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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Semel Institute for Neuropsychiatry & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Headache Research and Treatment Program, Department of Neurology David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Shirley and Stefan Hatos Center for Neuropharmacology, UCLA, Los Angeles, CA, USA; Department of Psychiatry, University of Illinois at Chicago (UIC), Chicago, IL, USA.
Amynah A
AA
Pradhan
Monique L
ML
Smith
Jekaterina
J
Zyuzin
Andrew
A
Charles
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D005996:Nitroglycerin / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000502:physiology
D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D005996:Nitroglycerin
aura; chronic migraine; headache; hyperalgesia; negative affect; nitroglycerin