title: Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release.
abstract: OBJECTIVE
  We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil. arocha@ufc.br
authors.forename: F A C
authors.initials: FA
authors.lastname: Rocha
authors.forename: F S
authors.initials: FS
authors.lastname: Silva
authors.forename: A C R M
authors.initials: AC
authors.lastname: Leite
authors.forename: A K R M
authors.initials: AK
authors.lastname: Leite
authors.forename: V C C
authors.initials: VC
authors.lastname: Girão
authors.forename: R R
authors.initials: RR
authors.lastname: Castro
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018771:Arthralgia / Q000188:drug therapy / Q000378:metabolism; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology*; D054360:Chemokine CXCL1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D006162:Guanylate Cyclase / Q000378:metabolism; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects*; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068581:Tadalafil; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D002243:Carbolines; D054360:Chemokine CXCL1; D018925:Chemokines; C513297:Cxcl1 protein, rat; D007375:Interleukin-1; D009292:Narcotic Antagonists; D010069:Oxadiazoles; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; D009270:Naloxone; D000068581:Tadalafil; D015054:Zymosan; D006162:Guanylate Cyclase; D006152:Cyclic GMP