137 Involvement of Histamine H3 Receptor Agonism in Premature Ejaculation Revealed by a Novel Evaluation System
Authors: Kiyohara K , Uta D , Nagaoka Y , Kino Y , Nonaka H , Ninomiya M , Fujita T 
Published: May 2022

ABSTRACT

Introduction
Premature ejaculation (PE) has been defined by the International Society for Sexual Medicine (ISSM) as follows: men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Although local anesthetics and serotonin selective reuptake inhibitors (SSRIs) have been mainly used for the treatment of PE, there are several safety concerns and weak efficacy. To date, there have been no pharmacological treatments for PE approved by the Food and Drug Administration (FDA) in the United States. Therefore, there is still a need for the development of novel therapeutics that have sufficient efficacy and fewer side effects. We identified Histamine H3 receptor (H3R) as a potential target for treatment of PE. It is well known that H3R is mainly expressed by neuronal cells of the central nervous system, but its expression on peripheral nerves, especially Aβ sensory nerves, has also been reported. Activation of H3R in peripheral sensory neurons has been reported to inhibit mechanical stimulation-induced pain. This suggests that H3R stimulation can suppress neural activity induced by mechanical stimulation in the penis, but there have been no reports on the role of H3R in ejaculation function, and its mechanism of action is unknown.

Objective
In order to characterize the role of H3R in ejaculation prolongation, electrophysiological and behavioral studies were performed with imetit (H3R agonist) and ciproxifan (H3R antagonist) in male rats.

Methods
We developed a novel electrophysiological evaluation system for analyzing the spinal-penile neurotransmission mechanism, investigated the effects of imetit on penile neurotransmission. Also, we evaluated the effect of imetit on mechanical stimuli induced neuronal firing at genitofemoral nerve. For evaluating the effects of imetit for ejaculation, we used the copulatory behavior test in order to directly measure ejaculation latency (EL), which is a primary endpoint in clinical trial.

Results
In vivo electrophysiological study, imeit significantly attenuated the mechanical stimuli induced firing at spinal dorsal horn in a novel evaluation system. This inhibitory effect of imetit was also observed at genitofemoral nerve. Inhibition on firing was significantly inhibited by ciproxifan, but not inhibited by H4R antagonist.
In the copulatory behavior test, imetit showed a strong prolongation effect on EL. This effect was significantly inhibited by ciproxifan.

Conclusions
These results suggest that stimulation of H3R suppresses the mechanical stimuli induced neuronal firing on spinal-penile neurotransmission system, resulting in prolongation of ejaculation latency. H3R agonist is expected as a new treatment for PE.

Disclosure
Work supported by industry: yes, by Mitsubishi Tanabe Pharma Corporation. A consultant, employee (part time or full time) or shareholder is among the authors (Mitsubishi Tanabe Pharma Corporation).