Cortical Spreading depression (CSD) is a transient wave of hyperexcitability, followed by a prolonged period of depressed activity that travels through the brain.

In humans, CSD is thought to manifest itself as an aura, which may precipitate the pain phase later on.

In rats, THC dose dependently suppressed CSD amplitude, duration and propagation through CB1 but not CB2 activation (Kazemi et al., 2012).

The pain phase of Migraine is mediated by and can be blocked through both CB1 and CB2 receptors (Greco et al., 2014).

Pre-administered Anandamide significantly reduced nociceptive behavior in rats, suggesting that Migraine may actually be a manifestation of a dysfunctional endocannabinoid system (Greco et al., 2011), which in turn offers interesting possibilities for endo- and plant cannabinoids in the treatment of Migraine.

TRPV1 has also been implicated in the pathophysiology of Migraine.

Interestingly, blocking TRPV1 function has no effect but stimulating these receptors offers pain relief; in fact transient activation is followed by prolonged de-sensitization and thus effective pain relief.

TRPV1-mediated antinociception is thought to work in synergy with CB1-mediated neuronal inhibition in pain management (Hoffmann et al., 2012).

An important structure in pain processing is the ventrolateral periaqueductal grey (vlPAG).

In the vlPAG, pain processing depends on cross-talk between the endocannabinoid and serotonin signaling system (Akerman et al., 2013).

Whether this opens more therapeutic avenues remains to be elucidated.

Literature:

Akerman, S., Holland, P.R., Lasalandra, M.P., and Goadsby, P.J. (2013). endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in Migraine. J. Neurosci. Off. J. Soc. Neurosci. 33, 14869–14877.

Greco, R., Mangione, A.S., Sandrini, G., Maccarrone, M., Nappi, G., and Tassorelli, C. (2011). Effects of Anandamide in Migraine: data from an animal model. J. Headache pain 12, 177–183.

Greco, R., Mangione, A.S., Sandrini, G., Nappi, G., and Tassorelli, C. (2014). Activation of CB2 receptors as a potential therapeutic target for Migraine: evaluation in an animal model. J. Headache pain 15, 14.

Hoffmann, J., Supronsinchai, W., Andreou, A.P., Summ, O., Akerman, S., and Goadsby, P.J. (2012). Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system. pain 153, 2226–2232.

Kazemi, H., Rahgozar, M., Speckmann, E.-J., and Gorji, A. (2012). Effect of cannabinoid receptor activation on spreading depression. Iran. J. Basic Med. Sci. 15, 926–936.