Involvement of Histamine H(3) Receptor Agonism in Premature Ejaculation Found by Studies in Rats

Several of the drugs currently available for the treatment of premature ejaculation (PE) (e.g., local anesthetics or antidepressants) are associated with numerous safety concerns and exhibit weak efficacy. To date, no therapeutics for PE have been approved in the United States, highlighting the need to develop novel agents with sufficient efficacy and fewer side effects. In this study, we focused on the histamine H(3) receptor (H(3)R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H(3)R/H(4)R agonist), ciproxifan (an H(3)R antagonist), and JNJ-7777120 (an H(4)R antagonist) in vivo. Our in vivo electrophysiological experiments revealed that imetit reduced mechanical stimuli-evoked neuronal firing in anesthetized rats. This effect was inhibited by ciproxifan but not by JNJ-7777120. Subsequently, we evaluated the effect of imetit using a copulatory behavior test to assess ejaculation latency (EL) in rats. Imetit prolonged EL, although this effect was inhibited by ciproxifan. These findings indicate that H(3)R stimulation suppresses mechanical stimuli-evoked neuronal firing in the spinal–penile neurotransmission system, thereby resulting in prolonged EL. To our knowledge, this is the first report to describe the relationship between H(3)R and PE. Thus, H(3)R agonists may represent a novel treatment option for PE.