Two TRPV1 receptor antagonists are effective in two different experimental models of migraine

Abstract

Background: The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine.

Methods: Male Sprague-Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery.

Results: Inflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner.

Conclusion: Our results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine.

Fig. 1

IS-induced up-regulation of c-fos can be abolished through block of TRPV1. a Intracisternal administration of inflammatory soup (IS; black bars) induces an increase in the amount of cells showing c-fos like immunoreactivity (c-fos LI) in the trigeminal brain stem complex. This increase was significant at all levels of the TNC when compared to control animals (white bars), injected with an identical volume of vehicle. These two groups also received an injection of sumatriptan vehicle. Administration of sumatriptan (300 μg/kg; grey bars) before injection of IS did not affect the IS-induced up-regulation of c-fos. b The TRPV1 antagonist JNJ-38893777 reduced the elevated c-fos expression, seen after injection of IS, in a dose-dependent fashion. The antagonist was injected intravenously in 0.03 mg/kg (black bars), 0.3 mg/kg (light grey bars) and 3 mg/kg (dark grey bars) over a period of 20 min before application of IS. c The TRPV1 antagonist JNJ-17203212 was injected in 0.3 mg/kg (black bars), 3 mg/kg (light grey bars) and 30 mg/kg (dark grey bars) previous to IS administration. A dose-dependent reduction in IS-induced c-fos expression could be observed. The highest dose completely abolished c-fos up-regulation in most parts of the TNC. # compares to vehicle + vehicle treated group (no IS administration) at the same level of TNC. * compares to IS + vehicle treated group at the same level of TNC. n.s. not significant (compared to IS + vehicle). *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 2

TRPV1 antagonists are effective in blocking capsaicin-induced CGRP release. a Injection of capsaicin (4 μmol/kg) into the carotid artery caused an increase in CGRP concentration in jugular vein blood. The increase was substantial within 5 min and still significant albeit slightly decreasing after 15 min. Administration of sumatriptan (300 μg/kg; black bars) prior to capsaicin treatment reduced the elevated CGRP levels significantly, although they were still considerably higher than baseline values. b The TRPV1 antagonist JNJ-38893777 in the highest dose of 3 mg/kg (dark grey bars) reduced jugular CGRP levels after capsaicin significantly, returning them to near baseline levels within 10 min. Lower doses of 0.3 mg/kg (light grey bars) and 0.03 mg/kg (black bars) were less effective. c JNJ-17203212 had a dose-dependent effect on the capsaicin-induced increase in jugular CGRP concentration. CGRP release was completely abolished within 10 min when the antagonist was administered at 30 mg/kg (dark grey bars) and within 15 min when administered at 3 mg/kg (light grey bars). The lowest dose of 0.3 mg/kg (black bars) reduced the CGRP levels significantly but not to the level of the pre-capsaicin baseline after 15 min. d Neither JNJ-38893777 (black bars) nor JNJ-17203212 (grey bars) when used in their highest doses had any effect on jugular CGRP levels in animals that did not receive an injection of capsaicin. Values were not significantly different compared to the respective baseline. # compares to baseline values of the same group. * compares to capsaicin + vehicle at the same time point. n.s. not significant (compared to baseline values of the same group). *p < 0.05; **p < 0.01; ***p < 0.001