Background
One of the main trends in migraine studies is to find out the most sensitive and preferably non-invasive biomarkers serving for the diagnostic and personalized treatments of this often-intractable disorder. Application of capsaicin to the skin is widely used to monitor the reactiveness of local blood flow following activation of capsaicin-sensitive TRPV1 receptors [
1,
2]. The underlying mechanism of redness (flare) is mainly associated with the release of the neuropeptide CGRP from nociceptive C-fibers expressing TRPV1 receptors in membrane [
3]. Several recent studies in animals and humans suggested the role of TRPV1 receptors in migraine [
4,
5]. Accumulated evidence also suggested that CGRP is the main neuropeptide implicated in migraine pathology [
6‐
8]. Many modern approaches for migraine treatment are based on inhibition of CGRP driven pro-nociceptive activity [
7,
9]. This requires simple tests to evaluate the release of CGRP in humans. Thus, capsaicin-induced increase in dermal blood flow (DBF) is widely used to test the activity of potential anti-migraine medicines [
2]. Apart from general pharmaceutical significance, this DBF method could be attractive to develop personalized approaches for migraine treatments, for instance, to test the sensitivity of the particular individual to capsaicin as a prognostic of CGRP mediated component in his/her vascular reactions. In this regard, it is worth noting that people with TRPV1 rs8065080 polymorphism are differentially sensitive to capsaicin [
1] providing a genetic background for the distinct reactivity.
A recent study has shown that migraine patients reported higher level of capsaicin-induced feeling of pain and larger areas of flare [
10]. In most studies simple measurement of the flare size is commonly used as the index of activation of capsaicin receptors [
4,
10] although it is clear that this general reaction is determined by many non-specific factors such as the thickness of skin, its native color and, importantly, the level of CGRP released from the skin nerves [
2].
Laser Doppler imaging systems are commonly used for assessment of the cutaneous microcirculation [
11,
12]. However, these systems provide sequential scanning of the area under study, which increases the time needed to collect information from the area under study when its size is big and high spatial resolution is required. In contrast, imaging photoplethysmography (IPPG) systems acquire information from multiple points in parallel and simultaneously thus providing high spatial and temporal resolution [
13]. It was shown recently that these systems are capable to visualize capillary blood flow [
14,
15] making IPPG method more preferable for detailed study of spatial-temporal variations of microcirculation. Previously we suggested the non-invasive IPPG technique to evaluate the vascular reactions in migraine [
16,
17]. Recently we advanced this technique by linking peripheral changes in pulsatile blood flow with heart rate, which largely increased the sensitivity of this combined approach [
18]. In the current study, we used IPPG to monitor parameters of local blood circulation in the skin during capsaicin applications in patients with migraine and compared those with microcirculation in control group. With this technique we find out highly heterogeneous (both in time and space) reaction of migraine patients to stimulation of TRPV1 receptors that control local microcirculation. We also show that BPA does not always coincide with redness (or skin flare) and can serve as potential biomarker of blood flow changes associated with migraine and probably with other cardiovascular diseases.
Discussion
Based on innovative IPPG technique, we present here the novel method for evaluation of capsaicin induced changes in peripheral blood flow that is more sensitive than the commonly used skin redness analysis. The main finding of our study is the remarkable variability (both in space and time) in skin microcirculation after capsaicin application in migraine patients. We suggest this novel phenomenon can serve as a quantitative biomarker of vascular changes in this disorder and probably as a predictive parameter for efficiency of anti-migraine CGRP-based drugs.
Despite the high prevalence of migraine, the pathogenesis of migraine pain remains unclear. However, recent animal and human studies suggested the significant role of TRPV1 receptors expressed in meningeal nerve fibers in migraine pathology [
4,
5]. Accumulated evidence suggests that the neuropeptide CGRP is released upon activation of TRPV1 receptors as the main triggering factor implicated in migraine pain [
6‐
8]. Therefore, the inhibition of the pro-nociceptive action of CGRP represents one of the most promising approaches for migraine treatment [
7,
9]. For instance, the most specific agents for migraine treatment are represented by triptans which block CGRP release [
21‐
23]. Another promising approach is neutralization of CGRP (or its receptors) by specific antibodies [
24‐
26]. Although other treatment strategies are possible, the known contribution of CGRP to migraine pathology in the individual patients could predict the efficiency of triptans or CGRP antibodies.
