Preclinical pearls offer insights into migraine sex differences and sensory thresholds

Speaking at #MTIS2020, Professor Frank Porreca, University of Arizona, USA, identified recent pearls of preclinical research that provide new understanding of mechanisms that contribute to migraine, generate new mechanistic hypotheses, and help to prioritise targets for novel therapeutic interventions. Of particular interest were mechanistic insights into sex differences in migraine and a new hypothesis of migraine as a sensory threshold disease.

Sexual dimorphism in migraine

Many reasons likely exist for the higher prevalence of migraine in women. One new concept is of fundamental differences between male and female nocioceptors with differences at both the transcript and protein levels that contribute to migraine attacks. How this happens is an area of ongoing research.

Both the calcitonin gene-related peptide (CGRP) and prolactin systems show sexual dimorphism in migraine models. Supradural administration of CGRP produces female-specific migraine-like pain behaviours in rodent migraine models. Application of CGRP produces a facial grimace response in female mice that is not observed in male mice and could be relevant to the higher prevalence of migraine in females.1

Basic differences between women and men exist in mechanisms that promote pain in migraine

Prolactin is a neuroendocrine substance associated with milk production that has more than 300 identified biological effects. Emerging evidence suggest a role for prolactin in female-selective pain. Prolactin induces female predominant increased sensitivity to pain responses in inflammatory models.2 Further, there is evidence that a prolactin receptor (long isoform) regulates nociceptor sensitisation and opioid-induced hyperalgesia selectively in females.3 These findings have clinical implications for the discovery of new therapies for pain control in women.4


Migraine as a sensory threshold disease

Migraine encompasses a broad spectrum of sensory symptoms beyond headache -- including sensory phobias, cognitive and mood changes and allodynia -- which indicates altered sensitivity to sensory input. A recent hypothesis by Peng and May suggests that migraine can be understood as a sensory threshold disease.5 People with migraine exhibit lower sensory thresholds with increasing vulnerability to pain episodes. Intrinsic oscillations occur in sensory thresholds over time, and during a migraine attack the sensory threshold is decreased making the production of migraine symptoms more likely including the activation of nociceptors to produce pain.

Migraine may be considered as a sensory threshold disorder

The frequency of migraine is predictive of migraine chronification. A vulnerability to normally subthreshold stimulus may result from a priming effect of previous events that induce amplification, i.e., peripheral and central sensitisation such that a normally innocuous second hit becomes a noxious trigger. Hyperalgesic priming models with a variety of different stimuli can be used to give insights into mechanisms underlying the vulnerability to normally subthreshold stimuli, and also medication overuse headache (MOH). Preclinical models suggest a differential medication overuse risk profile for different classes of drugs that has implications for reducing the burden of MOH.6-8

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


  1. Avona A, et al. J Neuroscience 2019;39(22):4323-31.
  2. Patil M iScience 2019;20:449-65
  3. Chen Y, et al. Science Transl Med. 2020;12(529):eaay7550
  4. Chen Y, et al. Trends Neurosci 2020;43(8):635-48
  5. Peng KP & May A. Pain 2019; 160(9):1494-1501
  6. Bonnet, Nat Commun 2019;10(1):4253.
  7. Saengjaroentham C, et al. Brain 2020;143(9):2681-88
  8. Rau JC, Navratilova E, et al. Cephalalgia 2020;40(9):903-12