FIGURE 4.

Progesterone attenuates pain-related behavior through disruption of the Sig-1R/TRPV1 complex. Sig-1R and TRPV1 channels are physically associated in the endoplasmic reticulum (ER), improving TRPV1 stability and resulting in suitable TRPV1 expression in the plasma membrane, where the channel transduces painful signals. Consequently, non-pregnant mice display pain behaviors in response to capsaicin paw-injection (left). However, in pregnant mice (right), when progesterone levels considerably increase, the formation of the complex between Sig-1R and the Binding immunoglobulin protein (BiP), is promoted. This maintains Sig-1R in a sequestered state and blocks its association with the TRPV1 channel, improving protein instability and avoiding degradation through the proteasomal pathway. Thus, TRPV1 protein levels in the plasma membrane decrease, leading to an increased pain threshold in response to capsaicin in pregnant mice.