resiniferatoxin and Spinal-Cord-Injuries

To access by a placebo-controlled randomized clinical trial the effect of intravesical resiniferatoxin on the urodynamic parameters of patients with neurogenic detrusor overactivity (NDO) of spinal origin.. Twenty eight patients with spinal NDO were randomised to receive intravesically 50 nM resiniferatoxin dissolved in 10% ethanol in saline (RTX group) or only the vehicle solution (placebo group). Filling cystometries were obtained in each patient at 1 month and 1 week before and at 1 and 3 months after treatment. In a visual analog scale patients were asked to estimate the discomfort induced by treatment. Patients were also persuaded to fill a micturition chart during the 3 days preceding each cystometry.. The RTX and placebo groups were homogeneous in what respects the volume to first involuntary detrusor contraction (FDC, 143+/-95 ml and 115+/-58 ml, respectively, p=0.3) and maximal cystometric capacity (MCC, 189+/-99 ml and 198+/-111 ml, respectively, p=0.8). At the end of the study, mean FDC and MCC in the RTX group, 184+/-93 ml and 314+/-135 ml, respectively were significantly higher than in the placebo group, 115+/-61 ml (p=0.03) and 204+/-92 ml (p=0.02). In the visual analogue scale discomfort caused by treatment was similar. Only 10 patients in the RTX group and 6 patients in the placebo group completed adequately the micturition chart. Mean frequency and urinary incontinence decreased significantly only in the RTX group.. Intravesical RTX is effective in increasing bladder capacity in spinal NDO patients. Such increment might contribute to decrease urinary frequency and incontinence of these patients.

Topics: Administration, Intravesical; Adult; Aged; Diterpenes; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscle Contraction; Muscle Hypertonia; Pain Measurement; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urodynamics

Chemical defunctionalization of C-fiber bladder afferents with intravesical vanilloids such as capsaicin (CAP) or resiniferatoxin (RTX) improves detrusor hyperreflexia in humans and animals. The little existing data comparing the efficacy and tolerance of these 2 vanilloid agents seem to favor RTX in 10% alcohol over CAP, which is usually diluted in 30% alcohol. We compared the efficacy and tolerability of the 2 vanilloid agonists in what to our knowledge is the first randomized, controlled study comparing nonalcohol CAP vs RTX in 10% alcohol in neurogenic patients with detrusor hyperreflexia.. This single center, randomized, double-blind, parallel groups study included 39 spinal cord injured adults with detrusor hyperreflexia. On day 0 patients were randomized to receive 1, 100 ml intravesical instillation of 100 nMol/l RTX diluted in 10% ethanol or 1 mmol/l CAP diluted in glucidic solvent. Efficacy (voiding chart and cystomanometry) and tolerability were evaluated during a 3-month followup.. On day 30 clinical and urodynamical improvement was found in 78% and 83% of patients with CAP vs 80% and 60% with RTX, respectively, without a significant difference between the 2 treated groups. The benefit remained in two-thirds of the 2 groups on day 90. There were no significant differences in regard to the incidence, nature or duration of side effects in CAP vs RTX treated patients.. Our results strongly argue for the importance of accounting for the role of vanilloid solute when interpreting the efficacy and tolerance of vesical vanilloid instillation in detrusor hyperreflexia cases. They suggest that a glucidic solute is a valuable solvent for vanilloid instillation.

Topics: Administration, Intravesical; Adult; Capsaicin; Diterpenes; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurotoxins; Reflex, Abnormal; Spinal Cord Injuries; Urinary Bladder, Neurogenic

