sildenafil-citrate and Pain

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS). The most common clinical manifestations of MS are spasticity, pain, vesico-urethral disorders, cognitive impairments, chronic fatigue and sexual dysfunction. This review aims to explore the possible therapeutic options for managing sexual dysfunction in people with MS (PwMS).. A thorough search of the PubMed Medline database was performed. Records were limited to clinical studies published between 01/01/2010 up to 01/01/2022. The results were screened by the authors in pairs.. The search identified 36 records. After screening, 9 records met the inclusion-exclusion criteria and were assessed. The pharmacological approaches investigated the effectiveness of sildenafil, tadalafil and onabotulinumtoxinA. Of the interventional studies the non-pharmacological investigated, the effectiveness of aquatic exercises, the application of pelvic floor exercises,the combination of pelvic floor exercises and mindfulness technique, the combination of pelvic floor exercises and electro muscular stimulation with electromyograph biofeedback, the application of yoga techniques and the efficacy of assistive devices like the clitoral vacuum suction device and the vibration device.. The management of sexual dysfunction in PwMS needs to be further investigated. A team of healthcare professionals should be involved in the management of SD in order to address not only the primary (MS-related) SD symptoms but the secondary and tertiary as well. The main limitations that were identified in the existing literature were related to MS disease features, sample characteristics and evaluation tools and batteries.

Topics: Exercise Therapy; Humans; Multiple Sclerosis; Pain; Sexual Dysfunction, Physiological; Sildenafil Citrate

This systematic review evaluates maternal tolerance and obstetric and perinatal outcomes following sildenafil citrate (SC) use in human pregnancy.. Scopus, PubMed, Cochrane Library, Web of Science, Embase, and Google Scholar were searched. Relevant full-text studies including case series and reports in English were included. Publications were excluded if the pregnancy was terminated or if SC was used only at conception.. Sixteen studies were included (n = 165). Indications for use and outcomes were variably reported. Maternal outcomes reported were headache (45.8%, 49/107), visual disturbances (17.3%, 14/81), dyspepsia/epigastric pain (15.8%, 15/95), and hypotension (0%, 0/39). There were more caesarean (83.3%, 55/66) than vaginal deliveries (16.7%, 11/66) and postpartum haemorrhage occurred in 3.9% (3/76) of women exposed to SC. Neonatal outcomes including nursery admission (67.3%, 35/52), Apgar scores <7 at 5 min (7.1%, 4/56), and cord arterial pH <7.1 (0%, 0/17) were reported. Stillbirths (4.3%, 3/69) and neonatal deaths (3.9%, 5/129) were comparable to SC-naïve groups. There were no congenital malformations (0%, 0/35).. Despite limited data, overall there does not appear to be any severe adverse maternal side effects nor any increase in the rate of stillbirths, neonatal deaths, or congenital anomalies attributed to SC.

Topics: Delivery, Obstetric; Female; Headache; Humans; Infant, Newborn; Pain; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Sildenafil Citrate; Vision Disorders

Systemic sclerosis (SSc)-related digital vasculopathy can progress from severe Raynaud's phenomenon to digital ulceration, is a major cause of pain and disability, and impacts negatively on quality of life. Current treatments are often ineffective and poorly tolerated. This review summarises some of the progress which has been made in the last 12 to 18 months in terms of our understanding of disease process, measurement and treatment.. The most important findings include that we can now better predict which patients with SSc are most likely to develop digital ulcers. In terms of treatment, a multicentre trial showed that the phosphodiesterase inhibitor sildenafil confers some benefit in SSc-related digital ulceration. Topical therapies are being explored: iontophoresis of vasodilators increases local blood flow, and in an avian model, VEGF121 fibrin applied in a gel matrix improved wound healing.. Progress is being made. Advances in our understanding of SSc-related vasculopathy continue to lead to exploration of new treatment approaches. Clinical trials and observational studies are challenging, but are being facilitated by developments in outcome measures and improved infrastructures and networking, allowing trials in much larger numbers of patients than have previously been possible.

