Analgesic effect of the neuropeptide cortistatin in murine models of arthritic inflammatory pain

Abstract

Objective. To investigate the role of the antiin-flammatory neuropeptide cortistatin in chronic painevoked by joint inflammation.Methods. Thermal and mechanical hyperalgesiawas evoked in mouse knee joints by intraplantar injec-tion of tumor necrosis factor-a and intraarticularinfusion of Freund’s complete adjuvant, and the anal-gesic effects of cortistatin, administered centrally, peri-pherally, and systemically, were assessed. In addition,the effects of cortistatin on the production of nociceptivepeptides and the activation of pain signaling wereassayed in dorsal root ganglion cultures and in inflam-matory pain models. The role of endogenous cortistatinin pain sensitization and perpetuation of chronic in-flammatory states was evaluated in cortistatin-deficientmice. Finally, the effect of noxious/inflammatory stimuliin the production of cortistatin by the peripheral noci-ceptive system was assayed in vitro and in vivo.Results. Expression of cortistatin was observed inpeptidergic nociceptors of the peripheral nociceptivesystem, and endogenous cortistatin was found to partic-ipate in the tuning of pain sensitization, especially inpathologic inflammatory conditions. Results showedthat cortistatin acted both peripherally and centrally toreduce the tactile allodynia and heat hyperalgesiaevoked by arthritis and peripheral tissue inflammationin mice, via mechanisms that were independent of itsantiinflammatory action. These mechanisms involveddirect action on nociceptive neurons and regulation ofcentral sensitization. The analgesic effects of cortistatinin murine arthritic pain were linked to binding of theneuropeptide to somatostatin and ghrelin receptors,activation of the G protein subunit Gai , impairment ofERK signaling, and decreased production of calcitoningene-related peptide in primary nociceptors.Conclusion. These findings indicate that cortista-tin is an antiinflammatory factor with potent analgesiceffects that may offer a new approach to pain therapy inpathologic inflammatory states, including osteoarthritisand rheumatoid arthritis