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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

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
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Fig2: 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

Mentions: Baseline plasma CGRP levels in jugular vein blood were not different between any of the groups. In the control group treated intravenously with vehicle, we measured a baseline CGRP concentration of 65.7 ± 15.7 pg/ml. Injection of capsaicin (4 μmol/kg) into the carotid artery caused a significant increase in CGRP blood levels that was sustained for 15 min (Fig. 2a). We measured a CGRP concentration of 998.9 ± 69.9 pg/ml 5 min after capsaicin administration, 916.5 ± 70.5 pg/ml after 10 min and 738.8 ± 52.4 pg/ml after 15 min (n = 9, p < 0.001 at all time points). To demonstrate that the capsaicin-induced increase in CGRP blood levels was mediated via the trigeminal nerve system, we administered the common migraine drug sumatriptan (300 μg/kg) subcutaneously, prior to capsaicin treatment. Sumatriptan significantly reduced the increase in jugular CGRP levels (Fig. 2a). In this group, we measured only 589.5 ± 30.1 pg/ml 5 min after capsaicin administration, 570.2 ± 28 pg/ml after 10 min (both p < 0.001) and 450.1 ± 39 pg/ml (p = 0.002; n = 8) after 15 min.Fig. 2


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)

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
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Fig2: 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
Mentions: Baseline plasma CGRP levels in jugular vein blood were not different between any of the groups. In the control group treated intravenously with vehicle, we measured a baseline CGRP concentration of 65.7 ± 15.7 pg/ml. Injection of capsaicin (4 μmol/kg) into the carotid artery caused a significant increase in CGRP blood levels that was sustained for 15 min (Fig. 2a). We measured a CGRP concentration of 998.9 ± 69.9 pg/ml 5 min after capsaicin administration, 916.5 ± 70.5 pg/ml after 10 min and 738.8 ± 52.4 pg/ml after 15 min (n = 9, p < 0.001 at all time points). To demonstrate that the capsaicin-induced increase in CGRP blood levels was mediated via the trigeminal nerve system, we administered the common migraine drug sumatriptan (300 μg/kg) subcutaneously, prior to capsaicin treatment. Sumatriptan significantly reduced the increase in jugular CGRP levels (Fig. 2a). In this group, we measured only 589.5 ± 30.1 pg/ml 5 min after capsaicin administration, 570.2 ± 28 pg/ml after 10 min (both p < 0.001) and 450.1 ± 39 pg/ml (p = 0.002; n = 8) after 15 min.Fig. 2

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