Topics: Fingers; Humans; Pain; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Vascular Endothelial Growth Factor A; Vasodilator Agents

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

Topics: Anemia, Sickle Cell; Blood Transfusion; Clinical Trials as Topic; Disease Management; Gastrointestinal Diseases; Humans; Hydroxyurea; Hypertension, Pulmonary; Muscular Diseases; Nervous System Diseases; Pain; Phenotype; Piperazines; Purines; Retinal Diseases; Sildenafil Citrate; Sulfones; Treatment Outcome

To describe the urologic and sexual complications of male survivors of sexual torture, including prevalence, sequelae, diagnosis, and treatment.. Through chart reviews, we identified all male survivors of torture who had been treated for physical and/or psychological symptoms due to sexual trauma at the Boston Center for Refugee Health and Human Rights at Boston Medical Center between January 1, 2001 and January 1, 2002. Of the 72 men seen, 20 (28%) were survivors of sexual trauma. Our study focused on genital trauma leading to urologic and/or sexual dysfunction. Therefore, all cases of male genital trauma that had been referred to the urology department (3 of 20) were selected for this review.. The patients presented with chronic genital and erectile pain, lower urinary tract symptoms, and sexual dysfunction. The diagnostic workup included history, physical examination, and ultrasonography. Treatment included steroid injections for chronic pain and oral erectogenic agents for sexual dysfunction.. The apparent prevalence and severity of the physical and mental sequelae to sexual trauma make it an important area for screening when treating survivors of torture. Our study is the first of its kind to document urologic complications of sexual torture in a foreign-born U.S. cohort of tortured men, including prevalence, diagnosis, and treatment. The proposed use of steroid injections in the clinical treatment of these patients has not been previously reported.

Topics: Adult; Africa; Anal Canal; Boston; Burns, Electric; Cohort Studies; Electroshock; Erectile Dysfunction; Genitalia, Male; Humans; Male; Middle Aged; Pain; Piperazines; Prisoners; Purines; Rape; Refugees; Sex Offenses; Sildenafil Citrate; Sulfones; Survivors; Torture; Triamcinolone; Urethral Stricture; Urinary Tract; Wounds, Nonpenetrating

The aim of this study was to investigate the impact of the addition of 50 mg daily sildenafil to pentoxifylline-colchicine combination ther-apy on the Peyronie's plaque features in patients with the acute phase of Peyronie's disease (PD).. In this retrospective and non-randomized clinical study, patients were divided into 2 groups as group 1; (n = 107) who received colchicine and pentoxyfillin plus 50 mg daily oral sildenafil, and as group 2; (n = 79) who received only colchicine and pentoxyfillin. Patients were compared in terms of degree of curvature, pain in erection and erectile function at the baseline and at 6-month follow up. Pain in erection and erectile func-tion were evaluated by visual Analogue Scale (EF-VAS), and the shortened version of the International Index of Erectile Function (IIEF-5). Improvement in the degree of curvature and change in EF-VAS scores were primary endpoints of the study. Change in IIEF-5 score was the secondary endpoint of the study.. The two groups were statistically similar in terms of demographics and baseline features of PD. A statistically signifi-cant reduction in degree of curvature and EF-VAS scores was shown in group 1 compared to group 2.There was also a signifi-cantly higher IIEF-5 score in group 1 compared to group 2. No significant side effects were detected in both groups during treatment period.. Adding sildenafil to pentoxifylline-colchicine com-bination treatment seems to improve PD related symptoms in the acute phase PD. PDE5i may contribute to relieve the Peyronie's symptoms in ED patients through their antifibrotic effects.

Topics: Colchicine; Erectile Dysfunction; Humans; Male; Pain; Penile Induration; Penis; Pentoxifylline; Retrospective Studies; Sildenafil Citrate; Treatment Outcome

Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)?. A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects.. Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow.. A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study.. Participants were women in good health, were aged 18-35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post-treatment, patients were asked to provide assessment of their degree of pain using two scales: (i) pain on the 5-level ordinal scale used for TOPAR4 calculation and (ii) pain level on the VAS. The study ended 4 h after treatment initiation.. Twenty-five subjects completed the study. Using the TOPAR4 score, the sildenafil citrate group had significantly better pain relief compared with the placebo group [mean (SD): 11.9 (3.2) versus 6.4 (2.1), respectively; difference in means = 5.3; 95% CI: (2.9,7.6); P < 0.001)]. On the VAS, sildenafil citrate provided better pain relief than placebo at each time point. At the 2-h time point, the PI was significantly lower in the sildenafil citrate group compared with the placebo group [mean (SD): 1.6 (0.6) versus 2.3 (0.5), respectively; difference in means = -0.7; 95% CI: (-1.2, -0.1); P = 0.01)].. Since we did not meet our sample size due to the loss of funding and could not confirm our primary hypothesis, larger studies of longer duration, likely multi-center, are needed to confirm the findings from this study.. A number of medications have been investigated to improve the treatment options for PD, but most have proven unsuccessful or to have an unfavorable risk/benefit ratio. Since PD is a condition that most women suffer from and seek treatment for at some point in their lives, our study offers hope that vaginal sildenafil citrate is a safe and effective option for patients who do not desire or are unresponsive to treatments now available on the market.. Funding for this study was provided by National Institutes of Health (NIH) grants RO3 TW007438 and K24 HD01476. The authors report no relevant conflicts of interest.. NCT00123162 (Clinical trials.gov).

