Y Nagakura1, S Kakimoto, N Matsuoka. 1. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. yukinori.nagakura@jp.astellas.com
Abstract
BACKGROUND AND PURPOSE: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. EXPERIMENTAL APPROACH: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus (house musk shrews). A slowly degradable ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP), was used to activate the P2X receptors, and either the non-selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A-317491, were tested against the agonist-induced response. KEY RESULTS: Intraperitoneal injection of alpha,beta-meATP produced significant emetic responses in ferrets (1 - 30 mg kg(-1)) and in Suncus murinus (5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre-treatment with PPADS (100 mg kg(-1)) or A-317491 (100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. CONCLUSIONS AND IMPLICATIONS: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and.or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms.
BACKGROUND AND PURPOSE: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. EXPERIMENTAL APPROACH: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus (house musk shrews). A slowly degradable ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP), was used to activate the P2X receptors, and either the non-selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A-317491, were tested against the agonist-induced response. KEY RESULTS: Intraperitoneal injection of alpha,beta-meATP produced significant emetic responses in ferrets (1 - 30 mg kg(-1)) and in Suncus murinus (5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre-treatment with PPADS (100 mg kg(-1)) or A-317491 (100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. CONCLUSIONS AND IMPLICATIONS: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and.or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms.