Study identification

This systematic review followed the PRISMA guidelines [48]. We performed our search on four electronic databases (the Cochrane Library, Scopus, Web of Science, Medline) on 8th August 2023. The search was carried out by an information specialist skilled in systematic reviews in the University of Eastern Finland. The following search string was used:

#1 "Migraine Disorders"[mh]

#2 migrain*[tw]

#3 #1 OR #2

#4 Biophysics[mh] OR "Biomechanical Phenomena"[mh]

#5 biophysic*[tw] OR biomechanic*[tw] OR mechanobiolog*[tw] OR mechanosensitiv*[tw] OR mechanotransduct*[tw] OR "mechanical force*"[tw] OR "mechanical propert*"[tw] OR "mechanical stress*"[tw] OR "mechanical tension*"[tw] OR "physical force*"[tw].

#6 piezo1[tw] OR "piezo 1"[tw] OR piezo2[tw] OR "piezo 2"[tw] OR trpm3[tw] OR "trpm 3"[tw] OR trpv4[tw] OR "trpv 4"[tw] OR trpc[tw] OR trek1[tw] OR "trek 1"[tw] OR traak[tw]

#7 #4 OR #5 OR #6

#8 #3 AND #7

#9 #8 AND 2000:2023[dp] AND english[la]

Study selection

The authors ADP and PM conducted individual assessments of all articles based on their titles and abstracts. Articles that could potentially meet the eligibility criteria in Table 1 of connecting mechanosensitivity and migraine pain passed the selection.

Table 1 Papers eligibility criteria

In cases in which disparities arose between the two assessors, those were resolved through discussions. Following this, a manual review of references of pertinent primary articles was carried out to identify any potentially additional eligible studies that might have been overlooked by the initial search strategy (Fig. 2).

Fig. 2

Article selection process

Emerging role of mechanosensitive receptors in migraine

It is now clear that mechanosensitive channels, widely present in our body, regulate many vital functions, including tactile sensations, proprioception and acute protective pain response [31]. Indeed, the extensive studies on polymodal (including mechanotransduction) TRP and highly mechanosensitive Piezo receptors led to a Nobel Prize in 2021 [49]. Notably, key migraine researchers won the prestigious Brain Prize that same year, reflecting recognition and growing interest in both areas of biomedical research. However, results of the current review indicate that, despite the wealth of knowledge in these apparently distinct domains, studies bridging the gap between mechanosensitive receptors and migraine remain relatively scarce.

Our search of reliable sources automatically selected 478 papers and reviews, which were reduced to 69 after selection based on titles and abstracts specifically focusing on mechanosensitive receptors in migraine. After excluding the review articles (33/69) and carrying out an additional screening of the full texts, the final number of original articles was 36. Additional 3 papers were included in the review after accurate citation searching, for a total of 39 articles.

As shown in Fig. 3A, our analysis revealed an increasing research interest in mechanosensitive mechanisms involvement in migraine over time. One of first articles on TRP mechanosensitive receptors in migraine according to our search criteria, was published in 2007 [50]. The number of these articles raised especially after 2011, reaching peaks in 2013, 2017, 2019 and 2021 with 4 papers, and in 2022 with 6 original papers. In the current year 2023, still ongoing, only 2 papers have been published so far.

Fig. 3

Statistics on the selected articles on mechanosensitive channels and migraine. A Publishing timeline of papers on mechanosensitive receptors in migraine. B Relative number of papers on the main mechanosensors involved in migraine pain

The resulting 39 original articles investigated the direct involvement of the specific type of mechanosensitive receptors in migraine mechanosensitivity and mechanical allodynia (Fig. 3B). Five mechanosensitive channels related to migraine pain have become the center of attention in recent times (Fig. 2B). Figure 3B shows that transient receptor potential (TRP) channels are the most studied group (20 papers), followed by two-pore-domain potassium channels (K2P, 9 papers), Piezo (5 papers), acid sensitive ion channels (ASICs, 3 papers), and N-methyl-D-aspartate (NMDA) receptors (2 papers).

TRP and their modulators in migraine mechanosensitivity

In our selection, 20 papers link TRP channels to migraine, of which 17 were directly selected from the string and 3 more were retrieved from further the reference search.

Notably, TRPV1 is the best studied ion channel in nociceptors known to be activated by capsaicin [51], but also sensitive to other triggers such as (endo)vanilloids, acid and heat [36, 50] (Table 2). These stimuli can activate but also desensitize specific sensory nerve fibers, including those responsible for mechanosensitivity, releasing inflammatory neuropeptides [52]. TRPV1 is playing a significant role in sensory afferents in the stomach, intestine, and colon [53] and mediates nociception, pain hypersensitivity, and mechanosensitivity.