Topics: Adolescent; Adult; Double-Blind Method; Dysmenorrhea; Female; Humans; Pain; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Topics: Anemia, Sickle Cell; Double-Blind Method; Exercise Tolerance; Female; Hemodynamics; Hospitalization; Humans; Male; Middle Aged; Pain; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tricuspid Valve Insufficiency; Vasodilator Agents

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC(0-infinity) and C(max) for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan C(max) was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC(0-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.

Topics: Administration, Oral; Adolescent; Adult; Analysis of Variance; Area Under Curve; Chromatography, High Pressure Liquid; Cross-Over Studies; Drug Interactions; Endothelin A Receptor Antagonists; Female; Follow-Up Studies; Half-Life; Headache; Humans; Male; Middle Aged; Pain; Phenylpropionates; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Tandem Mass Spectrometry; Young Adult

Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Brain; Cerebral Arteries; Cerebrovascular Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Female; Headache; Hemodynamics; Humans; Male; Muscle, Skeletal; Pain; Papaverine; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Time Factors; Ultrasonography, Doppler, Transcranial; Vasodilator Agents

Topics: Animals; Biomarkers; Diabetes Mellitus; Diabetic Neuropathies; Hyperalgesia; Hypoglycemic Agents; Interleukin-6; Metformin; Mice; Nitrites; Pain; Sildenafil Citrate; Tumor Necrosis Factor-alpha

One of the main functions of the sensory system in our body is to maintain somatosensory homeostasis. Recent reports have led to a significant advance in our understanding of pain signaling mechanisms; however, the exact mechanisms of pain transmission have remained unclear. There is an urgent need to reveal the precise signaling mediators of pain to provide alternative therapeutic agents with more efficacy and fewer side effects. Accordingly, although the anti-inflammatory, antioxidative and anti-neuropathic effects of astaxanthin (AST) have been previously highlighted, its peripheral antinociceptive mechanisms are not fully understood. In this line, considering the engagement of l-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) signaling pathway in the antinociceptive responses, the present study evaluated its associated role in the antinociceptive activity of AST. Male mice were intraperitoneally (i.p.) injected with l-arginine (100 mg/kg), SNAP (1 mg/kg), L-NAME (30 mg/kg), sildenafil (5 mg/kg), and glibenclamide (10 mg/kg) alone and prior to the most effective dose of AST. Following AST administration, intraplantarly (i.pl) injection of formalin was done, and pain responses were evaluated in mice during the primary (acute) and secondary (inflammatory) phases of formalin test. The results highlighted that 10 mg/kg i.p. dose of AST showed the greatest antinociceptive effect. Besides, while L-NAME and glibenclamide reduced the antinociceptive effect of AST, it was significantly increased by l-arginine, SNAP and sildenafil during both the primary and secondary phases of formalin test. These data suggest that the antinociceptive activity of AST is passing through the l-arginine/NO/cGMP/KATP pathway.

Topics: Analgesics; Animals; Arginine; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Glyburide; KATP Channels; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pain; Signal Transduction; Sildenafil Citrate; Xanthophylls

Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome is a form of a rare, clinical subtype of systemic sclerosis, known as limited systemic sclerosis. Limited systemic sclerosis, including CREST syndrome, manifests as fibrotic skin changes restricted to the hands and face, with vascular, musculoskeletal, and visceral involvement. We present a case of a 75-year-old woman with a longstanding history of CREST syndrome complicated by a digital ulceration and persistent pain associated with recalcitrant Raynaud phenomenon. After failing a number of first-line pharmacologic therapies such as diltiazem, sildenafil, and topical nitropaste, the patient was started on a trial of botulinum toxin for the left second digit, with 10 unit injections into both webspaces for a total of 20 units. Following injection, the patient reported no further baseline pain in the affected finger and an over fifty-percent improvement in discomfort with manipulation of the digit at a follow-up time of one week. The ulceration started healing within the following three weeks. This result was maintained at a follow-up time of six weeks.

