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

Meents JE, Hoffmann J, Chaplan SR, Neeb L, Schuh-Hofer S, Wickenden A, Reuter U - J Headache Pain (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Uniklinik RWTH Aachen, Pauwelsstr. 30, D-52074, Aachen, Germany, jmeents@ukaachen.de.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig1: 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

Mentions: C-fos LI was mainly found in laminae 1 and 2 of the trigeminal nucleus caudalis (TNC) and was most pronounced in the lower levels, corresponding to C1. Only a few cells were seen in all other laminae, in accordance with previously published data [31, 33]. Intracisternal injection of 10-fold concentrated IS (10 mM histamine, serotonin; 1 mM bradykinin, prostaglandin E2; pH 5.5; adapted from [35]) resulted in an increased expression of c-fos within the TNC as compared to controls, which were exposed to an identical volume of vehicle for the same duration (Fig. 1a). After IS stimulation, we counted 9.1 ± 1.5 cells per section at the rostral level of the TNC (p = 0.002), 25.4 ± 3.3 cells in the caudal TNC (p < 0.001), 29 ± 4.8 cells at the C1 level (p = 0.002), and 27.8 ± 2.5 cells at the C2 level (p < 0.001, n = 7). For comparison, in animals treated with vehicle, we only counted 1.7 ± 0.3 in the rostral and 4.7 ± 1.1 in the caudal TNC, 8.7 ± 2.8 and 8.3 ± 3.6 at C1 and C2, respectively (n = 6).Fig. 1


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

Meents JE, Hoffmann J, Chaplan SR, Neeb L, Schuh-Hofer S, Wickenden A, Reuter U - J Headache Pain (2015)

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
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Fig1: 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
Mentions: C-fos LI was mainly found in laminae 1 and 2 of the trigeminal nucleus caudalis (TNC) and was most pronounced in the lower levels, corresponding to C1. Only a few cells were seen in all other laminae, in accordance with previously published data [31, 33]. Intracisternal injection of 10-fold concentrated IS (10 mM histamine, serotonin; 1 mM bradykinin, prostaglandin E2; pH 5.5; adapted from [35]) resulted in an increased expression of c-fos within the TNC as compared to controls, which were exposed to an identical volume of vehicle for the same duration (Fig. 1a). After IS stimulation, we counted 9.1 ± 1.5 cells per section at the rostral level of the TNC (p = 0.002), 25.4 ± 3.3 cells in the caudal TNC (p < 0.001), 29 ± 4.8 cells at the C1 level (p = 0.002), and 27.8 ± 2.5 cells at the C2 level (p < 0.001, n = 7). For comparison, in animals treated with vehicle, we only counted 1.7 ± 0.3 in the rostral and 4.7 ± 1.1 in the caudal TNC, 8.7 ± 2.8 and 8.3 ± 3.6 at C1 and C2, respectively (n = 6).Fig. 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Uniklinik RWTH Aachen, Pauwelsstr. 30, D-52074, Aachen, Germany, jmeents@ukaachen.de.

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.

No MeSH data available.


Related in: MedlinePlus