Table 3.
Studies on the Role of Cannabinoids in Headache Pathogenesis
| Mechanistic category | Significant findings | Source |
|---|---|---|
| Systemic | Variants in the cnr1 gene (encodes for the CB1 receptor) resulting in decreased expression of CB1 associated with migraine and trigeminovascular activation. | Juhasz et al.75 |
| Levels of AEA are decreased in the cerebrospinal fluid of individuals with chronic migraine, whereas levels of CGRP and NO (inhibited by AEA) are increased. | Sarchielli et al.76 | |
| Endocannabinoid deficiency theorized as a possible cause for migraine and other chronic pain disorders, including chronic migraine and medication-overuse headache. | Cupini et al.77 | |
| Female migraineurs have increased FAAH and EMT activities. | Cupini et al.78 | |
| Cortex | CB1 agonists suppress glutamatergic neurotransmission by inhibiting NMDA receptors. | Hampson et al.79 |
| CB1 agonists suppress CSD. | Kazemi et al.80 | |
| Vasculature | AEA reduced nitroglycerin-induced neuronal activation in the nucleus trigeminalis caudalis. | Greco et al.81 |
| AEA inhibits dural blood vessel dilation induced by CGRP, capsaicin, and NO (model of trigeminovascular nociceptive response). AEA also prevented the release of NO by CGRP in dural arteries. | Akerman et al.82 | |
| Hyperalgesia induced by NO nearly eliminated in FAAH deletion or with FAAH inhibitor. | Nozaki et al.83 | |
| AEA activates TRPV1 on afferent trigeminal ganglion neurons, leading to CGRP release and cranial vasodilation. | Akerman et al.93 | |
| CBD is TRPV1 agonist. Could desensitize receptor and inhibit pathophysiological mechanism of headache. | Bisogno et al.84 | |
| Platelets | Endocannabinoid levels reduced in platelets of patients with migraine. | Rossi et al.85 |
| Platelets of women with migraine showed increased activity of FAAH when compared with men with migraine. | Cupini et al.78 | |
| Cannabinoid compounds may stabilize and inhibit 5HT release from platelets during a migraine. | Volfe et al.96 | |
| Brainstem | CB1 receptor activation in PAG and RVM leads to top-down modulation of pain. | Kelly and Chapman86 |
| AEA potentiates 5HT1A and inhibits 5HT2A receptors. | Boger et al.87 | |
| Endocannabinoids interact with serotonergic neurons in the brainstem dorsal raphe to modulate pain mechanisms. | Haj-Dahmane and Shen88 | |
| NO increases activity of FAAH, leading to increased breakdown of endocannabinoids in the midbrain/PAG. | Greco et al.30 | |
| Elevation of endocannabinoid levels in the PAG modulates descending nociceptive pathways via CB1 and TRPV1. | Maione et al.89 | |
| CB1 receptor activation in the vlPAG attenuated trigeminocervical complex activity. This effect was inhibited by the addition of the CB1 receptor antagonist or the 5HT1B/1D receptor antagonist. | Akerman et al.90 |
AEA, anandamide; CB1, cannabinoid receptor type 1; CBD, cannabidiol; CGRP, calcitonin gene-related peptide; CSD, cortical spreading depression; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; NMDA, N-methyl-d-aspartate; NO, nitrous oxide; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; vlPAG, ventrolateral PAG.