Bladder afferent fibers The bladder afferent pathway is composed of myelinated Aδ fibers and unmyelinated C fibers. Myelinated Aδ fibers are fast-conducting fibers (30 m/s), which mainly transmit signals from mechanoreceptors, sensing bladder distension or bladder wall pressure, and most of the micturition afferent pathway is mediated by Aδ fibers under normal conditions. Unmyelinated C fibers are slow conducting fibers (0,3m/s), which anatomically account for 70% of bladder afferent fibers, mainly transmitting noxious signals and initial pain sensation. Under normal conditions, C-fibers are dormant, but when C-fibers are activated in neuropathic and inflammatory environments, C-fiber impulses are increased, promoting or triggering urination.C-fiber neurons have a dual function: (1) sensory afferent function; and (2) localized release of Substance P, Neuropeptide A, Calcitonin Gene Related Peptide (CGRP), and other neuropeptides. 2, the pharmacology of RTX RTX (Resiniferatoxin) is a kind of stimulating dry latex extracted from plants similar to cactus, containing a diterpene plant related to the diterpene alcohol, and chili pepper chorine molecular structure is similar to RTX acts on a group of special sensory neurons (dorsal root ganglion and Gasserian ganglion), which can make the C-fiber neuron cell mitochondrial swelling, and the C-fiber neuron cell mitochondria swelling. RTX also reduced the synthesis of substance P, CGRP and other neuroproteins in neurons. RTX has been shown to activate C-fiber membrane receptors and attenuate afferent nerve impulses.RTX, as a special C-fiber neurotoxin, is a bladder sensory nerve blocker and can be used in the treatment of LUTS.The desensitization effect of RTX on the distribution of bladder sensory nerves is concentration-dependent and rarely produces toxic stimulation of the bladder. Low concentrations of RTX desensitize afferent neurons, inhibit afferent C-fibers, and cause a decrease in the density of C-fibers in the subepithelial tissue of the bladder. Generally speaking, RTX can effectively stimulate the low-domain C fibers that play a dominant role in voiding control, but not the high-domain C fibers associated with bladder injury receptors. Because RTX can specifically block the afferent C fibers, it can weaken or inhibit the autonomous urethral muscle activity and achieve the purpose of treating urethral hyperreflexia. RTX and capsaicin belong to the same vanilloid family of drugs, and both act on the same specific knowledge site, i.e., VR1, but there are still significant differences between the two: (1) RTX is a larger molecule and more fat-soluble, and its permeability in the tissue is slower, so its action produces slower onset of effect. Capsaicin is fast acting, short lasting and explosive. RTX, on the other hand, has a slow and long-lasting effect, and causes calcium inward flow by inhibiting voltage-dependent sodium channels. Under similar conditions, the inward flow caused by RTX is 300 times stronger than that caused by capsaicin, and calcium ions accumulate to a certain concentration in the cell, causing nerve desensitization. (iii) Capsaicin initially caused C-fiber excitation, depolarization of peripheral nerve endings and release of action potentials, followed by desensitization of injury receptors (depletion of neuropeptides), whereas RTX initially caused only slight excitation, followed by rapid desensitization. RTX is 1000-fold more potent than chili peppers because of its high vanilloidal structure. 100 nM RTX and 1 mM chili peppers resulted in complete desensitization, but RTX was less stimulatory to bladder afferent nerves. Capsaicin causes severe discomfort during instillation, such as pain, burning sensation, urinary frequency, urinary incontinence, hematuria and urinary tract infection, autonomic dysreflexia (headache, anxiety, nausea and vomiting, cold sweating, erectile dyskinesia, bradycardia, and blood pressure as high as 170/102 mmHg), etc. Patients usually need to be instilled under general anesthesia, while RTX does not cause, or only causes, mild discomfort. 3, vanilloid receptor subtype 1 vanilloid receptor subtype 1 (referred to as VR1), VR1 is a non-selective cation channel, can be expressed in the unmyelinated afferent fibers, mainly located in the spinal cord, spinal ganglia and visceral organs (such as the bladder, urethra, colon).RTX is a powerful activator of VR1. Gene expression of VR1 in peripheral tissues is limited by the number of C fibers produced by posterior root ganglion neurons.RTX binds to VR1 and opens calcium channels on sensory neurons.A large amount of calcium ions inwardly flow into C fibers, prompting the release of substance P and CGRP from the nerve endings, which produces a sensation of pain or itch and a contraction of the detrusor muscle.RTX in turn depolarizes afferent nerves of the injury receptor, causing a RTX can depolarize the afferent nerves of the injury receptors, leading to a decrease in the bioelectric activity of the C fibers and desensitization, and the desensitization induced by RTX can reduce the sensory afferents of the C fibers of the bladder and lead to a decrease in the number of spinal neurons excited by the bladder stimulus. RTX for lower urinary tract symptoms (1), RTX for neurogenic urethral hyperreflexia Spinal cord lesions block the neural pathway between the sacral medulla and the pontine micturition center, inhibiting the sacral supramedullary reflexes that normally control micturition in adults, which are controlled by involuntary sacral medullary reflexes, which vary according to the intensity of the incoming stimulus. The suprasacral reflex is conducted by sensory afferent fibers of myelinated Aδ fibers in the pelvic nerves, whereas the sacral myelinated reflex relies on unmyelinated C fibers, which can cause neurogenic urethral hyporeflexes in spinal cord lesions. As early as 1989, RTX has been used to treat neuropathy-induced detrusor hyperreflexia. Giannantoni et al. randomized 24 spinal cord injury patients with intractable