Resiniferatoxin (RTX), a substance isolated from some species of Euphobia, is a specific C-fiber neurotoxin which produces desensitization rather than excitation. At first, we performed intravesical RTX therapy on eight patients with neurogenic detrusor overactivity. After we confirmed the safety and efficacy, a Japanese RTX study group was organized and a new protocol made. The multicenter trial was performed in Japan. However, the efficacy of the treatments was different among the institutions. Therefore, we have compared the results between the first protocol and the new one at our hospital.. The first and second protocol involved the RTX solution (30 mL of 500 nM, and 100 mL of 1 micro M, respectively) being instillated in the bladder for 30 min by almost the same procedures. Effects on bladder function were evaluated during treatment and at follow up.. For the first and second protocols, six out of eight patients noted symptomatic improvement while two patients did not notice any change in the degree of incontinence for one month. The mean urodynamic bladder capacity had significantly increased from 138.0 +/- 64.4 mL to 227.3 +/- 112.4 mL and 133.1 +/- 43.3 mL to 247.0 +/- 102.3 mL 1 month after RTX treatment for the first and second protocols, respectively (P < 0.05). No severe side-effects were seen in either group.. Intravesical RTX improved bladder capacity in patients with neurogenic detrusor overactivity in both protocols. The concentration of RTX did not exhibit any change in the effect and safety in our hospital. Intravesical RTX is a promising treatment for neurogenic detrusor overactivity.

Topics: Administration, Intravesical; Adult; Clinical Protocols; Diterpenes; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neurotoxins; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urodynamics

Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH).. Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 mL of placebo (n = 8 patients) or 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 12 posttreatment.. Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Patients in the 0.5-microM and 1.0-microM groups with MCC < 300 mL at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. There were no long-term complications.. Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

Topics: Administration, Intravesical; Adult; Aged; Diterpenes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Hypertonia; Nerve Fibers, Unmyelinated; Nervous System Diseases; Neurotoxins; Pain Measurement; Risk Factors; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics

To investigate if intravesical administration during spinal shock of resiniferatoxin (RTX), an ultrapotent desensitizing agonist of transient receptor potential vanilloid-1 (TRPV1), would silence TRPV1-expressing bladder afferents at an early stage of disease progression and modulate neurogenic detrusor overactivity (NDO) emergence.. Rats submitted to largely incomplete spinal cord transection at T8/9 spinal segment were treated with intravesical RTX (50 nM) or its vehicle during spinal shock. Four weeks after spinal lesion, bladder-reflex activity was evaluated by cystometry under urethane anesthesia, after which the bladder, spinal cord, and dorsal root ganglia were collected and processed.. We found improvements on bladder function several weeks after early intravesical RTX administration, including a marked decrease of intravesical pressures and amplitude of bladder contractions. Such strong long-lasting urodynamic effects resulted from the very potent desensitizing activity of RTX on peripheral terminals of sensory afferents, an effect restricted to the bladder.. Our results support that an early intervention with RTX could potentially attenuate NDO development and ensuing urinary incontinence, with a dramatic impact on the quality of life of spinal cord injury patients.

Topics: Administration, Intravesical; Animals; Calcitonin Gene-Related Peptide; Diterpenes; Female; Ganglia, Spinal; GAP-43 Protein; Neurons, Afferent; Rats; Rats, Wistar; Reflex; Spinal Cord Injuries; TRPV Cation Channels; Urinary Bladder; Urinary Bladder, Overactive; Urodynamics

We investigated the effect of resiniferatoxin (RTX)-treatment on cystometric parameters in the spinal cord injury (SCI) rats in both conscious and urethane-anesthetized conditions and evaluated the influence of urethane-anesthesia on the effect of RTX on lower urinary tract (LUT) function in SCI rats.. Female Sprague-Dawley rats were used. SCI was created by transection of the T8-T9 spinal cord. Four weeks after the transection, the animals were placed in a restraint cage for the first cystometric measurements in a conscious state. Secondary cystometric measurements were performed in a conscious condition following the 1 day after RTX-(0.3 mg/kg) or vehicle-subcutaneous injection. Then the animals were injected with urethane (1.5 g/kg, subcutaneously), and cystometric measurements were repeated four times every 1 hr-interval.. After the RTX-treatment in a conscious condition, urinary retention was observed in three out of five animals. In addition, the number of non-voiding contractions (NVCs) significantly decreased although their amplitude did not change significantly. After the urethane-injection, all of the animals treated with RTX developed urinary retention. The amplitude of NVCs significantly decreased, whereas the number of NVCs did not change significantly in the RTX-treated group. No cystometric parameters significantly changed after either vehicle- or urethane-injection in the vehicle-treated group.. The present results indicate that the suppressive effects of RTX on NVCs as well as voiding contractions in SCI rats can be enhanced by urethane-anesthesia. Such suppressive effect of urethane-anesthesia itself should be taken into consideration when we evaluate a drug-effect on LUT function in rats with SCI.

