The mechanism(s) behind the beneficial

Tramadol is a well-known analgesic drug,

effect of the PDE 5 inhibitors on LUTS/OAB

which by itself, it is a very week m receptor ago-

and their site(s) of action largely remain to be

nist. However, it is metabolized to several differ-

elucidated.

ent compounds,some of them almost as effective

as morphine at the m receptor. The drug also

CNS Targets

inhibits serotonin (5-HT) and noradrenaline

reuptake.123 This profile is of particular interest,

Anatomically, several CNS regions may be

since both m-receptor agonism and amine

reuptake inhibition may be useful principles for

involved in micturition control: supraspinal

treatment of OAB/DO.

structures, such as the cortex and diencephalon,

When tramadol is given to a normal, awake

midbrain, and medulla, but also spinal struc-

rat, the most conspicuous changes in the cys-

tures (see, Fowler et al.2). Several transmitters

tometrogram are increases in threshold pres-

and their receptors are involved in the reflexes

sure and bladder capacity. Naloxone can more

and sites described above and may be targets for

or less completely inhibit these effects.124 There

drugs aimed for control of micturition.13

is a small difference between the doses of mor-

Although few drugs with a CNS site of action

phine that cause inhibition of micturition and

have been developed, several agents acting on

those increasing bladder capacity and evoking

the CNS may have effects on micturition.

urinary retention. Tramadol has effects over a

much wider range of doses, which means that it

Opioid Receptors

could be therapeutically more useful for mictu-

rition control. It may be speculated that the dif-

Endogenous opioid peptides and corresponding

ference is dependent on tramadol also inhibiting

receptors are widely distributed in many regions

the 5-HT and noradrenaline reuptake.124

in the CNS of importance for micturition con-

Clinically, tramadol seems to be as effective as

trol, e.g., the PAG, the PMC, the spinal parasym-

antimuscarinics in the treatment of idiopathic

pathetic nucleus, and the nucleus of Onuf.117

OAB, as shown in a double-blind, placebo-con-

It has been well established that morphine,

trolled, randomized study.125 However, consid-

given by various routes of administration to ani-

ering its adverse effect potential, it may not be

mals and humans, can increase bladder capacity

an ideal agent for OAB treatment.

and eventually cause urinary retention. Given

intrathecally (i.t.) to anesthetized rats and intra-

Serotonin (5-HT) Mechanisms

venously (i.v.) to humans, the m-opioid receptor

It is well established that the lumbosacral auto-

antagonist, naloxone, has been shown to stimu-

late micturition,119,120 suggesting that a tonic

nomic, as well as the somatic motor nuclei

activation of m-opioid receptors has a depres-

(Onuf’s nuclei), receive a dense serotonergic

sant effect on the micturition reflex.

input from the raphe nuclei, an innervation

Morphine given i.t. was effective in patients

which is not subjected to the general decline in

with DO due to spinal cord lesions,121 but was

lumbosacral spinal innervation found with

associated with side-effects, such as nausea and

increasing age.126 Multiple 5-HT receptors have

pruritus. Further side-effects of opioid receptor

been found at sites where processing of afferent

agonists comprise respiratory depression, con-

and efferent impulses from and to the LUT take

stipation and abuse. Attempts have been made

place.127 Although, as pointed out by de Groat,128

to reduce these side effects by increasing selec-

there is some evidence in the rat for serotoner-

tivity towards one of the different opioid recep-

gic facilitation of voiding, the descending path-

tor types.122 At least three different opioid

way is essentially an inhibitory circuit, with

receptors – m, d, and k – bind stereospecifically

5-HT as a key neurotransmitter. Thus, electrical

with morphine, and have been shown to inter-

stimulation of 5-HT-containing neurons in the

fere with voiding mechanisms. Theoretically,

caudal raphe nucleus causes inhibition of blad-

selective receptor actions, or modifications of

der contractions.129,130 Most experiments in rats

effects mediated by specific opioid receptors,

and cats indicate that activation of the central

may have useful therapeutic effects for micturi-

serotonergic system by 5-HT reuptake inhibi-

tion control.

tors, as well as by 5-HT1A and 5-HT2 receptor