resiniferatoxin and Chronic-Disease

Resiniferatoxin (RTX) and botulinum toxin subtype A (BTX-A) are increasingly viewed as potential treatments for lower urinary tract symptoms (LUTS) refractory to conventional therapy. RTX, a capsaicin analogue devoid of severe pungent properties, acts by desensitizing the transient receptor potential vanilloid type 1 (TRPV1) receptor and inactivating C-fibers. BTX-A cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, therefore impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. In patients with neurogenic and idiopathic detrusor overactivity, RTX and BTX-A have been shown to increase the volume to first detrusor contraction, increase bladder capacity, and improve urinary incontinence and quality of life. Recent data also suggest a role for these neurotoxins in treating urgency, the primary symptom in overactive bladder (OAB) syndrome. Furthermore, experimental data strongly support the use of both neurotoxins in the treatment of pain and frequency in patients with interstitial cystitis/painful bladder syndrome (IC/PBS), although the results from available clinical trials for this use are still inconclusive. In spite of promising results overall, it should be made clear that the administration of these neurotoxins is still considered an experimental procedure and that more clinical studies are necessary before a license for their use will be issued by health authorities.

Topics: Animals; Botulinum Toxins, Type A; Chronic Disease; Cystitis; Diterpenes; Humans; Neuromuscular Agents; Urinary Bladder, Overactive

The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.

Topics: Adrenergic beta-Agonists; Afferent Pathways; Animals; Apoptosis; Blotting, Western; Cardiomegaly; Cardiovascular System; Chronic Disease; Diterpenes; Fluorescent Antibody Technique; Heart; Heart Failure; Isoproterenol; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Reflex; Stroke Volume; Sympathectomy; Sympathetic Nervous System; TRPV Cation Channels

Cold allodynia is a frequent clinical symptom of patients with neuropathic pain. Despite numerous studies of cold allodynia, using animal models of neuropathic pain, little is known about its underlying mechanisms. This study was performed to establish a method for the pharmacologic evaluation of cold allodynia using several analgesics in a chronic constriction injury (CCI) rat model of neuropathic pain. Compared with the results obtained before the CCI operation, the CCI rats placed on a cork plate at 20 degrees C exhibited a slight change in the paw withdrawal latency because of the mechanical stimulus mediated by the injured paw touching the plate. By contrast, there was a significant reduction in the paw withdrawal latency on a cold metal plate compared with that on the cork plate after the CCI surgery, with the maximum decrease occurring on postoperative day 7. This reduction is thought to specifically reflect cold-induced pain behavior. In addition, both naïve and CCI rats showed behavioral changes at 5 and 0 degrees C, but not at 10 degrees C or higher. Interestingly, a subcutaneous morphine dose of 6 mg/kg completely inhibited cold allodynia induced at 10 degrees C on postoperative day 7. Under this condition, both the sodium channel blocker mexiletine (10 and 30 mg/kg, subcutaneously) and the calcium channel alpha2delta subunit blocker pregabalin (30 and 100 mg/kg, orally) significantly suppressed cold allodynia. Additionally, both resiniferatoxin (0.3 mg/kg, subcutaneously), an ultrapotent analog of capsaicin that desensitizes C fibers, and the VR1 channel antagonist N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (10 and 30 mg/kg, orally) significantly prolonged the paw withdrawal latency. In conclusion, our data suggest that the activation of C fibers mediates cold allodynia.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Calcium Channel Blockers; Chronic Disease; Cold Temperature; Constriction, Pathologic; Disease Models, Animal; Diterpenes; gamma-Aminobutyric Acid; Male; Mexiletine; Morphine; Nerve Fibers, Unmyelinated; Pain; Pain Measurement; Peripheral Nervous System Diseases; Pregabalin; Pyrazines; Pyridines; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatic Nerve; Sodium Channel Blockers; TRPV Cation Channels

Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients.. In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells--either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine--was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristics--especially pain levels--were registered in a prospective database and correlated with VR1 expression.. Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis.. Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Division; Cell Line, Tumor; Chronic Disease; Deoxycytidine; Diterpenes; Drug Synergism; Drug Therapy, Combination; Female; Fluorouracil; Gemcitabine; Humans; Immunohistochemistry; Male; Middle Aged; Mitochondria; Oxidative Stress; Pain; Pancreas; Pancreatic Neoplasms; Pancreatitis; Prospective Studies; TRPV Cation Channels

