Roles of testosterone in pain-related empathetic behaviors in mice

Empathetic responses, including socially-transferred pain hypersensitivity (STPH) and the targeted caring behaviors shown as allolicking (injury site targeted licking) and allogrooming (body grooming) toward a familiar demonstrator with pain, can be quantified in rodents using a dyadic social interaction (DSI) paradigm. These responses exhibit sex differences. Although our prior research established that β-estradiol is selectively required for allolicking, but not allogrooming in female mice, the overall scope of sex hormones remains unclear. Here, we discovered androgen deficiency following bilateral orchiectomy (ORC) in male observers impaired engagement of allolicking and allogrooming, STPH and social sniffing, but not self-grooming towards a familiar demonstrator. A 7-day replacement therapy with testosterone propionate (TP; 0.5, 1.0, 2.0 mg/kg bw, s.c.) prevented these deficits, but β-estradiol (E₂; 0.5, 1.0, 2.0 mg/day, s.c.) failed. Moreover, E2 administration significantly suppressed both allolicking and allogrooming in intact male observers. In intact female observers, TP selectively enhanced both sniffing and allogrooming in terms of time and bouts, however, it suppressed the bouts of allolicking although the total time of allolicking remained unchanged. TP had no effects on STPH or self-grooming in intact female observers. Thus, we demonstrate that testosterone is essential for sniffing, allolicking and allogrooming behaviors in male and allogrooming (but not allolicking) in intact female, while estrogen inhibits empathetic behaviors in intact male. This fundamental sexual dimorphism in hormonal regulation offers promising insights for developing sex-specific hormone therapies following gonadectomy.