Mechanisms underlying the sexual inhibitory effect of tramadol; a study in serotonin transporter knockout rats
Esquivel Franco, DC1; Olivier, B2; Waldinger, MD3; Gutierrez Ospina, G4; Olivier, JDA1
1: University of Groningen, GELIFES, Netherlands; 2: Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Netherlands ; 3: Drexel University, College of Medicine, USA; 4: Universidad Nacional Autonoma de Mexico, Instituto de Investigaciones Biomedicas, Mexico
Materials and methods: A crossover and randomized design was performed with 36 sexually experienced male Wistar rats (SERT+/+, SERT+/-, SERT-/-; N=12 each). Rats received acute intraperitoneal doses of 0, 5, 10, 20, 40 and 50 mg/kg tramadol hydrochloride. Furthermore, WAY100635 (5-HT1A receptor antagonist) was tested in doses 0, 0.1, 0.3 and 1 mg/kg IP and naloxone hydrochloride (µ-opioid receptor antagonist) in doses 0, 5, 10 and 20 mg/kg, IP. Finally, we tested combinations of vehicle + vehicle, vehicle + tramadol (20 mg/kg), tramadol (20mg/kg) + WAY (0.3 mg/kg), tramadol (20mg/kg) + naloxone (20mg/kg), and tramadol (20mg/kg), + WAY (0.3 mg/kg) + naloxone (20 mg/kg). Experiments were performed over several months on a 30-min sexual behavior test.
Results: In all SERT groups, intermediate and high doses of tramadol (20, 40 and 50 mg/kg) significantly decreased ejaculation, mount and intromission frequencies and at the highest dose a total inhibition effect was present. The latencies of ejaculation, mount and intromission were increased which in combination with the decreased frequencies resulted in a decreased efficiency to achieve ejaculation. WAY100635, did not affect sexual behavior in SERT+/+ animals. In accordance with previous findings, sexual behavior was inhibited in SERT-/- animals. Naloxone alone had no effect on sexual behavior, but in combination with WAY100635 or naloxone, tramadol strongly inhibited all sexual behavior parameters. The mixture of tramadol, WAY100635 and naloxone lead to complete elimination of sexual behavior in all groups.
Discussion: Acutely administered, tramadol inhibits sexual behavior in male rats. Previously it was postulated that the effects of tramadol on sexual behavior were mainly due its 5-HT reuptake blocking effects. Our results in SERT-/- animals suggest that also the µ opioid receptor agonistic properties of tramadol may contribute to its effects observed in sexual behavior.
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