Topics: Anesthesia; Anesthetics, Intravenous; Animals; Diterpenes; Drug Interactions; Female; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Urethane; Urinary Bladder

Recently, a temporal "coherent" fractal structure and synchronization of rhythms were proposed as two essential indicators for efficient voiding during micturition in female rats. The former was correlated with the intensity and the latter the frequency of physiological signals embedded in random noise. Studies using both indices confirmed that synergic co-activations of bladder and external urethral sphincter (EUS) of female rats were present during the voiding of urine. Therefore, it would be interesting to investigate if these two criteria could be used in the performance evaluation of pharmacological effects on spinal cord-injured rats during micturition. In this paper, the primary goals were to (1) examine if the involved muscles in the lower urinary tract would be under similar synergic co-activations during the administration of capsaicin (CAP) and resiniferatoxin (RTX), and (2) characterize quantitatively the differences of their nervous responses simultaneously. A total of 62 micturition experiments were performed on sixteen spinal cord-injured adult female Sprague-Dawley rats, and then the electromyograms of EUS and cystometrograms of bladder were analyzed. Results based on the aforementioned criteria indicated that the synergy of bladder and EUS during micturition by using RTX was better than that of the CAP. Furthermore, the residue urine volumes for rats under the former treatment were smaller than those of the rats under the latter treatment. Consequently, we concluded that the administration of RTX was more effective than CAP in facilitating voiding in the spinal cord-injured rats.

Topics: Animals; Capsaicin; Disease Models, Animal; Diterpenes; Electromyography; Female; Models, Biological; Rats; Rats, Sprague-Dawley; Sensory System Agents; Spinal Cord Injuries; Urethra; Urinary Bladder; Urinary Bladder, Neurogenic; Urination

Recently, it has been demonstrated that intrathecal delivery of resiniferatoxin (RTX) produces strong analgesia, even in models of bone cancer pain. RTX has been investigated to treat bladder dysfunction of spinal origin, applied by intravesical instillation. However, RTX delivered by this route was not completely satisfactory in controlling urinary incontinence and high intravesical pressure. Thus, the present study assessed the effects of intrathecal injections of RTX in bladder dysfunction in rats with spinal cord transection (SCT). Bladder function was evaluated in SCT rats 24 h following intrathecal administration of RTX. Detrusor overactivity and intravesical pressure were reduced in a dose-dependent manner. This was accompanied by a decrease in spinal cord TRPV1 and CGRP, but not in IB4 binding sensory fibres. Also, intrathecal RTX induced a dose-dependent reduction in spinal cord activation of the ERK pathway. Overall, our results show that intrathecal administration of RTX effectively reduces detrusor overactivity and reduces intravesical pressure in models of complete chronic spinal cord transection by suppressing the activity of TRPV1 expressing afferent fibres. Also, intrathecal RTX decreases sensory input, as shown by reduced spinal ERK activation. These findings might be relevant for the management of patients with spinal cord injuries.

Topics: Animals; Calcitonin Gene-Related Peptide; Diterpenes; Extracellular Signal-Regulated MAP Kinases; Female; Injections, Spinal; Lectins; Neurotoxins; Rats; Rats, Wistar; Reflex; Ribosome Inactivating Proteins, Type 1; Saporins; Spinal Cord; Spinal Cord Injuries; TRPV Cation Channels; Urinary Bladder; Urinary Bladder, Overactive; Urination

The function of the transient receptor potential vanilloid 1 (TRPV1) cation channel was analyzed with RNA interference technologies and compared to TRPV1 knockout mice. Expression of shRNAs targeting TRPV1 in transgenic (tg) mice was proven by RNase protection assays, and TRPV1 downregulation was confirmed by reduced expression of TRPV1 mRNA and lack of receptor agonist binding in spinal cord membranes. Unexpectedly, TRPV3 mRNA expression was upregulated in shRNAtg but downregulated in knockout mice. Capsaicin-induced [Ca(2+)](i) changes in small diameter DRG neurons were significantly diminished in TRPV1 shRNAtg mice, and administration of capsaicin hardly induced hypothermia or nocifensive behaviour in vivo. Likewise, sensitivity towards noxious heat was reduced. Interestingly, spinal nerve injured TRPV1 knockout but not shRNAtg animals developed mechanical allodynia and hypersensitivity. The present study provides further evidence for the relevance of TRPV1 in neuropathic pain and characterizes RNA interference as valuable technique for drug target validation in pain research.

