Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects

Abstract

Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties.

Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

“…Our model is also fit to measure the effects of psychotropics in addition to antidepressants. We have studied various drugs, e.g., apomorphine, tramadol [62], and several serotonergic drugs and have found inhibitory, facilitatory, or no effects. The model is very useful to study the brain mechanisms underlying various aspects of sexual behavior and of sexual dysfunction.…”

Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats

“…For the second experiment in slow ejaculating rats, animals were only administered S15535 in a randomized design similar to the first set of animals. As described previously in Olivier et al (2017), when pharmacological tests are performed, male rats are given a 30-min habituation time in the test boxes right after drug administration via IP injection, before the female rat is introduced. All behavior during the 30-min test is videorecorded after introduction of the female and were also livescored; the following parameters of the ejaculation series were deduced (Chan et al, 2011): number of ejaculations/test (E), number of mounts (M), number of intromissions (I), latency (s) to first mount (ML), latency (s) to first intromission (IL) and latency (s) to the first ejaculation (EL).…”

“…Because it is important to have comparable pharmacodynamics and kinetics in pharmacological studies, a test of fixed duration has been chosen: 30 min (1800 s). In the cases where drug-treatment had no "effect" on ejaculation and sexual behavior, or few or no animal achieved a first ejaculation it was not possible to perform statistical analyses and for those cases we assigned values of 1800 s (i.e., the maximum test duration) for some latencies (ejaculation, mount and intromission latency), although this is undoubtedly a matter of discussion as we have discussed before (Chan et al, 2011;Olivier et al, 2017). All tables and figures show the results for the first Ejaculation Series only.…”

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

“…Previously, we found ( Olivier et al, 2017a ) found that tramadol inhibits sexual behavior in male rats and postulated this to be mainly due to its SSRI properties, although tramadol’s μ-opioid receptor agonistic activity might contribute in a minor way to sexual behavior inhibition. Serotonergic activation of sexual activity in male rats is primarily based on activation of 5-HT 1A receptors based on the pro-sexual effects observed after 5-HT 1A receptor agonists ( Snoeren et al, 2014 ).…”

“…In the present studies, based on our previous work ( Olivier et al, 2017a ), we first explored several doses of tramadol (5, 10, 20, 40, and 50 mg/kg IP) on sexual behavior of wild type (SERT +/+ ), heterozygous (SERT +/- ), or SERT -/- male rats, selected, and trained for average sexual activity (2–3 ejaculations per 30-min test after a 6-weeks training period). Because we knew from previous studies ( Olivier et al, 2017a ) that a higher tramadol dose (40 mg/kg) in wild type rats could only marginally be influenced by naloxone, we combined a slightly inhibitory dose of tramadol (20 mg/kg) in all three genotypes with naloxone, a μ-opiate receptor antagonist. In another set of studies, we combined tramadol (20 mg/kg) with a selected, sexual behavior-inactive dose of the 5-HT 1A receptor antagonist WAY100,635 (0.3 mg/kg).…”