Abstract
BackgroundThe 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.MethodsMale 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.ResultsInflammatory 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.ConclusionOur 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.
Highlights
The capsaicin and heat responsive ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks
C-fos LI within TNC inflammatory soup (IS) induces an increase in c-fos LI within the trigeminal brain stem complex 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
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)
Summary
The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. We investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine. Even though the acute treatment of migraine has greatly improved with the development of 5-HT1B/1D receptor agonists (triptans), a substantial percentage of patients do not benefit from oral triptan formulations [2, 3]. Infusion of CGRP causes migraine-like disorders or even migraine without aura [10], and several CGRP receptor antagonists have been shown to be effective in the acute treatment of migraine [11,12,13]. It is well known that activation of the trigeminal nerve system induces a release of CGRP [14] and our group has recently demonstrated that this release could be almost completely abolished by destroying primary trigeminal afferents with neonatal capsaicin treatment [15]
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