Overactive bladder disorder (OAB) is one of the most common disorders in urology. In the United States, OAB is listed among the 10 most common chronic diseases, ranking ahead of diabetes and peptic ulcers in prevalence. A European survey showed that 17% of adults suffer from one or more of the symptoms of urinary frequency, urgency or urge incontinence, and the prevalence increases with age. Urinary incontinence is the most common symptom of OAB, with the literature reporting 3% of women aged 20-29 years and 45% of women aged 50-59 years suffering from urinary incontinence. The incidence of OAB caused by bladder outlet obstruction due to benign prostatic hyperplasia (BPH) is also high, with an incidence ranging from 52% to 82%, and some patients still have OAB that does not disappear after prostatectomy. Overactive bladder disorder occurs mostly in the elderly and children, and is also closely associated with concomitant certain neurological disorders.
The treatment of OAB is mainly achieved through the action on the efferent nerves. Oxybutynin (Oxybutynin) and the new generation of Tolterodine (Tolterodine), which are widely used clinically, are both postganglionic nerve fiber toxin tantaline receptor antagonists. Antitoxicodynamics not only interfere with the postganglionic effect of acetylcholine on the detrusor muscle, but also affect the release of acetylcholine from the parasympathetic nerves, thereby stabilizing the bladder. The cure/improvement rate of drug therapy is generally considered to be only 40%, with 71.8% of patients withdrawing from therapy after 6 months of medication. This suggests that efferent nerve blockade is not the only way to resolve OAB symptoms. So will blocking the afferent nerve result in improvement of the patient’s symptoms such as urinary frequency and urgency?
Current knowledge of the afferent nerves to the bladder The voiding reflex requires not only efferent nerve conduction from the spinal cord to the bladder, but also afferent nerve transmission from the bladder to the central nervous system. An intact afferent nerve is essential for transmitting signals of bladder distention and discomfort to the brain. Two types of sensory nerve endings exist in the tissue afferent nerve fibers (sensory fibers) within the bladder and urethral wall. One type of sensory nerve afferent fiber is called the A-δ fiber, which is found mainly in the collagen fiber tissue between the forceps and urethral smooth muscle cells. The other type is the weakly stained unmyelinated C-fibers, which account for 60% to 70% of bladder afferent fibers, contain large amounts of substance P, and are located mainly within the bladder and urethral mucosa and submucosal tissues. These receptors conduct pain, temperature and tactile sensations, are sensitive to chemical stimuli and insensitive to mechanical stimuli (bladder pulling action), and C fibers mainly sense injury signals and primary nociception. C-fibers in other parts of the body are capable of afferent stimulus sensation, for example, the reflex process of retracting the finger immediately upon encountering heat is a C-fiber afferent sensation. The C-fibers of the bladder are abundant in childhood and degenerate with age. When acute and chronic infections or long-term irritating lesions occur, the number of bladder C-fibers increases significantly, just like in childhood, and bladder C-fibers can then be afferent to stimulus sensation as well as C-fibers from other parts of the body. The resulting reflex function or desire to urinate is a manifestation of the body’s preventive mechanism to expel irritants or bacteria, but the bladder C-fiber sensory stimulus also causes the patient to have significant lower urinary tract symptoms. The role of C-fiber afferent nerves on bladder overactivity has been better defined by deGroat’s studies. In his experiments, he found that in cats, the initial bladder reflex disappeared after spinal cord dissection (inability to urinate), and a few weeks later C-fiber short-circuit conduction was re-established and the bladder emptied automatically. Humans have the same mechanism, and bladder overactivity due to various causes is due to re-establishment of C-fiber conduction. We have demonstrated in the past in acute and chronic domestic dog experiments that blocking C-fiber nerve afferents significantly increased bladder capacity in animals. C-fiber afferent nerve blockade in a rat obstructive model also significantly improved the post-infarct bladder response to obstruction, which was achieved by reducing bladder overactivity.
Exploration of afferent nerve blockade for OAB There are limited drugs available for bladder afferent nerve blockade, and the most studied are capsaicin, and resinferatoxin (RTX).
Mechanism of action of capsaicin Capsaicin is the most stimulating component of chili peppers, a pungent odor component widely found in Capsicum spp. The chemical name is 8methylN vanilly6nonenamide. The molecular formula is C18H27NO3, molecular weight is 305.40, molecular structure diagram is: Excitatory effect on the peripheral sensory nerve terminals, mainly some primary sensory neurons to feel the injury of unmyelinated C fibers, by releasing a large amount of substance P to deplete the sensory nerve P substance, and inhibit its synthesis, resulting in the loss of primary afferent nerve fiber activity, blocking the sensory conduction from the peripheral nerve to the central nerve pathway. Substance P is an undecapeptide derived from C-fiber nerve endings and is restricted to the afferent nerve pathway, which is associated with sensory afferents in the urination reflex. A single application of capsaicin can block the ability of substance P to conduct in the long term. Generally, the conduction ability of substance P in C-fiber nerve endings can be restored to the pre-blockade level after 3-12 months.
