Roles of dopaminergic receptors in bladder and erectile function at the spinal level

Department of Urology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan

Asian J Androl 2002 Dec; 4: 287-290           

Keywords: apomorphine; penile erection; micturition; spinal cord

At the spinal level, the dopaminergic, the a1 adrenergic and the neurokinin receptors play definite roles in the micturition control. From the anatomical point of view, the spinal center of micturition is located close to the center of erectile function. Recently, apomorphine is used for the treatment of erectile dysfunction and its mechanism of action is considered to be mainly through the central nervous system.

2 Dopaminergic receptors and bladder function at the spinal level

It is well known that patients with Parkinson's disease may have detrusor hyperreflexia, possibly as a consequence of nigrostriatal dopamine depletion and failure to activate the inhibitory dopamine (D) 1 receptors [1]. However, other dopaminergic systems may activate the D2 receptors, thus facilitating the micturition reflex [2]. Sillen et al [3] showed that apomorphine, which activated both D1 and D2 receptors, induced hyperactivity in anesthetized rats via stimulation of the central dopaminergic receptors. The effects were abolished by infracollicular transaction of the brain and by prior intraperitoneal administration of the centrally acting D2 receptor blocker, spiroperidol. Kontani et al [4] suggested that the bladder hyperactivity induced by apomorphine in anesthetized rats resulted from synchronous stimulation of the micturition centers in the brain stem and spinal cord and that the response was elicited by stimulation of both dopamine D1 and D2 receptors.

Both D1 and D2 receptors have been demonstrated by radioligand binding and autoradiography in the human bladder [5], but it has been suggested, based on experiments with metoclopramide in humans, that peripheral dopamine receptors are not important in vesico-urethral function [6]. Ishizuka et al [7] showed that systemic administration of apomorphine also stimulated micturition or induced bladder hyperactivity in unanesthetized rats. This bladder activity was abolished or suppressed by intrathecal administration of the a1-adrenoceptor blockers, indoramin and doxazosin. This supports the view that the apomorphine-induced bladder activity involves spinal  a1-adrenoceptors. They also showed that intra-arterial administration (close to the bladder artery) of indoramin and doxazosin attenuated the effects of apomorphine, which are similar to but not more pronounced than those after intrathecal administration. This makes the peripheral structures (ganglia, bladder) other possible sites of action. Facilitatory a1-adrenoceptors have been demonstrated on cholinergic neurons in the vesical ganglia of the cat [8-10], on dissociated bladder neurons from the rat major pelvic ganglion [11] and on cholinergic terminals in the rat bladder [12]. An effect of indoramin and doxazosin at the ganglionic and/or prejunctional level, leading to a decrease in acetylcholine release, can therefore not be excluded.

The parasympathetic center innervating the urinary bladder is controlled via supraspinal pathways originating in the dorsolateral pontine tegmentum, including the locus coeruleus, which consists chiefly of norepinephrine-containing cells and dopamine receptors [13]. After pretreatment with intraperitoneal carbidopa, intra-peritoneal L-dopa stimulates micturition or induces bladder hyperactivity in anesthetized rats. This was also the case in normal, conscious rats [7]. Sillen et al [14] suggested that the L-dopa induced hyperactivity is elicited chiefly via stimulation of central dopaminergic receptors, because the effects were abolished by prior intraperitoneal administration of the centrally acting D2 receptor blocker, spiroperidol. L-dopa most probably acts on the dopaminergic receptors in the locus coeruleus. Later on, Ishizuka et al showed this L-dopa induced bladder hyperactivity could be suppressed by the intrathecal administration of indoramin, a1 adrenoceptor antagonists [15, 16] or SR 140,333, neurokinin 1 receptor antagonist [17] (Figure 1). These facts imply that this hyperactivity partly mediated through the neurokinin receptors and also the a1 adrenoceptors at the spinal level.

Figure 1. Roles of doperminergic receptors for micturition in normal rat.

