How two sesquiterpenes drive horse manure rolling behavior in wild giant pandas

In this work, we discussed and counter-commented Paul J. Weldon's comments on our recent paper (Zhou et al. Proc Natl Acad Sci USA 117:32493, 2020a), where we reported that BCP/BCPO (beta-caryophyllene/caryophyllene oxide) in fresh horse manure is sufficient to drive manure rolling behavior (HMR) in giant panda and attenuate the cold sensitivity of mice by directly targeting and inhibiting transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals. The main question we arise in this response is: “which is the reasonable target of BCP/BCPO? Parasites or TRPM8?” Based on the knowledge of TRPM8-mediated cooling sensation, interaction between BCP/BCPO and TRPM8, BCP/BCPO concentration in horse manure samples, correlation between HMR frequency and habitat temperature, insecticidal activity of BCP/BCPO and thermal ecology of parasites, we prefer a simple idea that BCP/BCPO-induced TRPM8 antagonism bestows the wild giant pandas with cold tolerance at low-ambient temperatures. Compared with the speculation of insecticidal activity induced by HMR behavior, our study provided a comprehensive mechanism to confirm a physiological target of BCP/BCPO during the highly cold-correlated behavior.