Trigeminal antihyperalgesic effect of intranasal carbon dioxide

Abstract

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.

No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

“…We note that we did not strive for a specific model such as migraine headache but a robust model of craniofacial pain including TRPV1 activation affecting the first trigeminal branch. In our sample, participants showed a transient and significant increase in pain ratings after nasal application of capsaicin which is in line with other studies showing a subsequent and temporary regional sensitization [14,33]. Pain ratings peaked after 8-9 min which is congruent with an animal study on neuronal activity in the rat nucleus caudalis [34].…”

“…As shown by Tzabazis and colleagues in a rat model [14], nasal insufflation of CO 2 with flow rates of 0.8 l/min attenuated nocifensive behaviour after sensitization with capsaicin unlike lower flow rates of CO 2 (0.4 l/min) or air. In the nasal mucosa CO 2 decomposes into protons and carbonate catalyzed by mucosal carbonic anhydrase and activates TRPV1- and ASIC- positive neurons by proton accumulation.…”

“…More recently, CO 2 has been shown to be a powerful modulator of activated nociceptive trigeminal neurons [13]. Tzabazis and co-workers sensitized rat cheeks with capsaicin and insufflated CO 2 or air nasally [14]. Nocifensive behaviour defined as facial and hind paw withdrawal to radiant noxious heat was significantly attenuated by higher CO 2 flow rates of 0.8 l/min but not of 0.4 l/min CO 2 or air.…”

Dissecting the role of TRPV1 in detecting multiple trigeminal irritants in three behavioral assays for sensory irritation

“…This result is entirely consistent with the multitude of experiments indicating that TRPV1 is responsible for detecting capsaicin 34– 36 . Wildtype mice found capsaicin to be the least aversive of all the irritants tested in this assay.…”

“…Capsaicin, the active component of chili peppers, was used to clone the TRPV1 channel 5 and has been used as a topical TRPV1 agonist in a multitude of studies 34– 36 . While capsaicin is the prototypic exogenous TRPV1 agonist, the non-volatility of capsaicin restricts its use in experimental paradigms where the stimulus is administered as a vapor.…”