Dopaminergic mechanisms may be involved in the regulation of male sexual behavior [18]. Subcutaneously and centrally administered apomorphine, a dopamine receptor agonist which stimulates both dopamine D1-like (D1 and D5) and D2-like (D2, D3, D4) receptors, has been shown to induce penile erection in rats [19]. Most studies on the effects of apomorphine rely on behavioral assessments. However, it has been demonstrated that apomorphine induced increases in intracavernous pressure and erection in an awake rat model [20].

The site of action of apomorphine is considered to be the paraventricular nucleus of the hypothalamus (PVN) in the central nervous system [21]. The view that the effects of apomorphine are not peripherally mediated is further supported by the finding that ablation of efferent nerve and blood supply to the corpora abolished the erectile activity induced by systemic administration of apomorphine [20]. The fact that the effects of apomorphine were abolished after NO synthesis inhibition suggests that the apomorphine action is dependent on release of NO, possibly at both the central and peripheral sites [22, 23].

It has been shown that the erectile effect of systemically administered apomorphine can be blocked by oxytocin receptor antagonists given intracerebroventricularly, implying that dopamine receptor stimulation involves release of oxytocin, at least at the central level [24]. Oxytocin given intrathecally in rats has a proerectile effect [25, 26]. However, it is unclear whether the apomorphine action at the spinal level is dependent on oxytocin release.

The existence of dopamine projections from the A₁₁ cell group in the brain to the spinal cord as well as an intrinsic dopamine innervation within the spinal cord raises the possibility of and additional direct action of apomorphine at the spinal level [27, 28]. Immunocystochemical studies revealed that dopamine fibers and terminals exist in virtually all laminae throughout the spinal cord [29,30]. Furthermore, studies using ligand-binding techniques have shown the presence of D1 and D2 receptors in the spinal cord [31]. In male rats, D2 receptors identified with immunochemistry and in situ hybridization have been located in the parasympathetic nucleus of the lumbosacral spinal cord, which contains the cellulard bodies of the proerectile autonomic neurons innervating the penis [32].

Giuliano et al [33] measured the intracavernous pressure (ICP) and blood pressure in anesthetized rats receiving apomorphine intravenously and intrathecally. Erections could be evoked by both ways of administration, implying that there may be dopaminergic receptors for erection at the spinal level. They suggested that the spinal site of action may participate in the generation of erection and exert a facilitatory effect on erection of supraspinal origin. Recently, Yaici et al also showed the catecholaminergic neurons, which regulate penile erection at the spinal level by retrograde tracing techniques and immunohistochemistry against synthetic enzymes of noradrenaline and adrenaline [34]. Their data implies a cathecholaminergic control of autonomic and somatic motoneurons regulating penile erection at the spinal level. Ishizuka et al [35] also demonstrated the importance of the spinal action of apomorphine, since after subcutaneous administration the changes in the intracavernous pressure in the normal and spinally transected rats were almost the same.

4 Further interests of spinal sites of action for erectile function from the data of bladder function

Besides the erectile effect, subcutaneously given apomorphine induces bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system [4, 36] and in clinical studies, apomorphine has been shown to increase voiding efficacy in patients with Parkinson's disease. Steers et al [37] reported that sublingual apomorphine could improve bladder function in spinal cord injured patients. This implies that apomorphine may have a spinal action for stimulation of voiding (Figure 2). At the sacral level (S2-S4), bladder parasympathetic preganglionic neurons (PGN) are located in the lateral part of the sacral intermediate gray matter [38]. These neurons also regulate reflex erection and change in blood flow in the genital area. Also entering the sacral level are sensory nerve impulses from the sex organs via both the parasympathetic and somatic nerves [23, 39].

Figure 2. Roles of doperminergic receptors for micturition and penile erection in rat with spinal cord injury.

At the spinal level, neurokinin [17] and a1 adrenergic receptors [15, 16] play certain roles in the regulation of bladder function. Anatomically, the spinal center of micturition is located close to the spinal center for erectile function. Further study will be needed to clarify the role of neurokinin and a1 adrenergic receptors in the erectile function at the spinal level.

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Correspondence to: Dr Osamu Ishizuka, Department of Urology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

Tel: +81-263 37 2661,   Fax: +81-263 37 3082

Email: ishizuk@hsp.md.shinshu-u.ac.jp

Received 2002-07-22    Accepted 2002-11-12