Opioid Control of the Hypothalamus-Pituitary-Adrenal Axis Cyclically Fails in Menstrual Migraine

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Abstract
To assess the biological correlates of the precipitation of migraine attacks in the perimenstrual period, plasma b-endorphin (b-EP) and cortisol responses to naloxone (8 mg iv) and corticotropin releasing hormone (100 μg iv) were evaluated in both the follicular phase and the premenstrual period in 7 patients suffering from menstrual migraine and in 7 healthy, asymptomatic control volunteers. In the controls, naloxone evoked a significant release of both b-EP (F = 5.86, p < 0.002) and cortisol (F = 4.43, p < 0.008), independently of the menstrual cycle phase (F = 0.31 and 1.04, for b-EP and cortisol, respectively). Menstrual migraine patients, on the other hand, showed a significant hormone response only in the follicular phase, not in the premenstrual period. Corticotropin releasing hormone significantly increased b-EP and cortisol in both the controls and the menstrual migraine patients, independently of the menstrual cycle phase. In both the naloxone and corticotropin releasing hormone testings, the basal b-EP levels measured in the premenstrual period were lower than those observed in the follicular phase (p < 0.02). These data demonstrate a cyclical, premenstrual dysfunction of the hypothalamic control exerted by opioids on the hypothalamus-pituitary-adrenal axis. Impairment of this fundamental adaptive mechanism (involved in stress responses and in pain control) could establish a causal relationship between menstrual-related migraine attacks and premenstrual opioid hyposensitivity.