Aims-Clinical studies demonstrate attenuation of trigeminal-related pain states such as migraine by intranasal CO 2 application. This study investigated the underlying mechanisms of this observation and its potential use to reverse trigeminal pain and hypersensitivity.Main methods-We used a behavioral rat model of capsaicin-induced trigeminal thermal hyperalgesia, intranasal CO2 application and several pharmacologic agents such as carbonic anhydrase, acid-sensing ion channels (ASICs), and TRPV1 blocker as well as acidic buffer solutions to investigate and mimick the underlying mechanism.Key findings-Intranasal CO 2 application produced a robust dose-dependent antihyperalgesic effect in rats that lasted at least one hour. Blockade of nasal carbonic anhydrase with a dorzolamide solution (Trusopt® ophthalmic solution) showed only a non-significant decrease of the antihyperalgesic effect of intranasal CO 2 application. Pharmacologic blockade of ASICs or TRPV 1 receptor significantly attenuated the antihyperalgesic effect of CO 2 application. The effect of intranasal CO 2 application could be mimicked by application of pH4, but not pH 5, buffer solution to the nasal mucosa. As with CO 2 application, the antihyperalgesic effect of intranasal pH4 buffer was blocked by nasal application of antagonists to ASICs and TRPV 1 receptors.Significance-Our results indicate that intranasal CO 2 application results in a subsequent attenuation of trigeminal nociception, mediated by protonic activation of TRPV 1 and ASIC channels. A potential central mechanism for this attenuation is discussed. The antihyperalgesic effects of intranasal CO 2 application might be useful for the treatment of trigeminal pain states.
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