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EDITORIAL FOCUS
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064
EFFORTS DURING THE PAST SEVERAL YEARS have enabled an enhanced level of understanding of urinary bladder physiology and pathophysiology, with continued exploitation of muscarinic receptors as drug targets, and the identification of novel molecular underpinnings of pathways such as C fiber afferents and the vanilloid TrpV1 receptors, the noncholinergic nonadrenergic mechanisms and P2X receptors (P2X1, P2X3), urothelial signaling processes, and the central mechanisms of control of micturition involving diverse transmitter systems. The findings reported in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology by Lee and coworkers (9) now provide valuable insight into a potential role of neuronal nicotinic ACh receptors (nAChRs) in the central control of voiding function.
Micturition is a complex process requiring coordination of autonomic, somatic, and central nervous system pathways that involve bladder urothelium, ganglionic, spinal, and supraspinal mechanisms. The innervation of the urinary bladder by sacral parasympathetic and sympathetic nerves controls the voiding
and the filling phases of micturition. Specifically, the sacral
parasympathetic system provides excitatory input to the bladder and inhibitory
input to the urethra, whereas the thoracolumbar sympathetic nerves provide
excitatory input to the urethra and bladder neck and both excitatory and
inhibitory inputs to the parasympathetic ganglia
(7). nAChRs are known to play
an integral role in the control of bladder function as mediators of fast
synaptic transmission in both the parasympathetic and sympathetic autonomic
ganglia (5). These receptors,
located throughout the central and peripheral nervous system
(10), are assembled from a
family of at least 12 distinct subunits, 
2–10 and
2–4, and function as homomers of a single subunit (such as
7), as simple heteropentamers as one type of -subunit and one
type of -subunit (such as 42-receptors), and as complex
heteropentamers of three or more subunits (such as
354-receptors). In contrast to the neuromuscular junction
(11
), diverse nAChR subtypes predominate in the
brain (42, 7, etc.) and the autonomic nervous system
(e.g., 34). The observed multiorgan autonomic dysfunction in mice
lacking the 3 alone or 24 combinations points to the
involvement of nAChRs containing these subunits in the autonomic control of
end organs such as the urinary bladder
(11,
12). Both
24-/- or
3-/- mice showed no sensitivity to
nicotine in vitro and developed severe bladder distension within 2 days after
birth, and those that survived displayed enlarged bladders, dribbling
urination, bladder infection, and urinary stones. Peripheral nAChR-mediated
control of autonomic function may also occur at the level of the neuroeffector
junction; little information is, however, available on the subunit composition
of nicotinic receptors expressed in the pelvic plexus and intramural ganglia
of the bladder. Preliminary reports demonstrating expression of several nAChR
subunit mRNAs in rat bladder urothelium have recently appeared
(3).
Although peripheral nAChRs located in the autonomic ganglia containing the 3-subtype are generally considered as the primary peripheral mediators of bladder function, the role of nAChR subtypes in the central nervous system (CNS) controlling micturition is far less understood. Nonetheless, it is well
appreciated that various transmitter pathways in the CNS play a major role in
controlling voiding function and urine output through both afferent and
efferent brain-spinal pathways. CNS regulation of voiding is complicated by
the fact that reflex pathways that mediate bladder function are also under
voluntary control. The pontine micturition center (PMC), an area of the
rostral pontine tegmentum located in the brain stem, is thought to serve as a
relay center receiving information from the periaqueductal gray (PAG), which
becomes activated by spinal A-bladder afferents and subsequently
transmits back efferent information through the sacral cord to activate
parasympathetic neurons so as to inhibit urethral sphincter motoneurons during
voiding. Glutamatergic transmission from the PMC is considered essential in
controlling the spinal efferent pathways that regulate autonomic control of
voiding function. In turn, several other neurotransmitter systems can modulate
glutamatergic transmission at the level of the PMC. Whereas GABA and
enkephalins have an inhibitory effect, dopamine activates the PMC and ACh is
thought to contribute to both excitatory and inhibitory synaptic activity
(6). In the latter case, the
role of cholinergic modulation is likely influenced by the type of cholinergic
receptor present in the PMC or other nuclei involved in the CNS control of
bladder function.
Lee et al. have now examined central nicotinic receptor pathways controlling micturition in the rat by evaluating (±)-epibatidine (2), a nonselective high-affinity neuronal nicotinic receptor agonist, originally isolated from the Ecuadorian frog, Epipedobatus tricolor, in awake and urethane-anesthetized rats on voluntary and reflex voiding function, respectively (9). The authors show that a small dose of the nAChR agonist epibatidine (0.1 µg) injected intracerebroventricularly increased voiding frequency in both awake and anesthetized rats, but without affecting voiding pressure, and that the inhibitory effect produced by epibatidine could be antagonized by pretreatment with the nicotinic antagonist chlorisondamine intracerebroventricularly. In contrast, a higher dose of epibatidine (1 µg) administered either intracerebroventricularly or intravenously evoked an excitatory effect on voiding, possibly through activation of ganglionic nAChRs, given the observation that intracerebroventricular chlorisondamine failed to block the augmented response. With intracerebroventricular epibatidine administration, the authors speculate that the higher dose may be capable of entering the systemic circulation or, alternatively, may activate lower affinity nAChRs located centrally to elicit excitatory effects on voiding function. Lee and colleagues also discuss the possibility that the inhibitory effect produced by (±)-epibatidine may involve the nAChR-mediated activation of descending serotonergic pathways in the brain stem, such as the nucleus raphe magnus, that modulate serotonin release in the spinal cord to increase bladder capacity, a mechanism also previously proposed as underlying the antinociceptive activities of nAChR agonists (4).
Several transmitter pathways in the CNS can modulate voiding function (1), but few drugs with a defined central site of action have been developed thus far for the treatment of voiding disorders. The observation that neuronal nAChRs may indeed modulate central control of voiding function and that pharmacological activation of nAChRs in the brain can inhibit voiding reflexes raises the possibility that nAChR agonists may have utility in treating neurogenic voiding dysfunction. However, because of the lack of pharmacological selectivity of (±)-epibatidine and chlorisondamine, the question of which nAChR subtypes are specifically involved in mediating central regulation of voiding function, and whether the latter activity can be dissociated from potential side effect liabilities will require further study. In this regard, preliminary studies using subtype selective agonists have begun to emerge (8). Future studies using selective agonist and antagonist tools could help elucidation of the subtype(s) involved and the mechanisms underlying central control of voiding function, which could ultimately set the stage for targeting distinct nicotinic receptor subtype(s) for the potential treatment of lower urinary tract symptoms.
FOOTNOTES
Address for reprint requests and other correspondence: M. Gopalakrishnan, Neuroscience Research, Dept R47W Bldg. AP9A-3, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL
60064 (E-mail:
murali.gopalakrishnan{at}abbott.com).
REFERENCES
3 neuronal nicotinic acetylcholine receptor.
Proc Natl Acad Sci USA 96:
5746–5751, 1999.2 and the 4 subunits of neuronal nicotinic
acetylcholine receptors. J Neurosci
19: 9298–9305,
1999.
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