Table_9_Tramadol’s Inhibitory Effects on Sexual Behavior: Pharmacological Studies in Serotonin Transporter Knockout Rats.PDF

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.

曲马多（Tramadol）是治疗人类早泄（PE）的有效药理学干预手段。为探究曲马多的抑制作用是否主要由其选择性5-羟色胺再摄取抑制（SSRI）效应介导，本研究检测了曲马多对血清素转运蛋白野生型（SERT+/+）、杂合型（SERT+/-）及敲除型（SERT-/-）三类大鼠性行为的量效影响。为进一步探究是否存在其他机制参与其抑制效应，本研究联合使用曲马多与两种拮抗剂——5-羟色胺1A受体拮抗剂WAY100,635以及μ阿片受体拮抗剂纳洛酮（naloxone），并检测其对大鼠性行为的作用。
实验结果显示：曲马多可在所有基因型大鼠中呈剂量依赖性降低其性活动水平。所有实验中，SERT+/-大鼠的性行为响应与SERT+/+大鼠无显著差异。WAY100,635对SERT+/+大鼠的性行为无显著影响，但可在SERT-/-大鼠中呈剂量依赖性降低其性活动水平。当以0.3 mg/kg的WAY100,635联合20 mg/kg曲马多给药时，可显著降低SERT+/+大鼠的性活动水平，且对SERT-/-大鼠的抑制效果更强。纳洛酮对SERT+/+大鼠的性行为无一致性影响，但在SERT-/-大鼠中，所有给药剂量均可轻度降低其射精频率。当以20 mg/kg纳洛酮联合20 mg/kg曲马多给药时，两种基因型大鼠的射精频率均出现下降。值得注意的是，联合使用20 mg/kg曲马多、0.3 mg/kg WAY100,635及20 mg/kg纳洛酮时，可完全消除SERT+/+与SERT-/-大鼠的所有性行为。
本研究结果表明，曲马多对SERT+/+雄性大鼠性行为的抑制作用主要（即便不是完全）由SERT抑制介导，且5-羟色胺1A受体发挥了重要作用，不过不能排除其他系统（如去甲肾上腺素能系统）的影响。由于选择性5-羟色胺再摄取抑制剂类药物需长期给药方可产生性抑制效应，因此曲马多有望作为早泄的“按需”治疗手段，具备临床治疗潜力。