Author: Andrew F Russo

Sex dependent sensitivity to CGRP

Recent studies reported by Dr Greg Dussor (University of Texas, Dallas) at the 2017 American Headache Society meeting in Boston, USA, have opened up an exciting new perspective on CGRP actions. Dr Dussor’s unexpected finding is that CGRP can directly stimulate the dura of female, but not male, rodents to cause periorbital hypersensitivity.

First a little background. It has been speculated for decades that release of CGRP from trigeminal fibres in the meninges causes neurogenic inflammation that sensitises the trigeminal nerve in migraine.1,2 However, while CGRP is clearly the most prevalent neuropeptide and potent vasodilator in the trigeminovasculature (McCulloch et al., 1986),3 there has been a dearth of evidence that CGRP could sensitise meningeal trigeminal nerve fibres. Indeed, prior studies had failed to find any effect of dural administration of CGRP or the receptor antagonist olcegepant on neural activity.4,5 This has been a puzzling finding given other data indicating that CGRP likely plays both peripheral and central roles in migraine, not the least of which is the efficacy of CGRP-blocking antibodies in clinical trials.6-8 Now, with 20-20 hindsight, it appears that the reason for those prior negative results is that those preclinical studies were done only on male, not female, rats.

In the current studies, Dussor and colleagues measured a behavioural output of periorbital hypersensitivity following application of CGRP on to the dura of both male and female mice and rats. Strikingly, CGRP caused cutaneous hypersensitivity to von Frey filaments only in female rodents, not in males. In addition, CGRP on the dura was able to prime female rodents to dural application of a pH 7.0 solution, which ordinarily does not cause a response. This observation is reminiscent of their prior studies showing priming with interleukin 6 (IL6),9 except that IL-6 worked in both male and female rodents.

While the downstream signalling mechanism that activates the nociceptor in response to CGRP remains to be determined, the upstream mechanism involves a second peptide, prolactin. Co-administration of a prolactin receptor antagonist (delta prolactin fragment) on to the dura blocked the CGRP response. This demonstrated that the prolactin receptor is required for CGRP effects in female rodents, and female-specific expression of the prolactin receptor on trigeminal nerve fibres seems likely to underlie the sex-specificity of CGRP activation.

Thus, the CGRP field has taken a quantum leap forward. A connection between two peptides has been revealed that nobody had ever suspected. This crosstalk between peptides illustrates how a network of neuropeptides may contribute to migraine.10 And, most importantly, this peptide crosstalk provides a molecular clue to the enigmatic sex bias of migraine.

Professor Andrew F Russo, PhD
Department of Molecular Physiology and Biophysics, University of Iowa
, Iowa City, USA

*Dr Russo is Dr Harold A. Myers Professor, Department of Molecular Physiology and Biophysics, University of Iowa, USA

References

  1. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1998;23:193-6.
  2. Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43:S16-20.
  3. McCulloch J, Uddman R, Kingman TA, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 1986;83:5731-5.
  4. Fischer MJ, Koulchitsky S, Messlinger K. The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci 2005;25:5877-83.
  5. Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 2005;58:698-705.
  6. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Ann Rev Pharmacol Toxicol 2015 55:533-52.
  7. Schuster NM, Rapoport AM. New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 2016;12:635-50
  8. Mitsikostas DD, Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol 2017;30:272-80.
  9. Burgos-Vega CC, Quigley LD, Avona A, et al. Dural stimulation in rats causes brain-derived neurotrophic factor-dependent priming to subthreshold stimuli including a migraine trigger. Pain 2016;157:2722-30.
  10. Russo AF. Overview of neuropeptides: awakening the senses? Headache 2017;57 Suppl 2:37-46.