Topics: Animals; Animals, Genetically Modified; Calcium; Capsaicin; Diterpenes; Ganglia, Spinal; Gene Expression; Green Fluorescent Proteins; Male; Mice; Neurons; Pain Measurement; Phenotype; Protein Binding; Reaction Time; RNA Interference; RNA, Small Interfering; Spinal Cord; Spinal Cord Injuries; TRPV Cation Channels

Clinical and basic studies have indicated that upper cervical spinal cord stimulation (cSCS) significantly increases cerebral blood flow (CBF), but the mechanisms are incompletely understood. This investigation was conducted to differentiate between stimulation of dorsal column fibers and upper cervical spinal cord cell bodies in cSCS-induced increases in CBF and decreases in cerebrovascular resistance (CVR). cSCS (50 Hz, 0.2 ms, 1 min) was applied on the left C1-C2 dorsal column of pentobarbital anesthetized, ventilated and paralyzed male rats. Laser Doppler flowmetry probes were placed bilaterally over the parietal cortex, and arterial pressure was monitored. cSCS at 30%, 60%, and 90% of motor threshold (MT) produced vasodilation bilaterally in cerebral cortices. Subsequently, cSCS was applied at 90% MT, and ipsilateral responses were recorded. Ibotenic acid (0.3 mg/ml, 0.1 ml) placed on dorsal surface of C1-C2 (n=7) to suppress cell body activity, did not affect cSCS-induced %DeltaCBF (42.5+/-8.1% vs. 36.8+/-7.1%, P>0.05) and %DeltaCVR (-19.4+/-4.2% vs. -15.2+/-5.6%, P>0.05). However, bilateral transection of the dorsal column at rostral C1 (n=8) abolished cSCS-induced changes in CBF and CVR. Also, rostral C1 transection (n=7) abolished cSCS-induced changes in CBF and CVR. Resinferatoxin (RTX), an ultrapotent transient receptor potential vanilloid type 1 (TRPV1) agonist, was used to inactivate TRPV1 containing nerve fibers/cell bodies. RTX (2 microg/ml, 0.1 ml) placed on the C1-C2 spinal cord (n=7) did not affect cSCS-induced %DeltaCBF (60.2+/-8.1% vs. 46.3+/-7.7%, P>0.05) and %DeltaCVR (-25.5+/-3.5% vs. -21.4+/-8.9%, P>0.05). However, i.v. RTX (2 microg/kg, n=9) decreased cSCS-induced %DeltaCBF from 65.0+/-9.5% to 27.4+/-7.2% (P<0.05) and %DeltaCVR from -28.0+/-7.6% to -14.8+/-4.2% (P<0.05). These results indicated that cSCS-increases in CBF and decreases in CVR occurred via rostral spinal dorsal column fibers and did not depend upon C1-C2 cell bodies. Also, our results suggested that cerebral but not spinal TRPV1 was involved in cSCS-induced cerebral vasodilation.

Topics: Afferent Pathways; Analysis of Variance; Animals; Cerebrovascular Circulation; Cervical Vertebrae; Diterpenes; Electric Stimulation; Functional Laterality; Ibotenic Acid; Laser-Doppler Flowmetry; Male; Neurotoxins; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; TRPC Cation Channels; Vasodilation