Table 2 Tested compounds promoting or counteracting migraine mechanical hypersensitivity and/or allodynia

Importantly, TRPV1 receptors is clearly implicated in modulation of mechanical pain in migraine [65]. TRPV1 was found to be abundant in the arterial walls of individuals suffering from chronic migraines [66]. The increased presence of TRPV1 receptors promoted the sensitivity of arteries to painful stimuli [66]. TRPV1 receptors were tested in animal migraine models treated with inflammatory soup [54], which promoted sensitization of the trigeminal nociceptive system. This sensitization has been associated with the development of headache and was likely the underlying mechanism of allodynia [24, 67]. In this study, the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 (Table 2) efficiently inhibited trigeminal activation [54]. However, the failure in clinical trials, of the TRPV1 antagonist SB-705498 to reduce capsaicin-evoked hyperalgesia [55] suggests that TRPV1 activation alone may not be the sole trigger of migraine.

Consistent with this, both in the WT and in TRPV1 knockout mice, modelling of migraine with the repetitive nitroglycerin (NTG) injections produced mechanical allodynia in the hindpaw but not in the face along with facial but not hind paw cold allodynia [68]. Therefore, the authors concluded that different peripheral hypersensitivities develop in the face versus hindpaw in this model [68].

In a Complete Freund’s Adjuvant (CFA) orofacial pain model in mice, it has been shown an increase in TRPV1 mRNA and protein immunoreactivity in TG neurons [56]. The study also found that the selective anti-soluble tumour necrosis factor alpha (TNF-alpha) compound XPro1595, reduced CFA-induced mechanical hypersensitivity in the orofacial region [56] suggesting the role of TNF-alpha in enhanced trigeminal mechanotransduction.

Another member of the TRP family, the TRPV4 channel responds to mechanical stimuli and changes in osmolarity [57]. Activation of TRPV4 channels in the rat dura has been shown to cause pain-like behavior, cephalic and extracephalic allodynia reflecting aberrant mechanical sensitivity, which was blocked by the TRPV4 antagonist RN1734 (Table 2) [57]. TRPV4 function in sensory neurons could be modulated downstream of the protease-activated receptor 2 (PAR2) signalling [69]. Consistent with the role in migraine mechanotransduction, PAR2 activation sensitizes meningeal nociceptors to mechanical stimulation [70]. Moreover, it has been found that PAR2 induced headache behaviours in mice was blocked by the selective PAR2 antagonist and was absent in PAR2 knockout mice [71]. Given the link between TRPV4 channels and PAR2 signalling, these studies provide indirect evidence that TRPV4 activity on meningeal nociceptors may contribute to headache, but it remains unclear whether TRPV4 plays a direct role in the ability of meningeal afferents to detect pressure changes. Thus, more studies are needed to better explore the potential role for this channel in migraine.

A polymodal TRPA1 channel in sensory neurons appears to be involved in pain transduction [59] since 42% and 38% of the rat dural afferents reacted to TRPA1 agonists mustard oil (MO) and umbellulone (UMO, Table 2) [59]. Application of 10% MO and 10% UMO to meninges resulted in a significant facial and hindpaw mechanical allodynia, sensitive to the TRPA1 antagonist HC-030031 (Table 2), which prevented cutaneous allodynia [59]. MO and UMO application to dura caused decreased exploratory rearing behavior, which was also sensitive HC-030031 [59]. These data suggested a possible role of TRPA1 channels in migraine mechanical pain. Moreover, TRPA1-mediated activity is likely involved both in migraine aura related phenomenon of CSD and sensitization of trigeminovascular system [72]. Interestingly, a focused study in rat and Rhesus monkey, of the selected fraction of meningeal afferents called ‘non-arterial diffuse dural innervation’ did not reveal immunolabeling of TRPV1 and TRPA1 receptors [73] suggesting their specific distribution in the meninges.

Transient receptor potential melastatin 3 (TRPM3) channels are widely expressed in human sensory neurons [74]. Notably, this mechanosensitive channel could be blocked by the female sex hormones oestradiol and progesterone [75]. Consistent with the role in migraine, two different selective TRPM3 agonists activated nociceptive firing in trigeminal nerve fibers in meninges [76]. Notably, however, that the nociceptive firing induced by TRPM3 agonists pregnenolone sulfate (PregS) or CIM0216 (Table 2) was much more prominent in female mice than in males [76]. This was in sharp contrast to the sex-independent activation of Piezo1 or TRPV1 channels in meningeal afferents. Advanced cluster analysis of meningeal spikes showed a sustained activation of nerve terminals mediated by TRPM3 channels with large-amplitude spikes specific in female mice, proposing a specific mechanosensitive profile in females. These findings suggest that TRPM3 channels may be involved in the generation of migraine pain, particularly in females [76].

