Tadalafil analgesia in experimental arthritis involves suppression of intra‐articular TNF release

Abstract

BACKGROUND AND PURPOSEWe investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis. EXPERIMENTAL APPROACHRats 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-a (TNF-a), 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 m-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil. KEY RESULTSTadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-a 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 IMPLICATIONSTherapeutic 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-a release in inflamed joints.

Strontium ranelate analgesia in arthritis models is associated to decreased cytokine release and opioid-dependent mechanisms

“…Rats do not express IL-8 but an ortholog cytokine, CINC-1, instead, which plays a major role in cell recruitment during inflammation [18]. Different from what was observed with TNFa and IL-1b, SR did not alter joint levels of CINC-1 in zymosan arthritis.…”

Involvement of NO–cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia

“…This reveals that in the functional up-or down-regulation of nociceptors, cGMP plays an important role (Duarte et al 1990). Additionally, in the modulation of pain perception (Jain and Kulkarni 1999;Pavone et al 1997;Tao et al 2000) and in nociception in arthritis (Rocha et al 2011) the involvement of NO-cGMP pathway has been suggested by various researchers.…”

“…Of the various PDEs, PDE-5, -6, and -9 are specific to cGMP; however, PDE5 is most relevant to cGMP inactivation inside cells (Rocha et al 2011). PDE5 inhibitors are known to be effective via NO-cGMP pathway (Chen et al 2012) and potentiate the effect of endogenously released NO by slowing the degradation of cGMP (Demchenko et al 2009).…”

Effects of the phosphodiesterase type-5 inhibitor tadalafil on nociception, morphine analgesia and tolerance in rats

“…In addition to our study, another study showed that the PDE 5 inhibitor sildenafil enhanced diclofenac anti-nociceptive effects in formalin tests [18]. Furthermore, one study demonstrated that the PDE 5 inhibitor tadalafil has analgesic effects on experimental arthritis by suppressing TNF alpha release in joints [19]. In contrast to these studies, it has been suggested that zaprinast, another PDE 5 inhibitor, has no effect on hyperalgesia induced by prostaglandin E2 [20].…”