δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice.

Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models.
Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation.
NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies.
These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder.
AuthorsAmynah A Pradhan, Monique L Smith, Jekaterina Zyuzin, Andrew Charles
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 9 Pg. 2375-84 (May 2014) ISSN: 1476-5381 [Electronic] England
PMID24467301 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright© 2014 The British Pharmacological Society.
Chemical References
  • Benzamides
  • Piperazines
  • Receptors, Opioid, delta
  • 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
  • Nitroglycerin
  • Animals
  • Avoidance Learning (drug effects, physiology)
  • Benzamides (pharmacology, therapeutic use)
  • Cortical Spreading Depression (drug effects, physiology)
  • Female
  • Hyperalgesia (drug therapy, physiopathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Migraine Disorders (drug therapy, physiopathology)
  • Nitroglycerin (toxicity)
  • Piperazines (pharmacology, therapeutic use)
  • Receptors, Opioid, delta (agonists, physiology)

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