detrusor hyperreflexia, and infused 100nMRTX+100ml0,9%NS into the bladder for 40 minutes, and showed significant improvement in uninhibited detrusor contraction and maximal bladder capacity (p<<0.05) in the patients 30 days after the infusion. Silva et al. also reported similar results, after treatment, patients' urinary incontinence improved or disappeared, the average frequency of urination was reduced, the average maximum bladder capacity increased (p=0.01), and 50% of the patients had sustained therapeutic effect up to 1 year. (2) RTX treatment for urethral instability (OAB) In patients with idiopathic OAB, the concentration of substance P and CGRP in the submucosal C-fibers of the bladder is very high, resulting in an increase in impulse afferents to the C-fibers of the bladder. Cold-induced contraction of the urethra is also a C-fiber-mediated voiding reflex that does not occur in normal subjects but occurs at a high rate in patients with urethral instability or BOO. In normal adults, C-fiber afferents play a minor role in voiding control, and desensitization of bladder C-fibers does not alter intravesical pressure or bladder capacity during the filling phase. Intravesical instillation of RTX in the bladder inhibited idiopathic involuntary contractions of the urethra, which may be due to the predominance of C-fibers in the sensory afferents to the bladder and the enhanced expression of VR1 in these patients, resulting in involuntary contractions of the urethra, or an overproduction of nerve growth factor (NGF) in the bladder, which sensitizes C-fibers, thereby increasing C-fiber afferents to the spinal cord. Silva et al. selected 13 patients with a mean age of 50 years and confirmed idiopathic urethral instability, and injected 50nMRTX+00ml0,9%NS into their bladders and kept them for 30 minutes to see whether RTX could specifically block C-fiber afferents and delay or eliminate involuntary urethral contractions. The mean bladder capacity at the time of the first contraction of the urethra muscle was increased at 30 and 90 days after RTX treatment, and incontinence and urinary frequency were significantly improved (p<0,001). Guan Zhizhen reported in 2004 that RTX was used to treat 30 patients with overactive bladder who were 39 years old and had been suffering from overactive bladder for 6 or 9 years. The average number of daytime urination before treatment was 15 and nighttime urination was 6,4. The bladder was irrigated with 100 ml of 100 nmol/LRTX solution for 30 min, and the frequency of urination began to improve 1 d after irrigating, and the symptoms of 2 cases with dysuria were relieved, and the average number of daily urination was 8 or 9 times, and the average number of nocturnal urination was 3 or 0 times after 1 week and 1 month of irrigating. Compared with before and after treatment, the number of urination was significantly reduced, and the difference was significant (P<0.001). Wang Feng reported in 2006 that 26 patients with idiopathic overactive bladder (IOAB) were randomly divided into group A and group B. In group A, 14 patients were treated with 100 nmol/L RTX 100 ml, and in group B, 12 patients were treated with 0.05% furacilin as a substitute for RTX. Clinical symptoms (number of times of urination per day, urgency of urination) were observed in the two groups before and after 1 month, and 3 months after the drug was administered. and first voiding sensory volume, maximum bladder pressure volume, maximum urine flow rate. Comparison of the parameters before and after treatment at 1 month and 3 months, the results were P<0101) in group A and P>0105 in group B. Half of the patients had mild urethral irritation or bladder area discomfort, which could be tolerated. (3), RTX treatment of bladder pain and interstitial cystitis It is thought that RTX can act on both VR1 and tachykinin (for pain mediators) nerve fibers (these fibers through the release of neuropeptides in the central and peripheral nervous system and play a dual function of sensory and motor). Lazzeri et al. randomly divided 18 patients with urinary frequency, urgency, nocturia, and pelvic pain into two groups: one group was infused with 30 ml of saline containing 0,1% alcohol + 10nMRTX in the bladder, and the other group was infused with the same dosage of saline, and bladder sensory hypersensitivity and bladder pain were observed at 1 and 3 months after treatment. The result was that the pain score improved significantly (p<0.01) at 1 month after instillation, but the improvement was not statistically significant (p>0.05) at 3 months. We have similar experience, but we need to accumulate more cases. 5, RTX bladder perfusion points and dosage Research has proved that bladder distension can lead to selective activation of sensory nerves, during bladder distension, the release of endogenous ATP may provoke the pelvic nerve afferent fibers in the bladder, in order to avoid too large a volume of perfusion to provoke the bladder, the volume of perfused fluid should be less than 100 ml. The commonly used dose of RTX perfusion is 10~100 nM, in order to prevent the irritation and adverse effect of RTX on the urethral mucosa, it should be used as a treatment. To prevent the irritation and adverse effects of RTX on the urethral mucosa, RTX should be dissolved in a small amount of 10% alcohol and diluted with 50 ml to 100 ml of saline, and then injected into the bladder at a slow rate of 20 ml per minute through a small ureter with a balloon, and then kept in the same position for 30 minutes and then discharged. Most patients have a burning pain during the infusion, which is generally tolerable, but for a few patients with more severe reactions, 40 ml of 1% lidocaine can be used to infuse the bladder, and then RTX can be infused again after 10 minutes. we have experienced better results in patients with strong reactions. One infusion can relieve the symptoms for 3-6 months, or up to a year in some cases. If the initial effect is unsatisfactory, another infusion can be tried after 2 weeks.