Topics: Acetylcholine Release Inhibitors; Administration, Topical; Aged; Botulinum Toxins; CREST Syndrome; Diltiazem; Female; Humans; Nitroglycerin; Pain; Raynaud Disease; Sildenafil Citrate; Treatment Failure; Ulcer; Vasodilator Agents

Sildenafil, a phosphodiesterase-5-inhibitor (PDE5i), could represent a new treatment in addition to the medical treatment and advice to walk in peripheral arterial disease (PAD).. We report a case of a 62-year-old heavy smoker man who developed a buttock claudication and a severe walking limitation following an aorto-bi-femoral bypass in 1992. Since 2003, each year, he has been referred for investigation of bilateral buttock claudication on treadmill using transcutaneous oxygen pressure (tcpO2) measurement during exercise to argue for the vascular origin of the walking impairment. He had a severe bilateral buttock ischemia and the maximum walking distance (MWD) he reached was 258 m in 2011 despite the medical optimal treatment and walking rehabilitation. Ethical approval is not necessary for this case report according to the French legislation and written consent to publication was obtained from the patient.. Sildenafil, 100 mg/d, was introduced in February 2015 and the MWD increased to 310 m only after 2 h after the first oral intake, then to 713 m after 3 weeks, and finally to 1313 m in January 2017.. Recently, the patient is treated with Sildenafil 100 mg/d. He has no more pain during walking and his quality of life has improved.. Sildenafil, a PDE5i, may represent a new therapeutic option in addition to the conventional optimal medical therapy in patients with arterial claudication. tcpO2 measurement during exercise is a promising technique for the diagnosis and monitoring of patients with PAD. A crossover, double-blind, prospective randomized monocenter study (ARTERIOFIL-NCT02832570) and a double-blind prospective randomized multicenter study (VALSTAR-NCT02930811) are ongoing to confirm our original observation.

Topics: Buttocks; Exercise Therapy; Humans; Intermittent Claudication; Male; Middle Aged; Pain; Peripheral Arterial Disease; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Smoking; Vascular Grafting; Walking

The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.

Topics: Analgesics; Animals; Calcium Channels; Chronic Disease; Drug Interactions; gamma-Aminobutyric Acid; Hyperalgesia; Ion Channel Gating; Ligands; Male; Models, Biological; Pain; Pain Threshold; Phosphodiesterase 5 Inhibitors; Piperazines; Pregabalin; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

Sildenafil increases the cyclic guanosine monophosphate (cGMP) by inhibition of a phosphodiesterase 5, thereby leading to an antinociceptive effect. The increased cGMP may exert the effect on an L-type calcium channel through the activation of protein kinase G (PKG). The purpose of this study was to examine the possible involvement of a PKG-Ltype calcium channel on the effect of sildenafil at the spinal level. Catheters were inserted into the intrathecal space of male SD rats. Pain was induced by applying 50 microL of a 5% formalin solution to the hindpaw. The sildenafil-induced effect was examined after an intrathecal pretreatment of a PKG inhibitor (KT 5823), or a L-type calcium channel activator (FPL 64176). Intrathecal sildenafil produced an antinociceptive effect during phase 1 (0 to approximately 10 min interval) and phase 2 (10 to approximately 60 min interval) in the formalin test. Intrathecal KT 5823 and FPL 64176 attenuated the antinociceptive effect of sildenafil during both phases. Sildenafil is effective against both acute pain and the facilitated pain state at the spinal level. In addition, the inhibition of an L-type calcium channel by activation of the PKG may contribute to the antinocieptive mechanism of sildenafil in the spinal cord.

