Biochemical Changes in Endocannabinoid System are Expressed in Platelets of Female but not Male Migraineurs

Abstract

The endogenous cannabinoid anandamide (AEA) plays important roles in modulating pain. Head pain is an almost universal human experience, yet primary headache disorders, such as migraine without aura (MoA) or episodic tension-type headache (ETTH), can represent a serious threat to well-being when frequent and disabling. We assessed the discriminating role of endocannabinoids among patients with ETTH or MoA, and control subjects. We measured the activity of AEA hydrolase and AEA transporter, and the level of cannabinoid receptors in peripheral platelets from MoA, ETTH and healthy controls. Sixty-nine headache patients and 36 controls were selected. Diagnosis of headache type was made according to the International Headache Society criteria. We observed significant sex differences concerning AEA membrane transporter and fatty acid amide hydrolase activity in all groups. An increase in the activity of AEA hydrolase and AEA transporter was found in female but not male migraineurs. Cannabinoid receptors were the same in all groups. Here we show that the endocannabinoid system in human platelets is altered in female but not male migraneurs. Our results suggest that in migraineur women an increased AEA degradation by platelets, and hence a reduced concentration of AEA in blood, might reduce the pain threshold and possibly explain the prevalence of migraine in women. The involvement of the endocannabinoid system in migraine is new and broadens our knowledge of this widespread and multifactorial disease.

Medical marijuana in neurology

“…These results suggest that impairment of the endogenous cannabinoid system may result in increased calcitonin gene-related peptide and no production, allowing for activation of the trigeminovascular system, subsequent sensitization and potential for 'chronification' of pain [25]. Evidence suggests that there is increased degradation of AEA in platelets of female (but not male) migraineurs, suggesting that the decreased level of circulating AEA may contribute to a reduced pain threshold [26]. PET has also demonstrated increased CB1 receptor binding in women with migraine, most pronounced in the anterior cingulate, mesial temporal and prefrontal and superior frontal cortices, areas well known to be involved in the affective component of pain [27].…”

Cannabinoid (CB1) Receptor Activation Inhibits Trigeminovascular Neurons

“…It has been suggested based on historical accounts that cannabinoid receptor activation may have antimigraine effects (Russo, 1998). Female migraineurs have increased degradation of anandamide in platelets compared with controls, consistent with lowered endocannabinoid tone (Cupini et al, 2006). Indeed cannabinoid receptor activation has been reported to alleviate headache in idiopathic intracranial hypertension (Evans and Ramadan, 2004).…”

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

“…Specifically, several studies have demonstrated the ability of estradiol exposure to lead to activation of ERK (Filardo, et al, 2000, Liverman, et al, 2009), increases in sodium gated channel activity (Kow, et al, 2006), as well as increased mRNA levels of FAAH (Cupini, et al, 2006, Greco, et al, 2010, Grimaldi, et al, 2012), the major metabolic regulator of anandamide, an endogenously produced cannabinoid. Furthermore, studies have shown that estradiol treatment leads to elevation in release of CGRP in the dura mater and trigeminal ganglion (Gupta, et al, 2007, Stucky, et al, 2011), key to vasodilation which plays a role in migraine onset and progression (Bigal and Walter, 2014, Goadsby, et al, 1990, Raddant and Russo, 2011).…”