Topics: Analgesics; Chronic Disease; Diterpenes; Euphorbiaceae; Humans; Pain; Phytotherapy; Plants, Medicinal

We previously demonstrated that somatostatin (SOM) released from the activated peripheral terminals of capsaicin-sensitive primary sensory neurons inhibits acute inflammation and nociception. This study was undertaken to examine this systemic "sensocrine" function of neuronally derived somatostatin in chronic inflammation in the Freund's complete adjuvant (CFA)-induced arthritis model.. Arthritis of the tibiotarsal joint of Lewis rats was evoked by subcutaneous injection of CFA into the left hind paw and the tail root. For 3 weeks, the volume of the paws was measured by plethysmometry, and the mechanonociceptive thresholds were measured by esthesiometry. Plasma concentrations of SOM were determined by radioimmunoassay, and histologic studies of the joints were performed. To impair the function of capsaicin-sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was injected subcutaneously (30, 70, and 100 microg/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c-SOM; 20 microg/kg) or, in another group, the synthetic heptapeptide agonist TT-232 (2 x 50-400 microg/kg) was administered intraperitoneally every day.. RTX pretreatment or c-SOM injection significantly increased edema and mechanical hyperalgesia of both CFA-treated and contralateral paws. The histologic score based on synovial thickening, cell infiltration, cartilage destruction, and bone erosion was also significantly higher both in the RTX- and the c-SOM-injected groups. These parameters were dose-dependently decreased by TT-232. Plasma SOM-like immunoreactivity increased 4-fold on the twenty-first day, and was inhibited by RTX pretreatment, as well as by daily administration of TT-232.. Our data suggest that SOM released into the circulation from capsaicin-sensitive afferents in response to prolonged activation exerts systemic antiinflammatory and analgesic effects. TT-232 can open new perspectives in the treatment of chronic arthritis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Chronic Disease; Disease Models, Animal; Diterpenes; Edema; Freund's Adjuvant; Hindlimb; Male; Peptides, Cyclic; Rats; Rats, Inbred Lew; Receptors, Drug; Sensory Receptor Cells; Somatostatin

To evaluate the effect of intravesical resiniferatoxin on spinal c-fos expression and bladder volume at reflex micturition in rats with chronic urinary bladder inflammation.. Of three groups of female Wistar rats, group 1 received cyclophosphamide (75 mg/kg body weight) intraperitoneally every third day (cyclophosphamide is an antitumoral agent that induces bladder inflammation after urinary excretion of its metabolite, acrolein); group 2 comprised sham-inflamed rats that received saline instead of cyclophosphamide, and group 3 received cyclophosphamide, as group 1, every third day but plus 10 nmol/L resiniferatoxin intravesically, through a urethral catheter, at 7 days. At 8 days, under urethane anaesthesia, a needle was inserted in the bladder dome and saline infused at 6 mL/h for 2 h. Finally the animals were perfusion-fixed through the ascending aorta with 4% paraformaldehyde. Transverse sections cut from L6 spinal cord segments were immunoreacted for Fos protein and positive cells in the dorsal horn counted. In a further set of equal groups the bladders were prepared in the same way under urethane anaesthesia and after 30-min of stabilization, saline was infused at 6 mL/h and the volume evoking reflex micturition determined.. The mean (SD) number of positive c-fos cells per spinal cord section was 85 (21), 42 (9) (P = 0.002) and 55 (10) in groups 1 to 3, respectively; the values for group 2 and 3 were similar (P = 0.22) and statistically less than that of group 1 (P = 0.02). Reflex micturition occurred at, respectively, 0.26 (0.09), 0.49 (0.18) and 0.52 (0.11) mL, being similar in group 2 and 3 (P = 0.74) but lower in group 1 (P = 0.003).. Intravesical resiniferatoxin decreases c-fos expression and increases bladder capacity in chronically inflamed rat bladders. These findings suggest that desensitizing the vanilloid receptor type 1 by intravesical resiniferatoxin is relevant to the treatment of pain and voiding frequency in patients with chronic inflammatory bladder conditions.

Topics: Animals; Chronic Disease; Cystitis; Diterpenes; Female; Neurotoxins; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reflex; Spinal Cord; Urinary Bladder; Urination

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