Tramadol's Inhibitory Effects on Sexual Behavior: Pharmacological Studies in Serotonin Transporter Knockout Rats.

Diana C Esquivel-Franco,Gabriel Gutiérrez-Ospina,Berend Olivier,Marcel D Waldinger,Jocelien D A Olivier

doi:10.3389/fphar.2018.00676

Abstract

Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose–response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a μ-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT-/- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as “on demand” therapy for PE.

Highlights

Tramadol is a worldwide used painkiller that produces antinociception by activation of μ-opioid receptors (Hennies et al, 1988)
The sexual performance of the animals during the duration of the study stabilized throughout the training session period
The ejaculation frequencies of serotonin transporter (SERT)+/− animals were never significantly different from the SERT+/+ rats; SERT−/− rats did not significantly differ in ejaculation frequencies compared to wild type rats over the whole duration of the experiments

Summary

Introduction

Tramadol is a worldwide used painkiller that produces antinociception by activation of μ-opioid receptors (Hennies et al, 1988). The first enantiomer [(+)-tramadol] and its metabolite [(+)-M1] are selective agonists of the μ-opioid receptor and have selective serotonin reuptake inhibitory (SSRI) effects as well; the second enantiomer [(−)-tramadol] and the (−)-M1 metabolite produce norepinephrine reuptake inhibition (Matthiesen et al, 1998). Due to its SSRI properties, tramadol has antidepressant-like effects (Rojas-Corrales et al, 1998, 2002). SSRIs are mainly used as antidepressants due to inhibition of the serotonin transporter (SERT), leading to an increased level of 5-HT in the synaptic cleft. SSRI treatment has been associated with the appearance of some serious side effects, like a decrease in the ability to reach ejaculation or orgasm (Balon, 2006); resulting in a significant impact on an individual’s life quality that in most cases leads to non-compliance to treatment (Higgins et al, 2010)

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