Objective
To systemically review preclinical studies investigating the implication of prolactin signaling in headache and migraine pathophysiology.
Background
The features of migraine attacks, including characteristics, duration, frequency, and prevalence, are sexâdependent with variability across a lifetime, indicating the involvement of the hypothalamusâpituitaryâgonadal axis. Prolactin is a key regulator of this axis, and a new line of evidence implicates prolactin signaling in sexârelated differences in pain perception.
Methods
In this systematic review, we searched PubMed and EMBASE for the terms prolactin, hyperprolactinemia, macroprolactinemia, hypoprolactinemia, migraine, headache, head pain, and trigeminal pain pathway to find preclinical studies investigating prolactin signaling in headache and migraine. Two reviewers independently screened 841 articles for population, intervention, comparison, outcome, and study design. Studies were restricted to the English language and were excluded if they had a nonexperimental methodology.
Results
Of a total of 15 preclinical articles selected, 11 were both ex vivo and in vivo, 3 were ex vivo, and 1 was an in vivo study. The main findings were that prolactin receptors are distributed in the trigeminal pain pathway, and prolactin induced migraineâlike behavior in rodents. Moreover, prolactin signaling has a crucial role in calcitonin geneârelated peptide (CGRP) release, a key molecule in migraine pathogenesis, and prolactin gene deletion attenuated CGRPâinduced migraineâlike behavior.
Conclusion
Preclinical data indicate a key role of prolactin and its receptors in mechanisms causing migraine. Further randomized and placeboâcontrolled clinical studies targeting prolactin signaling are needed to further clarify the influences of prolactin in migraineâattack initiation.