Department of Physiology and Anatomy, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
Department of Pharmaceutical Education Center, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
J Sex Med. 2021 Feb;18(2):231-239. doi: 10.1016/j.jsxm.2020.10.014. Epub 2020 Nov 23.
We previously reported that the combination of the dopamine (DA) receptor agonist apomorphine and the 5-hydroxytryptamine (5-HT) receptor agonist m-chlorophenylpiperazine (m-CPP) in rats potently and selectively facilitates the ejaculatory response through activation of D-like and 5-HT receptors, respectively.
The aim of this study was to clarify the target level of the proejaculatory effects induced by combination of these agonists.
For in vivo behavioral studies, apomorphine and m-CPP were given intracerebroventricularly and intrathecally alone or in combination with either drug administered systemically. Male rats were acclimated to observational cages bedded in paper towels, and the occurrence of ex copula ejaculation was assessed by evaluating the presence and weight of ejaculatory plugs dropped from the tip of the penis to the paper towels or adhered to the tip of the penis at 30 min after drug administration. For in vitro contraction studies, seminal vesicles isolated from rats were suspended in an organ bath to test contractile responses to drug combinations, and the effects of the combined drugs on the contractile response of noradrenaline were also tested.
The presence and weight of ejaculatory plugs produced by drug-induced ejaculation and the contractile responses of the seminal vesicle were evaluated.
Intrathecal m-CPP (10 μg), but not intracerebroventricular m-CPP, evoked the synergistic effects on ejaculation when used in combination with systemically administered apomorphine (0.1 mg/kg, subcutaneous). Moreover, the synergy between m-CPP and apomorphine was completely abolished by the intrathecal 5-HT receptor antagonist SB242084 (10 μg). Intrathecal or intracerebroventricular apomorphine (1-10 μg) evoked proejaculatory effects in combination with systemically administered m-CPP (0.3 mg/kg, intraperitoneal). The selective peripherally acting D-like receptor agonist carmoxirole did not evoke ejaculation when used in combination with m-CPP. Furthermore, isolated rat seminal vesicles were completely insensitive to the combination of apomorphine and m-CPP.
These results indicated that the synergistic effects of the drugs on ejaculation were induced at the central level but not at peripheral sites. Our findings also suggested that the 5-HT receptor mediated the stimulation of the spinal ejaculatory pattern generator and was synergistically potentiated by the spinal DA receptor and that activation of the supraspinal DA receptor was also involved in mediating these synergistic effects. Yoshizumi M, Yonezawa A, Kimura Y, et al. Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats. J Sex Med 2021;18:231-239.
我们之前的研究表明，多巴胺（DA）受体激动剂阿朴吗啡和 5-羟色胺（5-HT）受体激动剂间氯苯哌嗪（m-CPP）联合使用，通过分别激活 D 样和 5-HT 受体，在大鼠体内强有力地选择性促进射精反应。
本研究的目的是阐明这些激动剂组合诱导的促射精液效应的靶位水平。
对于体内行为研究，阿朴吗啡和 m-CPP 单独或联合使用时，通过脑室内或鞘内给药，同时通过全身给予一种药物。雄性大鼠适应于铺有纸巾的观察笼中，通过评估射精后从阴茎尖端滴落到纸巾上或粘附在阴茎尖端的射精塞的存在和重量来评估外射精液的发生。对于体外收缩研究，将从大鼠中分离出的精囊悬挂在器官浴中，以测试药物组合的收缩反应，还测试了联合药物对去甲肾上腺素收缩反应的影响。
评估药物诱导射精产生的射精塞的存在和重量以及精囊的收缩反应。
鞘内给予 m-CPP（10μg），但不是脑室内给予 m-CPP，当与全身给予阿朴吗啡（0.1mg/kg，皮下）联合使用时，可诱发协同的射精作用。此外，鞘内给予 5-HT 受体拮抗剂 SB242084（10μg）完全消除了 m-CPP 和阿朴吗啡之间的协同作用。鞘内或脑室内给予阿朴吗啡（1-10μg）与全身给予 m-CPP（0.3mg/kg，腹腔内）联合使用可引起促射精液作用。选择性外周 D 样受体激动剂 carmoxirole 与 m-CPP 联合使用时不会引起射精。此外，分离的大鼠精囊对阿朴吗啡和 m-CPP 的联合作用完全不敏感。
这些结果表明，药物对射精的协同作用是在中枢水平而不是在周围部位诱导的。我们的研究结果还表明，5-HT 受体介导了脊髓射精模式发生器的刺激，并被脊髓 DA 受体协同增强，而上脑 DA 受体的激活也参与了这些协同作用的介导。Yoshizumi M，Yonezawa A，Kimura Y，等。阿朴吗啡和间氯苯哌嗪对大鼠射精协同作用的中枢机制。性医学杂志 2021；18：231-239。
