| Background and objectives Chronic prostatitis is a common disease in urology. Prostatodynia and micturition dysfunction are two main symptoms of chronic prostatitis, but they remain unsolved in clinical therapy nowadays. So, it is necessary to explore some new analgesic drugs and therapeutic modalities for these two problems. The sense of prostatodynia is conveyed by C-fiber neurons. It was confirmed that axonal reflex pathway exists between prostate and bladder. Through this neural pathway, inflammatory stimulation from prostate can induce bladder unstable contraction. Neurogenic inflammation resulting from the excitation of C-fiber neurons is a crucial mechanism underlying prostatitis- induced unstable bladder. Therefore, longterm blockade of C-fiber neurons may be helpful to the therapy of prostatodynia and micturition dysfunction.With the development of analgesic research, it has been found that vallinoids can selectively block nociceptive neurons with a longlasting action. Thus, they may have significant values for the therapy of prostatodynia and micturition dysfunction. Due to different dose and administering mode, vanilloids can produce three different effects on nociceptive neurons: excitation, desensitization and neurotoxicity. Desensitization can block nociceptive neurons with a longlasting action, whereas neurotoxicity can selectively kill nociceptive neurons. Resiniferatoxin(RTX), an ultrapotent vanilloid with minimal exciting effect, can block C-fiber neurons in a highly selective manner. In this study, RTX was applied to be a blocker of C-fiber neurons.Nowadays, RTX analgesic research was focused on somatic nerve. Whether RTX can produce analgesic effect on visceral nerve needs to be determined by experimental study. In visceral nerve, RTX was mainly used to treat unstable bladder by means of intravesical filling. Its mechanism was considered that RTX could inhibit C fibers in bladder. In this study, RTX was administered through different routes to determine whether it could inhibit prostatodynia and micturition dysfunction resulting from prostatitis. Substance P(SP) and calcitonin gene-related peptide(CGRP) releasing form C-fiber neurons are key mediators in neurogenic inflammation and important neural transmitters in visceral pain. In this study, these two neuropeptides were observed as the indicator of prostatodynia. In clinic, sacral and intraprostatic injection have been reported to treat prostatic diseases. In this study, RTX was injected into rat intrathecal cavity and prostate to observe its effects on prostatodynia and unstable bladder. Intrathecal administration mainly target to dorsal root ganglion(DRG) of pelvic nerve, whereas intraprostatic administration exclusively target to prostatic afferent neurons.Methods Adult male Sprague-Dawley rats were adopted as subjects and were divided into four groups for different treatment. In sham operating group, sham operation was performed. In prostatitis group, Complete Freund's adjuvant(CFA) was injected into rat bilateral ventral prostates to induce chronic prostatitis. In intrathecal treating group, RTX was injected into L5-S2 intrathecal cavity after prostatitis formed. In intraprostatic treating group, RTX was injected into bilateral ventral prostates after prostatitis formed.SP and CGRP expressions in rat pelvic afferent neurons were investigated by immunohistochemistry, radioimmunoassay and RT-PCR. The duration of intrathecal RTX-induced analgesia was assessed by SP immunohistochemistry. Pelvic nerve afferent discharge was recorded to explore the electrophysiological mechanism underlying RTX-induced analgesia. In addition, filling cystometry was performed to show unstable bladder. Furthermore, simultaneous recording of filling cystometry and pelvic nerve afferent discharge was carried out to observe whether intrathecal RTX inhibit the sense of bladder filling.Results1. Chronic prostatitis was induced at 14 days after CFA injection into rat ventral prostate.2. SP and CGRP expressions in rat pelvic afferent neurons were up-regulated in response to prostatitis, but they were down-regulated after either intrathecal or intraprostatic RTX injection. Intrathecal RTX could reversibly inhibit SP expression for 28 days.3. The pelvic nerve afferent activity was enhanced by chronic prostatitis, whereas it was attenuated by either intrathecal or intraprostatic RTX administration.4. Prostatitis rats were characterized by a high incidence of unstable bladder. Intrathecal RTX could markedly decrease the incidence of unstable bladder, but intraprostatic RTX had no significant inhibition to unstable bladder.5. Sensitive pelvic nerve afferent discharge and regular micturition reflex in response to bladder filling revealed that intrathecal RTX can selectively inhibit pain sense without inhibiting effect on the sense of bladder filling.Conclusions and prospects1. Rat chronic prostatitis model can be made by CFA.2. Increased SP and CGRP expressions in pelvic nerve and enhanced pelvic nerve afferent activity in chronic prstatitis rats suggested that rat chronic prostatitis model can evoke prostatodynia.3. Decreased SP and CGRP expressions and attenuated pelvic nerve afferent activity in RTX-treated rats indicated that both of intrathecal and intraprostatic administration can significantly relief prostatodynia.4. Unstable bladder plays an important role in micturition dysfunction under the condition of chronic prostatitis. Intrathecal RTX application can markedly inhibit unstable bladder.5. RTX can block nociceptive neurons with a selective, long-lasting and reversible action. Therefore, our data suggested that intrathecal RTX application may have a bright prospect in the therapy of prostatodynia and unstable bladder.
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