Cold sensitive TRPM8 receptors, localized in small-diameter sensory neurons [60], are activated apart from cool temperatures, also by cooling substances such as icilin and menthol (Table 2) [60]. These channels appear to play a role in enhancing the transmission of mechanical sensory signals through C-fibers in the urinary bladder [77]. Moreover, it is known that many cold sensitive neurons also exhibit mechanosensitivity [78]. However, one study found that mice with ablation of TRPM8 neurons did not exhibit impairments in immediate mechanical responses [79]. The other investigation showed that TRPM8 channels activated by icilin evoke cutaneous allodynia [80]. In a study utilizing fluorescent tracer Fluoro-Gold within TRPM8EGFPf/+ mice to label dural afferent neurons, where migraine headache originates, Ren et al. (2018) surprisingly reported that only 3–4% of dural afferent neurons expressed TRPM8 channels. Therefore, while a significant proportion of dural afferent neurons do exhibit mechanosensitivity [81], TRPM8 expressing neurons are likely not represent an essential fraction of meningeal afferents [82]. AMG2850, a TRPM8 antagonist (Table 2), did not reverse CFA induced mechanical hypersensitivity or sciatic nerve ligation induced allodynia in rats [61]. These observations diminish the potential of TRPM8 antagonism as a promising therapeutic approach for migraine management. However, β-lactam derivative with TRPM8 antagonist activity, RGM8-51 (Table 2), decreased menthol induced neuronal firing in a primary culture of rat DRG neurons and mitigated, in a sex-dependent manner, the NTG-induced mechanical hypersensitivity in a in vivo NTG mouse model of chronic migraine [62].

TRPC4 channel is expressed in primary sensory neurons and associated with itching and pain [83]. A specific TRPC4 antagonist, ML204 decreased mechanical hypersensitivity in NTG acute and chronic migraine models in male and female mice and reduced migraine-like pain behaviours in both male and female mice in chronic NTG migraine model [63].

TRPC5 is another TRP channel from the same subfamily, expressed in sensory neurons that has been shown to mediate mechanical sensitivity and spontaneous pain in mice [64]. Table 2 lists lysophosphatidylcholine (LPC) as an endogenous agonist of both human and mouse TRPC5 [64]. In this study, it was found LPC appears to be an endogenous mediator of TRPC5 induced mechanical allodynia. It has been also shown that this compound was elevated in skin two hours after intraplantar injections of CFA and injury site-specific elevation in LPC were also shown in hindpaw of mice after incision [64]. Finally, it has been shown that TRPC5 associated mechanical allodynia was initiated after site specific increase in LPC [64].

Several papers simultaneously considered several types of above mentioned TRP channels in migraine related CGRP release. Thus, it has been revealed that capsaicin, TRPV1 agonist, cinnamaldehyde, TRPA1 agonist, TRPM8 agonist menthol could induce CGRP release from meningeal trigeminal afferents, TG and trigeminal nucleus caudalis (TNC) [58]. In the same study, mechanosensitive TRPV4 channels agonist 4α-PDD (Table 2) was also shown to induce a significant CGRP release from dural trigeminal afferents and TNC [58]. Moreover, the TRPV1 antagonist capsazepine, TRPA1 antagonist HC-030031 and TRPM8 antagonist AMTB (Table 2) blocked CGRP release from both peripheral (dura and TG) and central (TNC) parts of the trigeminovascular system implicated in generation of migraine pain. Likewise, the TRPV4 antagonist GSK-2193874 (Table 2) inhibited the release of CGRP from meningeal trigeminal nerve afferents and TNC [58].

In summary, the role of TRP channels in migraine mechanosensitivity presents a complex landscape with potential benefits for targeted therapies, but challenges still remain inviting more studies of this heterogeneous family of channels with the specific profile of the activators and inhibitors.

Mechanosensitive K2P channels implicated in anti-nociception

In this systematic review, 9 articles discussed K2P channels involvement of mechanosensitive mechanisms in migraine [37, 84,85,86,87,88,89,90]. Two representatives of K2P channels, TREK1 and TREK2 are expressed in nociceptive small and medium fibers and their activity is triggered by mechanical stimuli such as stretch, but also by temperature, low pH and the non-steroidal anti-inflammatory drug BL-1249 [41, 91]. Moreover, it has been shown that the three types of TREK channels can co-assemble not only with each other, but also with other K2P channel members, assuming different functions [91]. Thus, it was observed that wild type TRESK and TREK2 subunits co-assemble forming a common functional heterodimers in TG neurons [37].

TRESK is also one of such partners for other K2P channels and the only K2P channel regulated by intracellular calcium concentration through calcineurin-mediated phosphorylation [89, 92]. TRESK channels in trigeminal neurons can be activated by cell swelling and inhibited by cell shrinkage [86]. Indeed, while negative pressure causes a 1.51-fold increase in channel opening probability, arachidonic acid, acidic pH and hypertonic stimulation, stimulating cell shrinkage, prevent TRESK opening, which is typically observed in inflammatory states [86]. In line with this, it has been proposed that several key mediator