**6. Conclusions**

Studies from the last two decades show the importance of TRP channels in pain sensations caused by noxious temperatures and many chemicals. In particular, TRPA1 is activated in many conditions and its activity evokes an extremely uncomfortable sensation. Therefore, TRPA1 may be a crucial target for pain treatment, although TRPV1 contribution to more specific nociception cannot be disregarded. While some pharmaceutical companies are already focused on the development of TRPA1 and TRPV1 antagonists [189], ANO1 inhibition may also be effective in treating pain because the role of ANO1 is akin to an amplifier, and its suppression does not generate a painless condition. Namely, a level of nociception that is sufficient enough to sense damage for survival can be maintained in an ANO1-blocked state, but not with shutdown of the detectors, i.e., TRP channels.

Sensory systems do not only detect noxious stimuli but also participate in the establishment of inflammation or chronic pain. Neural excitation induces CGRP release from nociceptor termini, inducing inflammation that can ultimately lead to sensitization of nociceptors. Therefore, inhibition of CGRP release by suppression of TRP channel activity is expected to provide relief for intractable pain, headache, and migraine. However, this strategy may result in dangerous secondary effects in some diseases, including fungus infection. Bone is often disrupted in *Candida* infection, a situation induced by osteoclast activity. It remains unclear why osteoclast activity is up-regulated during infection, but in this case, CGRP release from nociceptors becomes beneficial by suppressing two pathways: TNF-α release from myeloid cells and overactivation of osteoclasts. Thus, inflammation induced by CGRP is not detrimental in some pathological conditions, yet targeting it for pain relief might not always be the best strategy.

In fact, pain sensation negatively controls our physiological conditions, including our emotions. Recent reports indicate that complete abolishment of pain induces a severe pathological condition to our body. Therefore, we believe that the important point of pain management is to decrease pain to a tolerable level, but one that is sufficient enough to maintain natural protection against tissue damage. To develop this strategy, there is a need for the discovery of new TRP channels and ANO1 inhibitors that could be used concomitantly and adjusted depending on each patient's condition.

**Author Contributions:** Writing—Original Draft Preparation (Parts 1 and 2), Y.T.; Writing—Original Draft Preparation (Parts 3 and 4), S.D. and K.M., respectively; Writing—Review & Editing, M.T.

**Funding:** This research was funded by Japan Society for the Prmotion of Science (JP17K15793 to Y.T.), Takeda Science Foundation (to Y.T.), and Japan Society for the Prmotion of Science (JP18H02970, JP19K22712 to K.M.).

**Acknowledgments:** This paper was supported by the Showa University School of Medicine. We thank Rachel James, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
