title: Treatment with Adenosine Receptor Agonist Ameliorates Pain Induced by Acute and Chronic Inflammation.
abstract: Rheumatoid arthritis is an inflammatory autoimmune condition, and tumor necrosis factor-α (TNF-α) plays an important role in its pathophysiology. In vitro, (E)-N'-(3,4-dimethoxybenzylidene)-N-methylbenzohydrazide (LASSBio-1359) has exhibited anti-TNF-α properties, and in vivo these effects are mediated via activation of adenosine receptor. This work investigates the antinociceptive action of LASSBio-1359 in murine models of acute and chronic inflammatory pain. Male mice received an intraperitoneal injection of LASSBio-1359 and then were evaluated in formalin- and carrageenan-induced paw edema assays. Complete Freund's adjuvant (CFA) was used to induce a mouse model of monoarthritis. These mice were treated with LASSBio-1359 by oral gavage to evaluate thermal and mechanical hyperalgesia. TNF-α and inducible nitric oxide synthase (iNOS) expression as well as histologic features were analyzed. The time of reactivity to formalin in the neurogenic phase was reduced from 56.3 ± 6.0 seconds to 32.7 ± 2.2 seconds and 23.8 ± 2.6 seconds after treatment with LASSBio-1359 at doses of 10 mg/kg and 20 mg/kg, respectively. A reversal of the antinociceptive action of LASSBio-1359 was observed in the inflammatory phase after treatment with ZM 241385 [4-(2-[7-amino-2-(2-furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol], an adenosine A2A antagonist. Carrageenan-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359. Similarly, CFA-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359 (25 and 50 mg/kg). Levels of TNF-α and iNOS expression increased in the monoarthritis model and were normalized in animals treated with LASSBio-1359, which was also associated with beneficial effects in the histologic analysis. These results suggest that LASSBio-1359 represents an alternative treatment of monoarthritis.
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Guilherme Carneiro
authors.initials: GC
authors.lastname: Montes
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Nathalia
authors.initials: N
authors.lastname: Hammes
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Miguel Divino
authors.initials: MD
authors.lastname: da Rocha
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Tadeu Lima
authors.initials: TL
authors.lastname: Montagnoli
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carlos Alberto Manssour
authors.initials: CA
authors.lastname: Fraga
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Roberto Takashi
authors.initials: RT
authors.lastname: Sudo
authors.affiliation: Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil gzsudo@oi.com.br.
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
mesh_terms: D000208:Acute Disease; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000150:complications; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000150:complications; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000596271:3,4-dimethoxyphenyl-N-methylbenzoylhydrazide; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D006835:Hydrazones; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II