Involvement of Histamine H3 Receptor Agonism in Premature Ejaculation Found by Studies in Rats.

Kazuhiro Kiyohara,Daisuke Uta,Midori Ninomiya-Baba,Yuuya Nagaoka,Hideki Nonaka,Takuya Fujita,Yurika Kino

doi:10.3390/ijms23042291

Abstract

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 H3 receptor (H3R) as a potential target for the treatment of PE and evaluated the effects of imetit (an H3R/H4R agonist), ciproxifan (an H3R antagonist), and JNJ-7777120 (an H4R 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 H3R 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 H3R and PE. Thus, H3R agonists may represent a novel treatment option for PE.

Highlights

According to the International Society for Sexual Medicine, men with lifelong and acquired premature ejaculation (PE) share the dimensions of short ejaculatory latency (EL), reduced or absent perceived ejaculatory control, and negative personal consequences [1,2,3]
We investigated the effect of imetit on mechanical stimuli-evoked firing of the pelvic nerve before and 5 min after the administration of the test compound
Imetit suppressed touch-evoked firing inputs to the deep dorsal horn neurons by blocking action potential conduction through Aβ fibers. These findings indicate that H3R agonists blocked nerve firing principally from Aβ fibers originating from the penis, and that H3 receptor agonism may represent a therapeutic agent for inhibiting subtle stimuli, such as touch sensation on the penis

Summary

Introduction

According to the International Society for Sexual Medicine, men with lifelong and acquired premature ejaculation (PE) share the dimensions of short ejaculatory latency (EL), reduced or absent perceived ejaculatory control, and negative personal consequences [1,2,3] According to their guidelines, pharmacological, psychological/behavioral, educational, and combination treatment interventions may be appropriate for PE [1]. No pharmacological treatments have been approved for PE by the Food and Drug Administration in the United States [5,6]. These issues necessitate the development of highly convenient novel therapeutics with sufficient efficacy and fewer adverse effects [7]

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