61] and its inhibition has become an important pharmacological target for analgesic treatments [62].…”

Structural basis for σ1 receptor ligand recognition

“…A brief survey of the literature reveals that when using σ 1 receptor ligands in cellular or biochemical assays, incubation times and temperatures vary from room temperature for 20 minutes 33 to 37 °C incubation for up to 72 hours 31 . Ligand concentrations are sometimes nearly 10,000-fold over K d [34][35][36] . Our data indicate that it can take 1.5 hours or longer to reach saturation at 37 °C, and at room temperature it can take nearly a day.…”

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

“…It has been also observed that gonadal oestradiol (E2) alters the sensation of pain through upregulation of vanilloid receptors 1 (TRPV1) that plays a critical role in triggering pain. An increase in progesterone seems to determine a down-regulation of TRPV1 receptors in the plasma membrane of sensory neurons, decreasing the perception of pain under physiological conditions like pregnancy [274]. In contrast, testosterone has been shown to play a key role in inhibiting the expression of TRPV1 at the sensory ganglion level in a model of chronic inflammatory pain induced in rats, thus confirming the presence of sex differences for neuropathic and/or chronic pain in both animals and humans.…”