Topics: Animals; Calcium Channel Agonists; Calcium Channels, L-Type; Carbazoles; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Male; Pain; Pain Measurement; Piperazines; Protein Kinase Inhibitors; Purines; Pyrroles; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

We recently found that the antinociceptive effects produced by intrathecal administration of sildenafil, a phosphodiesterase 5 inhibitor, were reversed by a nonspecific adenosine receptor antagonist, suggesting that adenosine receptors are involved in sildenafil-induced antinociception. Four adenosine receptor subtypes have been identified: A(1), A(2A), A(2B), and A(3). We examined the involvement of spinal adenosine receptor subtypes in the antinociceptive effects of intrathecal sildenafil. Intrathecal catheters were implanted in male SD rats, and nociception was assessed using the formalin test, which consisted of a subcutaneous injection of 50 microl of 5% formalin solution into the hind paw. We examined the effects of an adenosine A(1) receptor antagonist (CPT), an adenosine A(2A) receptor antagonist (CSC), an adenosine A(2B) receptor antagonist (alloxazine), and an adenosine A(3) receptor antagonist (MRS 1220) on sildenafil-induced antinociception. Intrathecal sildenafil suppressed formalin-induced flinching during phases 1 and 2 of the test in a dose-dependent manner. Intrathecal CPT, CSC, alloxazine, and MRS 1220 all suppressed the antinociceptive effects of sildenafil during both phases of the formalin test. These results suggest that sildenafil is an effective treatment for acute pain and the facilitated pain state at the spinal level. Additionally, spinal adenosine A(1), A(2A), A(2B), and A(3) receptors may play a role in sildenafil-induced antinociception.

Topics: Analgesics; Animals; Injections, Spinal; Male; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Sildenafil Citrate; Spinal Cord; Sulfones; Treatment Outcome

A 66-year-old man with diabetes and hypertension using statin was admitted to the hospital with progressive myalgia. He had been on rosuvastatin for five months. After beginning the use of phosphodiesterase-5 inhibitors, he presented with severe muscle pain and maintained penile erection. Several days after interruption of therapy, muscle pain and penile erection disappeared. This case demonstrates the interaction of sildenafil with rosuvastatin might result in myopathy.

Topics: Aged; Drug Interactions; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pain; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidines; Rhabdomyolysis; Rosuvastatin Calcium; Sildenafil Citrate; Sulfonamides; Sulfones

The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil.. Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 minutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined.. Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test.. Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.

Topics: Adenosine; Analgesics; Animals; Cyclic GMP; Dihydroergocristine; Injections, Spinal; Male; Pain; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Receptors, Serotonin; Sildenafil Citrate; Spinal Cord; Sulfones; Vasodilator Agents

Spinal sildenafil (phosphodiesterase 5 inhibitor) and clonidine (alpha-2 adrenoceptor agonist) have shown antinociception. The author examined the properties of drug interaction after concurrent administration of intrathecal sildenafil-clonidine, and further clarified the reciprocity of sildenafil and clonidine. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. The formalin test was used as a nociceptive test, which was induced by subcutaneous injection of 50 microl of 5% formalin solution into the hindpaw. The pharmacological interaction was characterized using an isobolographic analysis. Intrathecal sildenafil and clonidine dose-dependently suppressed the flinching response observed during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of sildenafil-clonidine in both phases. Intrathecal yohimbine antagonized the antinociceptive action of intrathecal sildenafil during both phases in the formalin test. However, intrathecal ODQ failed to antagonize the antinociceptive action of intrathecal clonidine. These results suggest that sildenafil and clonidine, and the mixture of the two are effective against acute pain and facilitated pain state at the spinal level. Furthermore, synergism was noted after delivery of sildenafil-clonidine mixture. The antinociception of sildenafil can be modulated by spinal alpha-2 adrenoceptor, while the effect of clonidine is independent on the guanyly cyclase.

Topics: Analgesics; Animals; Behavior, Animal; Clonidine; Cyclic GMP; Dose-Response Relationship, Drug; Drug Synergism; Guanylate Cyclase; Injections, Spinal; Male; Pain; Pain Measurement; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Sildenafil Citrate; Sulfones

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Synergism; Formaldehyde; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Time Factors

