Intra-Articular Blockade of P2X7 Receptor Reduces the Articular Hyperalgesia and Inflammation in the Knee Joint Synovitis Especially in Female Rats.
Synovitis is a key factor in joint disease pathophysiology, which affects a greater proportion of women than men. P2X7 receptor activation contributes to arthritis, but whether it plays a role in articular inflammatory pain in a sex-dependent manner is unknown. We investigated whether the P2X7 receptor blockade in the knee joint of male and female rats reduces the articular hyperalgesia and inflammation induced by a carrageenan knee joint synovitis model. Articular hyperalgesia was quantified using the rat knee joint incapacitation test and the knee joint inflammation, characterized by the concentration of cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cytokine-induced neutrophil chemoattractant-1, and by neutrophil migration, was quantified using enzyme-linked immunosorbent assay and by myeloperoxidase enzyme activity measurement, respectively. P2X7 receptor blockade by the articular coadministration of selective P2X7 receptor antagonist A740003 with carrageenan significantly reduced articular hyperalgesia, pro-inflammatory cytokine concentrations, and myeloperoxidase activity induced by carrageenan injection into the knee joint of male and estrus female rats. However, a lower dose of P2X7 receptor antagonist was sufficient to significantly induce the antihyperalgesic and anti-inflammatory effects in estrus female but not in male rats. These results suggest that P2X7 receptor activation by endogenous adenosine 5'-triphosphate is essential to articular hyperalgesia and inflammation development in the knee joint of male and female rats. However, female rats are more responsive than male rats to the antihyperalgesic and anti-inflammatory effects induced by P2X7 receptor blockade.



P2X7 receptors could be promising therapeutic targets in the treatment of knee joint disease symptoms, especially in women, who are more affected than men by these conditions.
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, São Paulo, Brazil.
Juliana Maia
JM
Teixeira
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, São Paulo, Brazil.
Elayne Vieira
EV
Dias
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, São Paulo, Brazil.
Carlos Amílcar
CA
Parada
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, São Paulo, Brazil. Electronic address: tambeli@unicamp.br.
Cláudia Herrera
CH
Tambeli
D000081:Acetamides / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004971:Estrus / Q000187:drug effects; D005260:Female; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007270:Injections, Intra-Articular; D015850:Interleukin-6 / Q000378:metabolism; D007719:Knee Joint; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013585:Synovitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C515928:(N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); D000081:Acetamides; D015850:Interleukin-6; D058920:Purinergic P2X Receptor Antagonists; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D009195:Peroxidase
P2X7 receptor; articular hyperalgesia; neutrophil migration; proinflammatory cytokine; sex difference; synovitis