Prospective urodynamic investigation before and after intravesical resiniferatoxin instillation treatment.. To evaluate the effectiveness of intravesical resiniferatoxin instillation for the treatment of neurogenic detrusor overactivity (NDO), using conventional and ice provocative urodynamic studies to monitor the activity of the unmyelinated C-fiber.. Spinal Cord Injury Unit, Yonsei Rehabilitation Hospital, Seoul, Korea.. A measure of 100 ml of resiniferatoxin solution, at a concentration of 100 nM diluted in 10% ethanol, was intravesically instilled into the bladder of 15 spinal cord injury patients with NDO. Conventional and ice provocative urodynamic studies were performed to evaluate the change in the involuntary detrusor activity, reflex volume, maximal bladder capacity, compliance, maximal detrusor pressure and reflex volume ratio 7 days before and 30 days after the instillation.. Before the intravesical resiniferatoxin instillation, all patients exhibited NDO in both the conventional and ice provocative urodynamic studies, with a mean reflex volume ratio of 0.45+/-0.22. There was no significant change in the maximal bladder capacity, compliance and maximal detrusor pressure at the follow-up urodynamic study, but the reflex volume ratio was significantly increased (P<0.05) after the intravesical resiniferatoxin instillation. Among the 15 patients, three (20%) showed complete and nine (60%) partial suppression of the unmyelinated C-fiber activities.. Intravesical resiniferatoxin instillation was partially controlled by the unmyelinated C-fiber activities, which were estimated by an ice provocative urodynamic study. Therefore, further studies on the optimal dosage and accurate indications for resiniferatoxin instillation are required.

Topics: Administration, Intravesical; Adult; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urodynamics

In this study we critically review our '10-year' experience with intravesical vanilloids (capsaicin and resiniferatoxin) in the treatment of neurogenic incontinence, addressing the issue of their introduction into daily clinical practice.. From July 1992 to June 2001, 54 patients suffering from detrusor hyperreflexia, due to spinal cord injuries, received intravesical instillation of capsaicin, and from January 1995 to June 2001, 47 patients received intravesical instillation of resiniferatoxin (RTX) in order to treat bladder dysfunction and symptoms. All patients presented detrusor hyperreflexia refractory to oral and/or intravesical oxibutynin and they displayed high-voiding pressure associated with frequent urine leakage. Capsaicin was used at a concentration of 10 mM; RTX was tested in two different concentrations: 10 nM and 10 microM. The outcome was considered according to simple parameters: (i) the number of patients who reported an improvement in clinical status (patient dry between clean intermittent catheterization) and urodynamic status (a bladder capacity 50% higher than pretreatment capacity, lasting more than 3 months after the instillation); (ii) the number of patients who continued intravesical therapy; (iii) the number of instillations they received; (iv) the length of the interval between 2 consecutive instillations, and (v) alternative therapies when vanilloids failed.. The topical intravesical instillation of capsaicin produced an improvement in symptoms and urodynamic parameters, in 29 patients (53.7%) after 3 months. In these 29 patients only 7 (24.13%) continued to received capsaicin in June 2001. The mean follow-up was 32.28 +/- 14.20 (range 8-52) months, the mean number of instillations was 6.14 +/- 2.54 (range 2-10) and the mean interval between the 2 consecutive instillations was 7.14 +/- 2.60 (range 4-12) months. The topical intravesical instillation of RTX produced an improvement in symptoms and urodynamic parameters in 73.33% of patients (a total of 45 patients) who received 10 microM. 18 of them (54.54%) continued to received RTX in June 2001. The mean follow-up was 27.88 +/- 10.95 (range 11-49) months, the mean number of instillations was 4.33 +/- 1.60 (range 2-8). The mean interval between 2 consecutive instillations was 9.61 +/- 2.99 (ranged 4-16) months.. The results obtained using RTX seem to be very promising with regard to efficacy and tolerance, particularly in comparison with capsaicin. Even if the number of patients who received capsaicin and RTX remains small, the intravesical vanilloid receptor agonist RTX could offer an attractive alternative to oral medications in the treatment of neurogenic incontinence.

Topics: Administration, Intravesical; Adult; Aged; Capsaicin; Diterpenes; Female; Humans; Male; Middle Aged; Neurotoxins; Retrospective Studies; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence

