Nalfurafine Hydrochloride

In mammals, testosterone secretion from the testes is stimulated by pulsatile gonadotropin-releasing hormone (GnRH) and subsequent pulsatile luteinizing hormone (LH) secretion. GnRH/LH pulses are promoted by neurokinin B-neurokinin-3 receptor (NK3R) signaling and suppressed by dynorphin A-κ-opioid receptor (KOR) signaling. In this study, we administered nalfurafine, a KOR agonist, and fezolinetant, an NK3R antagonist, to adult gonad-intact male rats and measured their plasma testosterone concentrations to evaluate their effects on testosterone secretion in male mammals. Rats were orally administered nalfurafine (0.001, 0.005, 0.01, 0.1, or 0.5 mg/kg body weight [BW]), fezolinetant (0.3, 1, 3, or 10 mg/kg BW), or a combination of both (0.01 + 1, 0.01 + 3, or 0.1 + 3 mg/kg BW). Blood samples were collected at multiple time points from 0 to 24 h post-administration to measure plasma testosterone concentrations. The nalfurafine-treated group showed reduced testosterone levels at 5-8 h and 5-10 h for the 0.1 mg/kg and 0.5 mg/kg doses, respectively, compared with the vehicle-treated (control) group. Similarly, the fezolinetant-treated group showed reduced testosterone levels at 2-8 h for the 10 mg/kg dose compared with the control group. Co-administration of nalfurafine and fezolinetant further suppressed testosterone levels, with significant reductions observed in the 0.01 + 1, 0.01 + 3, and 0.1 + 3 mg/kg groups at 2-6, 2-6, and 2-8 h, respectively. These findings demonstrate that the oral administration of nalfurafine and fezolinetant alone and in combination effectively suppresses testosterone secretion in male mammals.