Previous studies have found that sildenafil produces antinociception in experimental models. This work was undertaken to determine the participation of the NO/cGMP/K(ATP) pathway in the antinociception induced by sildenafil.. The antinociceptive effect of sildenafil was determined in the zymosan-induced writhing response in mice. Sildenafil (1-30 mg/kg; i. p.), given 30 min before zymosan (1 mg/animal; i. p.), inhibited the writhing response (5.0 +/- 1.3 versus 26.6 +/- 2.7; p < 0.001) in a dose-dependent manner. L-NAME (30 mg/kg; s. c.) significantly (p < 0.05) reversed this effect (16.6 +/- 3.1 versus 6.4 +/- 1.6) and L-arginine (200 mg/kg; i. p.) prevented the L-NAME effect (6.8 +/- 0.8 versus 16.6 +/- 3.1; p < 0.05). ODQ (0,3-1 mg/kg; i. p.) and glybenclamide (0.3-1 mg/kg; p. o.) pre-treatment significantly (p < 0.01) inhibited the antinociceptive effect of sildenafil (18.0 +/- 1.7 versus 2.1 +/- 1.0 and 5.5 +/- 0.7 versus 1.6+0.7, respectively). Diazoxide (10 mg/kg; s. c) significantly (p < 0.001) abolished the glybenclamide effect (1.6 +/- 0.8 versus 14 +/- 1.2).. The data indicate that the antinociceptive effect of sildenafil is dependent on the activation of the NO/cGMP/ K(ATP) pathway.

Topics: Analgesics; Animals; Behavior, Animal; Cyclic GMP; Dose-Response Relationship, Drug; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Pain; Piperazines; Potassium Channels; Purines; Quinoxalines; Signal Transduction; Sildenafil Citrate; Sulfones; Zymosan

Persistent stimulation of nociceptors and C-fibers by tissue injury causes hyperalgesia and allodynia by sensitization of nociceptors and facilitation of synaptic transmission in the spinal cord. The important participant in the inflammatory response of injured peripheral nerve may be nitric oxide (NO). The aim of the present study was to test the sensitivity of PDE5 inhibitor sildenafil in chronic constriction injury (CCI) model a rat model of neuropathic pain. Sciatic nerve injury is associated with development of hyperalgesia 14 days after the nerve ligation. Sildenafil (100 and 200 microg/rat, i.t.) produced a significant decrease in pain threshold, which in lower dose did not alter the nociceptive threshold. The hyperalgesic effect of sildenafil was blocked by L-NAME and methylene blue (MB), which on per se treatment showed antinociceptive effect in nerve ligated rats. The results from the present study indicated that the major activation of NO-cGMP pathway in the chronic constriction injury model of neuropathic pain. The aggravation of hyperalgesic response might be due to the increased cGMP levels resulting in PKG-I activation and its upregulation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperalgesia; Injections, Spinal; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pain; Pain Threshold; Piperazines; Purines; Rats; Rats, Wistar; Sciatic Neuropathy; Signal Transduction; Sildenafil Citrate; Sulfones

The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.

Topics: Analgesics; Animals; Apamin; Charybdotoxin; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Injections, Subcutaneous; Oxadiazoles; Pain; Pain Measurement; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Tetraethylammonium; Time Factors; Tolbutamide

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.

Topics: Analgesia; Animals; Blood Glucose; Body Weight; Carbazoles; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Indoles; Injections, Spinal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Streptozocin; Sulfones; Time Factors

Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetic Acid; Acetylcholine; Animals; Carrageenan; Cholinergic Agents; Cholinesterase Inhibitors; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Female; Guanylate Cyclase; Hyperalgesia; Male; Methylene Blue; Mice; Neostigmine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones

Topics: Adult; Breast Diseases; Erectile Dysfunction; Follow-Up Studies; Humans; Male; Pain; Piperazines; Purines; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Hyperalgesia; Male; Methylene Blue; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones; Time Factors

Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive effect of the PDE-5 inhibitor, sildenafil, alone or in combination with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In the present study we investigated the possible interaction between cyclooxygenase and NO-cGMP pathway in writhing assay and carrageenan-induced hyperalgesia in mice and rats, respectively. Sildenafil [1-2 mg/kg, i.p. or 50-100 microg/paw, intraplantar (i.pl.)], nimesulide (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) and diclofenac (1-2 mg/kg, i.p. or 25-50 microg/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil (0.5 mg/kg, i.p and 25 microg/paw, i.pl.) were co-administered with ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 microg/paw, i.pl.), there was a significant increase in the antinociceptive effect in both the models of peripheral nociception. Further, the potentiation of the effect was blocked by L-NAME (20 mg/kg, i.p., 100 microg/paw, i.pl.), a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.), a guanylate cyclase inhibitor. L-NAME or methylene blue itself had little or no effect on both the models of hyperalgesia. These results suggest that cyclooxygenase, NO and cGMP are relevant in the combination-induced antinociception. In conclusion, sildenafil induced antinociception, and its potentiation of the effect of the cyclooxygenase inhibitors nimesulide and diclofenac was probably mediated through the activation of the NO-cGMP pathway and inhibition of cyclic GMP degradation.