To investigate the therapeutic effect of resiniferatoxin in patients with chronic spinal cord lesions, as detrusor hyper-reflexia and external sphincter dyssynergia (DESD) are common phenomenon in such patients.. Twenty patients with chronic spinal cord lesions and DESD refractory to anticholinergic treatment were enrolled in a prospective study. They were treated with 30 mL of 10 micro mol/L resiniferatoxin for 30 min. Four types of response were recorded during instillation: type 1, a sustained high-pressure detrusor contraction followed by complete acontractility; type 2, a high-pressure contraction followed by progressively lower contractions; type 3, intermittent high-pressure detrusor contractions throughout the instillation; type 4, intermittent low-pressure detrusor contractions. The changes in clinical symptoms and urodynamics at baseline, during resiniferatoxin instillation and 1 month after treatment were compared.. All patients had DESD and 10 had autonomic dysreflexia; 18 had urinary incontinence and 13 had difficult urination. Continence and/or difficult urination improved in 12 patients, including all five with type 1, four with type 2, two with type 3 and only one with a type 4 response. Four patients became dry during the day and eight had less urgency and fewer incontinence episodes, and a significantly increased voided volume. Of the 13 patients who complained of difficult urination, eight had an improvement either by spontaneous voiding (five) or the Crede manoeuvre to voiding (three). The mean (sd) maximum cystometric capacity increased significantly after treatment, from 102.1 (31.5) to 236.6 (88.6) mL (P < 0.001), but the detrusor pressure showed no significant change, at 55.9 (23.2) to 47.5 (28.1) cmH2O. The external urethral sphincter showed intermittent activity during reflexic detrusor contractions at baseline.. Resiniferatoxin at 10 micro mol/L has a clinical effect on two-thirds of patients with a spinal cord lesion and detrusor hyper-reflexia, but not on the DESD. The initial response to resiniferatoxin instillation might predict a favourable therapeutic outcome.

Topics: Administration, Intravesical; Adult; Aged; Ataxia; Cholinergic Antagonists; Chronic Disease; Diterpenes; Drug Resistance; Female; Humans; Male; Middle Aged; Prospective Studies; Reflex, Abnormal; Spinal Cord Diseases; Spinal Cord Injuries; Treatment Outcome; Urinary Bladder, Neurogenic; Urinary Incontinence; Urination; Urodynamics

To compare conscious, normal rats and rats with chronic spinal cord injury (CSI) in terms of the rhythmic bladder contractions (RBCs) induced by intravesical infusion of saline, and to determine how these contractions are influenced by intravesical capsaicin and resiniferatoxin.. Female Sprague-Dawley rats, normal or with spinal transection at the level of Th8-Th9, were investigated cystometrically under isovolumetric conditions before and after intravesical administration of capsaicin or resiniferatoxin.. Spinal transection induced a significant increase in bladder weight. In both control and CSI animals, intravesical saline instillation induced reproducible RBCs that could be blocked by hexamethonium. Four weeks after the transection, the CSI animals had a significantly larger threshold volume than the controls, even after correction for bladder weight. The mean amplitude and duration of the RBCs did not differ between the two groups, but the frequency was significantly lower in CSI animals. Both capsaicin (0.1 and 1 mM) and resiniferatoxin (1 and 10 microM), instilled intravesically, were found to inhibit RBCs in both normal and CSI rats. There were no qualitative differences in the response to the drugs between the two groups. However, resiniferatoxin was approximately 100 times more potent than capsaicin.. Capsaicin and resiniferatoxin inhibited RBCs in both normal and CSI rats, suggesting that activity in sensory fibers (C and Adelta), which are sensitive to the action of these drugs, is initiated by bladder filling in both types of rat.

Topics: Administration, Intravesical; Animals; Capsaicin; Diterpenes; Dose-Response Relationship, Drug; Female; Muscle Contraction; Muscle, Smooth; Neurotoxins; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Urinary Bladder

Pain-like responses to cold or innocuous mechanical stimuli were observed chronically in rats after spinal cord ischemia. These resembled the symptoms of mechanical allodynia and cold hyperalgesia that are frequently observed in spinally injured patients. We evaluated the involvement of capsaicin-sensitive afferents in mediating these responses. A single subcutaneous injection of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, produced hypoalgesia to noxious heat stimulus and normalized the enhanced response to cold stimulus. In contrast, the mechanical allodynia-like response was not influenced by RTX. Thus, the enhanced response to cold, but not light touch, is mediated by capsaicin-sensitive afferents. Capsaicin and related compounds may have therapeutic potential in treating neuropathic pain elicited by some, but not all, modalities of stimulation.

Topics: Animals; Behavior, Animal; Capsaicin; Cold Temperature; Diterpenes; Female; Hyperesthesia; Hypesthesia; Neurons, Afferent; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley; Skin; Spinal Cord Injuries; Tail; Time Factors; Vocalization, Animal