Objectives: To examine the role of anandamide, the cannabinoid CB₁ and CB₂ receptor endogenous ligand, in a model of trigeminovascular nociceptive activation to determine if anandamide and the cannabinoids have therapeutic potential in migraine.

Methods: Male Sprague Dawley rats (n = 37, 285-375g) were anaesthetised with i.p. injection of pentobarbitone sodium and cannulated for measurement of blood pressure and intravenous administration of experimental drugs, and supplementary anaesthesia (pentobarbitone sodium). The parietal bone was thinned to form a cranial window through which the diameter of a branch of the middle meningeal artery was measured on-line with a video dimension analyser, the methods are reported in more detail in Williamson et al (1997a and b). Statistical analysis was performed using an ANOVA for repeated measures with bonferroni post-hoc correction for multiple comparisons followed by Student's paired t-test (SPSS v10.0).

Results: Electrical stimulation (50-300µA) and intravenous (iv) CGRP injections (1 µgkg^-1) reproducibly caused dural vessel dilation, 135 ± 4% and 106 ± 7%, respectively, as measured by intravital microscopy in the rat. Anandamide (iv) was able to inhibit vasodilation caused by electrical stimulation, 120 ± 8% to 53 ± 8% (3 mgkg^-1, t₁₁ = 7.6, P < 0.05) and CGRP 120 ± 7% to 89 ± 10% (3 mgkg^-1, n = 14, t₁₃ = 6.6, P < 0.05). The CB₁ receptor antagonist, AM251 was able to reverse the inhibitory effects of anandamide on electrical stimulation, 47 ± 13% to 99 ± 16 (3 mgkg^-1, n = 6, t5 = 4.3, P < 0.05) and CGRP injection, 87 ± 7% to 129 ± 11% (3 mgkg^-1, n = 8, t₇ = 6.1, P < 0.05). Anandamide (1, 3, 5 and 10 mgkg^-1) was also able to cause a dose-dependent vasodilation, 19 ± 9% (n = 12), 29 ± 5% (n = 37), 74 ± 7% (n = 13) and 89 ± 18% (n = 6) that was inhibited by capsazepine a VR1 receptor antagonist (n = 6, P < 0.05), rather than the CB₁ receptor antagonist.

Conclusion: Anandamide is able to block both neurogenic and CGRP-induced dural vessel dilation, via the CB₁ receptor. CB₁ receptors, therefore, have potential as novel therapeutic targets in migraine. Anandamide is also an agonist at the VR1 receptor and causes vasodilation, presumably by activating the release CGRP. Its action is blocked by capsazepine, the VR1 receptor antagonist.

Williamson DJ et al (1997a) Cephalalgia 17,518-524.
Williamson DJ et al (1997b) Cephalalgia 17, 525-531.