Migraine is a multifaceted neurovascular disorder burdening up to 15% of the world population with a great effect on life quality and global economy [1]. Despite being ranked as the second most disabling disease in the world [2], migraine treatment availability remains insufficient. Indeed, even the recent CGRP monoclonal antibodies still leave roughly 50% of migraine patients untreated [3–5]. Therefore, innovative therapeutics and targets are needed.

As a starting point for identifying new targets, this review will focus on immune cells in the trigeminovascular system, which is generally recognized to play a key role in migraine pain [6]. The trigeminovascular system is composed of afferent trigeminal nerve fibers in the meninges that innervate blood vessels and immune cells, cell bodies in the trigeminal ganglia (TG), and efferent central connections in the trigeminal cervical complex in the medulla [6–8]. During a migraine attack, calcitonin gene-related peptide (CGRP) is released from trigeminal sensory fibers and ganglia, which can promote neurogenic inflammation and nociceptive signals that are relayed to the brainstem and higher brain regions to generate the perception of pain (Fig. 1) [7, 9, 10]. Within the trigeminovascular system, as shown in Fig. 1, CGRP receptors are present on meningeal blood vessels, glia, and trigeminal ganglia neurons [11]. In addition to the canonical CGRP receptor, a second CGRP receptor, AMY₁, is also present on trigeminal ganglia neurons [12–14]. Immunohistochemical and RNA evidence for canonical receptor subunits (CLR and RAMP1) and AMY₁ receptor subunits (CTR and RAMP1) has been reported by several groups [12–18]. Importantly, a host of immune cells, including macrophages, monocytes, mast cells, dendritic cells, B cells, and T cells are known to express CGRP receptors and these cells are also present within the meninges and macrophage-like cells are also present in the ganglia (Fig. 1) [8, 11, 19].

While not the main focus of this review, glial cells can also play roles in the immune system [20], including release of inflammatory cytokines and central sensitization [21], which are both relevant to migraine. Of note, glia can express class II MHC molecules, as more commonly associated with B cells, macrophages, and dendritic cells. MHC expression in astrocytes and microglia can be induced or regulated by cytokines, neurotransmitters, and neuropeptides [22], such as might occur during a migraine attack. Beyond inflammatory events, there is disrupted astrocytic clearance of glutamate in familial hemiplegic migraine type 2, which leads to increased cortical neurotransmission [23]. In addition, the glymphatic system is an astrocyte-associated lymphatic system in the brain that is another area of possible glial involvement in migraine [24].

In migraine, CGRP is generally considered to be pro-inflammatory, but it can also have anti-inflammatory actions depending on the tissue microenvironment and specific target cells [11, 25]. In the skin, CGRP release following nociceptor stimulation promotes the recruitment and activation of immune cells and the production of proinflammatory cytokines in cutaneous inflammation [26]. Injection of CGRP into the rat TG has been shown to increase IL-1β mRNA and CGRP increased the release of IL-1β and other cytokines from cultured satellite glial cells (SGC) [27]. Similarly, injection of CGRP into the temporomandibular joint stimulated expression of proteins in the TG associated with peripheral and central sensitization and activated astrocytes and microglia in the trigeminal nucleus caudalis [28]. Another study found that intracisternal injection of CGRP increased pain responses and astrocyte activation, but not microglial activation [29]. In contrast, it has recently been shown that injection of CGRP into the rat TG shifts the polarity of macrophages to an anti-inflammatory M2 phenotype [30]. Thus, CGRP is likely to play a complex role in the neurogenic inflammatory process in migraine.

Nociceptors, glia, and immune cells are responsible for the neuroimmune communication, involving a repertoire of inflammatory mediators, such as cytokines, chemokines, and Toll-like receptors. In particular, Toll-like receptors, which have been traditionally found on innate immune cells, are also expressed in nociceptive neurons in both dorsal root ganglia and TG where they help regulate sensory functions, such as pain and itch [27, 31]. Additionally, the degranulation of mast cells requires interaction between mast cells and peripheral nerves, which is mediated by the calcium-dependent cell adhesion molecule N-cadherin [32]. Notably, a weak mast cell degranulating effect of CGRP indicated by histamine release was found in rat dura mater but not in the human dura [33, 34]. As mentioned above, in addition to mast cells, macrophages, dendritic cells, B cells, and T cells, have been reported to express the CGRP receptor [11, 19, 35], allowing CGRP to act as immunomodulator.

Dural stimulation with inflammatory mediators, such as inflammatory soup and complete Freund’s adjuvant (CFA), has been extensively studied in animal models to understand its effects on CGRP and related pain mechanisms [36, 37]. Application of CFA to the dura mater in rats resulted in increased CGRP-positive fibers in the trigeminal ganglion, correlating with periorbital allodynia [38]. Another study done on rats showed that inflammatory soup application led to heightened levels of CGRP and other sensitization markers in the trigeminal nucleus caudalis [39], and changes in locomotor behavior in another study done in mice [40], suggesting a possible link between inflammation and migraine-like symptoms.

Consistent with a possible meningeal neuroimmune interaction in migraine, cortical spreading depression is also able to activate meningeal macrophages and dendritic cells [41]. Another classical migraine trigger nitroglycerin (NTG) is also able to activate dural immune cells. Indeed, NTG caused delayed meningeal inflammation such as mast cell degranulation, macrophage activation, NF-κB-dependent upregulation of inducible nitric oxide synthase (iNOS), and the appearance of interleukin (IL)-1 beta (IL-1β) and IL-6 [42, 43]. Once activated, there is a feedback activation of neurons as the immune cells release lipids, cytokines, and growth factors that can play a key role in sensitizing nociceptor sensory neurons [44–47]. In this review we will address how cannabinoids might modulate this neuroimmune cycle in migraine.

Cannabinoids have attracted interest as potential anti-migraine compounds [48, 49]. Despite its side effects, medical marijuana has been reported to reduce migraine frequency attacks [50]. Traditionally, within the primary trigeminal nociceptive afferents, the activation of CB1 receptors by endogenous cannabinoids typically leads to the suppression of CGRP release from peripheral terminals [51–53]. Conversely, within central processes, endocannabinoids act to inhibit glutamate release, which in turn modulates the transmission of nociceptive signals to second-order neurons in the brainstem [51]. Apart from interacting with the conventional inhibitory CB1 and CB2 receptors, endogenous cannabinoids can also participate in neuromodulation mediated by non-cannabinoid receptors. For instance, it has been shown that anandamide (AEA) can activate the transient receptor potential vanilloid receptor (TRPV1) at elevated concentrations (Fig. 1). This activation might lead to the release of CGRP and facilitate nociceptive signaling [52, 54]. In this regard, the potential role of TRPV1 in migraine has been recently reviewed [55, 56]. However, the TRPV1 antagonist SB-705,498 showed no benefit in a clinical migraine study, highlighting that therapies targeting this receptor alone are insufficient for effectively treating migraine symptoms [57].

Meningeal immune cells express both cannabinoid receptors CB1 and CB2 with higher prevalence of CB2 (Fig. 1) [58]. Therefore, immune cells represent potential targets for an innovative migraine cannabinoid treatment through neuroimmune modulation. This review aims to evaluate recent studies on the efficacy and underlying mechanisms of cannabinoid-based treatments for migraine, with a particular emphasis on their interactions with immune cells.