**3. Conclusion**

Nociception is a neuronal process that protects against injurious stimuli that can be endogenously produced during inflammation or tissue injury processes. The transduction of these signals requires the activation of ion channels such as some members of the TRP family. In this chapter we have described how sex steroids influence nociception by regulating some of the TRP channels important for this neuronal process. Here we have described the data showing that estrogens and their nuclear receptors (ERα/β) positively regulate the expression of the TRPV1 and TRPA1 genes through a classical genomic pathway. The reports above discussed also show that progesterone and its nuclear receptors (PRA/B) negatively regulate TRPV4 gene expression.

We have also compiled and discussed the evidence about androstenedione's and testosterone's non-classical effects in the regulation of the activation of TRPA1 and TRPM8 ion channels directly. We have suggested a testosterone binding-pocket in the TRPM8 channel and we have also pinpointed an androstenedione bindingpocket in the C-terminal and pre-S1 regions of TRPV1 and TRPA1 channels [119].

These observations strengthen the notion that androgens act as direct molecular regulators of some nociceptive ion channels function, playing dual roles as nociceptive and antinociceptive molecules. For example, androstenedione has nociceptive actions on TRPA1 and TRPV1 activation and testosterone at low concentrations (picomolar range) can produce cold sensation through the TRPM8 channel, while high testosterone levels could improve resilience to cold sensation inhibiting the currents through TRPM8. Finally, the literature here reviewed shows that the nonclassical sex steroid effects are mediated by membrane receptors or even chaperones such as the Sig-1R, affecting signaling pathways and/or protein stability. This last finding exemplifies the antinociceptive effects of progesterone by which this hormone reduces the transduction of noxious stimuli mediated by TRPV1 channel activation. These data open a research field in which we will deepen our knowledge in the role of molecular sexual dimorphism and the interplay between nociceptive TRP channels and sex steroids.
