RESUMO
BACKGROUND: We previously showed that local use of periodate oxidized ATP (oATP, a selective inhibitor of P2X7 receptors for ATP) in rat paw treated with Freund's adjuvant induced a significant reduction of hyperalgesia Herein we investigate the role of oATP, in the rat paws inflamed by carrageenan, which mimics acute inflammation in humans. RESULTS: Local, oral or intravenous administration of a single dose of oATP significantly reduced thermal hyperalgesia in hind paws of rats for 24 hours, and such effect was greater than that induced by diclofenac or indomethacin. Following oATP treatment, the expression of the pro-inflammatory chemokines interferon-gamma-inducible protein-10 (IP-10), mon ocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) within the inflamed tissues markedly decreased on vessels and infiltrated cells. In parallel, the immunohistochemical findings showed an impairment, with respect to the untreated rats, in P2X7 expression, mainly on nerves and vessels close to the site of inflammation. Finally, oATP treatment significantly reduced the presence of infiltrating inflammatory macrophages in the paw tissue. CONCLUSION: Taken together these results clearly show that oATP reduces carrageenan-induced inflammation in rats.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Analgésicos não Narcóticos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Quimiocinas/biossíntese , Hiperalgesia/tratamento farmacológico , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/fisiologia , Trifosfato de Adenosina/uso terapêutico , Administração Cutânea , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina/toxicidade , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Quimiocina CXCL10 , Quimiocinas/genética , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Diclofenaco/administração & dosagem , Diclofenaco/uso terapêutico , Modelos Animais de Doenças , Membro Posterior , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Injeções Intravenosas , Interleucina-8/biossíntese , Interleucina-8/genética , Macrófagos/efeitos dos fármacos , Masculino , Antagonistas do Receptor Purinérgico P2 , Ratos , Ratos Wistar , Receptores Purinérgicos P2/biossíntese , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7 , Método Simples-CegoRESUMO
The neurotransmitter adenosine triphosphate (ATP) is released from sensory nerve endings during inflammation and acts at the level of P2X receptors. We used the irreversible inhibitor of P2z/P2X7 receptor, designated oxidized ATP (oATP), to test its possible antinociceptive activity in arthritic rats. We induced unilateral inflammation of the rat hind paw by local injection of Freund's complete adjuvant. Administration of the adjuvant resulted in a significant reduction of paw pressure threshold (PPT). Injection of oATP into inflamed paws significantly increased, in a dose-dependent manner, PPT values to levels comparable with or higher than those evaluated in control uninflamed paws. The data indicate that the P2z/P2X7 receptor system exerts a role in nociception and that oATP, by inhibiting such a receptor, reduces the nociceptive signal in the course of peripheral inflammation.