Capsaicin-induced increase in DBF presented as the skin redness is a simple test to evaluate the release of CGRP in peripheral tissues and to test the efficiency of anti-migraine medicines [
2]. Measuring the intensity of skin redness potentially could indirectly suggest the sensitivity to CGRP based medications. Consistent with this view, it has been shown recently that migraine patients have larger areas of skin redness after dermal application of capsaicin [
10] suggesting the larger release or higher reactivity of vessels to endogenous CGRP which is one of the most powerful vasodilators. Migraine has been suggested as a systemic vasculopathy [
27]. Vascular changes in migraine were suggested since the emergence of the famous Woolf’s vascular theory of migraine [
28]. This theory proposed the primary changes in the intracranial vessels which are hardly available. Nevertheless, the recent magnetic resonance angiography of extra- and intracranial vessels indicated the dilatation of blood vessels during migraine attack [
29]. The other study reported the local asymmetry of forehead blood flow in the affected side of the migraine patient’s face during an attack [
30]. However, unlike most of previous studies that have addressed the functional states of large vessels, our study was focused on variability of microcirculation in migraine patients. Here we report ‘
local asynchronous’ reactions in certain skin areas triggered by application of capsaicin which were higher presented in migraine. One of the main findings of our study is highly heterogeneous (in time and in space) reaction of migraine patients to stimulation of TRPV1 receptors. It became possible to obtain this novel finding through the use of the advanced IPPG technique allowing us to register the pulsatile blood flow with simultaneous ECG recordings, resulting in enhanced sensitivity of this approach [
18]. Another important observation is that the essential changes in BPA could develop without significant skin redness (evaluated here via calculation of the DC component of IPPG). Notably, the degree of DC changes in these relatively short period of capsaicin application was much weaker than BPA modulation. Taken together these data suggest that BPA measurement in hot spots and its variability (measured from the coefficient of BPA variations) represent the powerful biomarker of blood flow changes associated with migraine. The nature of migrating hot spots remains unclear but it could be related to the random opening and closure of precapillary sphincters which regulate blood flow in the capillaries and venules. This dynamic process could be determined by interaction of several competing mechanisms including CGRP mediated vasodilation and the opposite process of vasoconstriction based on direct activation of vascular TRPV1 receptors by capsaicin [
31,
32]. It is worth noting that the local anesthetic lidocaine was applied before capsaicin due to instructions of the Quatenza plaster manufacturer. Recent study reported that lidocaine can directly stimulate TRPV1 and TRPA1 receptors and release CGRP [
33] which potentially can induce vasomotor effects similar to those of capsaicin. However, in our conditions, relatively low concentrations of lidocaine did not produce measurable changes of the microcirculation.
Interestingly, the phenomenon of hot spots leading to asynchronous high intensity activation of local parts of the skin can unexpectedly slow down the global growth of the BPA masking thus the reactivity of the current individual to capsaicin. This can explain why we did not find significant changes in the speed of BPA growth in migraine patients in our small sample. Nevertheless, high variability of BPA in capsaicin test can predict the sensitivity of CGRP-specific treatments such as triptans and CGRP neutralizing antibodies.
Left-right side asymmetry (asynchronous reactions) in the sympathetic skin responses was also found in the headache-free period in unilateral migraine patients [
30]. One of the key questions is whether the local reaction represented as migrating hot spots after application of capsaicin to migraine patients was mediated by pure peripheral mechanisms or operated via central sensitization [
34]. The latter can potentially change the autonomous control of microcirculation via neuronal mechanisms. Indeed, we found recently that during interictal period in migraine patients a specific enhancement of the sympathetic control is observed [
35].
The main limitation of the study is that it was performed in a small cohort and the data should be confirmed in a larger population. However, even in a limited number of patients we found the novel criterion for evaluation of the peripheral blood flow such as the high variability of zones in the skin with increased BPA. In addition, the trend to a shorter latency in BPA increase should be revisited in a larger population. We also used lidocaine as the obligatory component of the pre-treatment that may have partially masked the intensity of capsaicin effects. The genetic reason for asynchronous activation of microcirculation remains unclear. As TRPV1 gene polymorphism determines sensitivity to capsaicin [
1] further studies are needed to explore the role of genotyping-based approaches in migraine patients. Suggested here BPA changes with IPPG technique could be used to determine the sensitivity of the particular person to capsaicin as a prognostic tool to identify the role of CGRP component in his/her vascular reactions.