Topics: Animals; Carrageenan; Cyclic GMP; Cyclooxygenase Inhibitors; Diclofenac; Drug Synergism; Enzyme Inhibitors; Female; Male; Mice; NG-Nitroarginine Methyl Ester; Pain; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides; Sulfones

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Formaldehyde; Inflammation; Injections, Spinal; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Rats, Wistar; Rolipram; Sildenafil Citrate; Spinal Cord; Sulfones

The antinociceptive activity of an inhibitor of phosphodiesterase 5, alone or combined with diclofenac, was assessed in the formalin test. Local administration of diclofenac produced a significant antinociception in both phases of the formalin test in female Wistar rats. In contrast, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3,4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, an inhibitor of phosphodiesterase 5) produced significant antinociception, only during the second phase of the formalin test. Non-effective doses of sildenafil (25-100 microg/paw) significantly increased the antinociceptive effect of an inactive dose of diclofenac (25 microg) in both phases of the test. The antinociception produced by the drugs alone or the combination was due to a local action, as its administration in the contralateral paw was ineffective. Since sildenafil is a potent and selective inhibitor of phosphodiesterase 5, our results suggest that this drug produced its antinociceptive activity, and increased that of diclofenac, probably through the inhibition of cyclic GMP degradation.

Topics: Analgesics; Animals; Cyclooxygenase Inhibitors; Diclofenac; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Female; Formaldehyde; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Although several lines of evidence have shown a role of the nitric oxide/cyclic guanosine monophosphate signaling pathway in the nociceptive mechanism, the exact role of the phosphodiesterase (PDE) 5 enzyme via the NO-cGMP pathway is not fully understood in pain response. The present study was aimed at exploring the role of the NO-cGMP pathway in nociceptive conditions in experimental animals. Peripheral nociception was assessed by acetic acid-induced chemonociception or carrageenan-induced hyperalgesia and central nociception was assessed by tail-flick and hot-plate methods. Sildenafil exhibited dose-dependent (1, 2, 5 and 10 mg/kg, i.p.) antinociception in both male and female mice against acetic acid-induced writhing. However, it did not alter the pain threshold in central nociception (5 and 10 mg/kg, i.p.). Local administration of sildenafil (50-200 microg/paw, i.pl) also attenuated carrageenan-induced hyperalgesia. In the peripheral nociceptive reaction (acetic acid-induced chemonociception), the antinociceptive effect of sildenafil (2 mg/kg, i.p.) was enhanced by co-administration of sodium nitroprusside (0.25 mg/kg), and L-arginine (50 mg/kg). Sildenafil-induced analgesia was significantly blocked by methylene blue (1 mg/kg), a guanylate cyclase inhibitor, but was not reversed by L-NAME (10 mg/kg), a nitric oxide synthase inhibitor. But a higher dose of L-NAME (20 mg/kg) significantly reversed sildenafil analgesia. Both of these agents also reversed the facilitatory effect of L-arginine (50 mg/kg) and sodium nitroprusside (0.25 mg/kg) on sildenafil analgesia. These results suggest that sildenafil-induced analgesia is mediated via the inhibition of PDE5. The results also indicate that the guanylate cyclase system is stimulated in the peripheral nociceptive reaction. In conclusion, sildenafil produces antinociception and its effect can be potentiated by sodium nitroprusside and L-arginine, probably through the activation of the NO-cyclic GMP pathway.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetic Acid; Analgesia; Animals; Arginine; Carrageenan; Central Nervous System; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Female; Hyperalgesia; Male; Methylene Blue; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Nociceptors; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Topics: Circumcision, Male; Enzyme Inhibitors; Erectile Dysfunction; Finasteride; Humans; Male; Mass Screening; Pain; Piperazines; Plant Extracts; Prostatic Hyperplasia; Prostatic Neoplasms; Purines; Serenoa; Sildenafil Citrate; Sulfones; Urology