NOP receptor agonist attenuates nitroglycerin-induced migraine-like symptoms in mice

Neuropharmacology. 2020 Jun 15;170:108029. doi: 10.1016/j.neuropharm.2020.108029. Epub 2020 Mar 6.


Migraine is an extraordinarily prevalent and disabling headache disorder that affects one billion people worldwide. Throbbing pain is one of several migraine symptoms including sensitivity to light (photophobia), sometimes to sounds, smell and touch. The basic mechanisms underlying migraine remain inadequately understood, and current treatments (with triptans being the primary standard of care) are not well tolerated by some patients. NOP (Nociceptin OPioid) receptors, the fourth member of the opioid receptor family, are expressed in the brain and periphery with particularly high expression known to be in trigeminal ganglia (TG). The aim of our study was to further explore the involvement of the NOP receptor system in migraine. To this end, we used immunohistochemistry to examine NOP receptor distribution in TG and trigeminal nucleus caudalus (TNC) in mice, including colocalization with specific cellular markers, and used nitroglycerin (NTG) models of migraine to assess the influence of the selective NOP receptor agonist, Ro 64-6198, on NTG-induced pain (sensitivity of paw and head using von Frey filaments) and photophobia in mice. Our immunohistochemical studies with NOP-eGFP knock-in mice indicate that NOP receptors are on the majority of neurons in the TG and are also very highly expressed in the TNC. In addition, Ro 64-6198 can dose dependently block NTG-induced paw and head allodynia, an effect that is blocked by the NOP antagonist, SB-612111. Moreover, Ro 64-6198, can decrease NTG-induced light sensitivity in mice. These results suggest that NOP receptor agonists should be futher explored as treatment for migraine symptoms. This article is part of the special issue on Neuropeptides.

Keywords: Cephalic pain; Glyceryl trinitrate; NOP receptor; Nitroglycerine; Ro 64-6198; Trigeminal ganglia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Migraine Disorders / chemically induced*
  • Migraine Disorders / drug therapy*
  • Migraine Disorders / metabolism
  • Nitroglycerin / toxicity*
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Spiro Compounds / pharmacology
  • Spiro Compounds / therapeutic use*
  • Trigeminal Nuclei / drug effects*
  • Trigeminal Nuclei / metabolism


  • Imidazoles
  • Receptors, Opioid
  • Ro 64-6198
  • Spiro Compounds
  • nociceptin receptor
  • Nitroglycerin