Twenty years ago, the Italian group, chaired by Maggi, pioneered the role of a specific capsaicin-sensitive subset of primary sensory nerves in the lower urinary tract [1]. With brilliant intuition, Maggi and colleagues showed that intravesical instillation of capsaicin—the source of red pepper’s pungent taste—in six patients with lower urinary tract symptoms (LUTS) produced a concentration-related reduction of the first desire to void and of cystometric bladder capacity. Clinically, the patients reported disappearance or marked attenuation of their symptoms after repeated instillations, providing the first indication that afferent nerves were present in the human urinary bladder. More recent studies have confirmed Maggi’s theory, and that success is summarized by Roosen and colleagues in this issue of European Urology [2]. When approaching this article, I think the reader should know what has been changing in recent years, what has been the basic science and the clinical rationale for investigating alternative pathways to cholinergic and adrenergic regulation of the lower urinary tract, and what lies ahead. The idea of local afferent modulation by targeting afferent nerves that control the lower urinary tract has gained the trust of urologists as a potential alternative to current drug therapies for LUTS [3]. For treating overactive bladder, the emerging concept is that it would be more desirable to prevent the micturition reflex by blocking the afferent branch instead of blocking the contraction of detrusor smooth muscle, as it results from the activation of efferent branch. In the past, many factors, such as the complex neurology of the voiding reflex; the simple, uncontroversial idea of antagonistic, parasympathetic cholinergic, and sympathetic adrenergic control of the lower urinary tract; and the interrelationship between voluntary somatic and involuntary control of micturition reflex, discouraged extensive research of a new approach for the treatment of LUTS. In recent years, neuropharmacology has gained advantages from basic science research, and the experimental results have been translated into clinical practice. Today we know that the neuromuscular junction is not a ‘‘fixed synapse junction,’’ with preand postjunctional specialization, and it releases multiple neurotransmitters such as monoamines, purines, amino acid, peptides, and nitric oxide. Further achievements included accepting the principles of cotransmission (axons releasemore thanone transmitter for eachactionpotential) and neuromodulation (locally released agents may modulate the amount of neurotransmitters released prejunctionally) and recognition that a subset of sensory nerves that are selectively sensitive to capsaicin and its transient receptor potential (TRP) family are of primary importance in functional regulation of the lower urinary tract [4]. New varieties of bladder receptors have been identified as being involved in regulating bladder sensory afferent nerve conduction [5], but as yet, the story seems far from over. Members of the TRP family Ca and Na permeable channels involved in promoting cellular death and inhibiting the growth of normal and neoplastic cells are showing altered expression in bladder and prostate cancer. TRP (TRPV1/TRPV2/TRPV6 and TRPM8) proteins have been shown to be valuable markers in predicting the progress of bladder and prostate cancers and are now under consideration as potential targets for chemoprevention and chemotherapy [6–8], in anticipation of a connection between functional and neoplastic diseases.
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Jan 1, 2022
Chanyang Ju + 8
Open Access