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Br J Pharmacol ; 164(2b): 828-35, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21557731

RESUMO

BACKGROUND AND PURPOSE: We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis. EXPERIMENTAL APPROACH: Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg·kg⁻¹ per os) or saline 2 h after intra-articular zymosan. Other groups received the µ-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil. KEY RESULTS: Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-α release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil. CONCLUSIONS AND IMPLICATIONS: Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-α release in inflamed joints.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Carbolinas/farmacologia , Nociceptividade/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artralgia/tratamento farmacológico , Artralgia/metabolismo , Artrite Experimental/induzido quimicamente , Quimiocina CXCL1/metabolismo , Quimiocinas/metabolismo , GMP Cíclico/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Injeções Intra-Articulares , Interleucina-1/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Tadalafila , Zimosan/farmacologia
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