Effects of Capsaicin on Urodynamics The role of Capsaicin in bladder function has been studied experimentally, and the results of these studies have shown that Capsaicin can produce a transient contraction of the bladder. In experiments with domestic dogs, this contraction lasts about 30 minutes and is caused by a large release of substance P. In humans this causes pain and burning irritation and is the reason why some patients need anesthesia. However, this contraction does not occur in rats in which capsaicin is applied intravesically again, indicating the fact that the conduction was blocked for a long time the first time. After a brief increase in excitability of the voiding reflex by local application of capsaicin, the bladder capacity was increased for a long time and bladder stability was increased without affecting its voiding function. We evaluated the effect of capsaicin on bladder function by using male mongrel dogs with 1uM or 100uM of capsaicin selected for the experimental group and bladder perfusion with alcoholic saline for the control group. Urodynamic examinations were performed and bladder pressure, volume and bladder compliance at the point of leakage were collected before, at the time of and 1, 1, 2, 4 and 12 weeks after the injection. The results showed that bladder perfusion with 1uM and 100uM capsaicin caused multiple bladder contractions after perfusion in 50% and 86% of dogs, respectively, followed by a decrease in bladder pressure and an increase in bladder volume, thus improving bladder compliance [6].
Effect of capsaicin on neuromediated substance P Immunohistochemical studies revealed that with increasing concentrations of capsaicin, there was a significant decrease in substance P-positive nerve fibers in the mucosal layer, perivascular submucosa, and muscular layer of bladder tissue, with significant differences between the high concentration group and the control group, indicating that high concentrations of capsaicin deplete substance P from sensory nerve endings in the bladder. This is because capsaicin inhibits sensory signaling by depleting substance P in the bladder. The local desensitizing effect of substance P immunoreactivity in the bladder of neonatal rats was studied with 50 mg of capsaicin per kg of body weight, and their bladder substance P immunoreactivity was reduced by 60-84%. We used domestic dogs as experiments and found significantly lower bladder substance P levels in the experimental group than in the control group from radioimmunoassays. The P substance decreased by 55% after 1 week and 57% after 4 weeks with 100 uM capsaicin, while it was still lower than the normal 53% after 12 weeks.
Effect of capsaicin on bladder morphology To understand the morphological response of bladder tissue to various doses of capsaicin, we observed bladder morphological changes after topical application of capsaicin. Sixty-six female SD rats were used for the experiment, and the animals were randomly divided into three groups, namely, the control group (N=18), the 100uM capsaicin bladder perfusion group (N=24), and the 2mM capsaicin bladder perfusion group (N=24). Capsaicin was injected into the bladder via urethral cannula. The animals were executed at 1 hour (N=6), 1 week (N=6), 4 weeks (N=6) and 8 weeks (N=6), and the bladders were removed, their wet weight was measured and examined by light microscopy. The results showed that capsaicin did not cause significant bladder weight increase. 100uM group microscopically showed only mild vasodilatation on the surface of the lamina propria; the group treated with 2mM capsaicin showed bladder mucosal erosion, edema, capillary dilatation of the lamina propria and focal damage on the surface of the muscularis. The changes in the mucosal layer began to repair after 1 week, when a slight chronic inflammation was seen between the muscle bundles, and many mast cells were seen between the muscle bundles, especially in the subplasma membrane at the proximal vessels. 8 weeks later the mucosal layer returned to normal, while the lamina propria became more dense and some focal calcifications appeared on the surface of the muscle bundles. CONCLUSION: 100uM capsaicin bladder perfusion is a safe treatment method. Excessively high doses of capsaicin can cause reversible mild mucosal injury and inflammatory changes.
Effects of capsaicin on the obstructed bladder It is generally believed that capsaicin cannot be used in cases of obstruction, and OAB is the most common problem of obstruction in clinical practice.In 1995 we studied the early kinetic effects of capsaicin on rats with partial bladder neck obstruction [8]. Twenty-six female SD rats, weighing 250-300 g, were used for the experiment. The rats were randomly divided into four groups: i.e., control group (CONN=4), capsaicin bladder perfusion group (CN=7), incomplete bladder neck ligation group (ON=7) and capsaicin bladder perfusion + incomplete bladder neck ligation group (OCN=8). Bladder pressure measurements were performed after two weeks. The results showed that the total bladder substance P content decreased by 52% and 53% in the C and OC groups, respectively, and that capsaicin eliminated the unstable bladder seen in normal and obstructed rats (CON:C=1:0; O_OC=5:0). The mean bladder volume increased in the C group after administration compared to the CON group (CON=0.31±0.04 ml vs. C=0.46±0.08 ml), whereas it decreased in the OC group compared to the O group (O=4.07±0.56 ml vs. OC=2.21±0.47 mlp.