Background Stress is the most commonly reported
migraine trigger.
Dynorphin, an endogenous
opioid peptide acting preferentially at
kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic
pain with features of
migraine and
medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic
pain. Methods Following
sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic
allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during
migraine.
Nor-binaltorphimine (
nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during
sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced
allodynia was determined by administration of
nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced
allodynia and increased plasma CGRP. Stress increased
dynorphin content and phosphorylated KOR in both the left and right CeA in
sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic
allodynia as well as extracephalic
allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced
allodynia selectively in
sumatriptan-primed rats. Both stress and U69,593-induced
allodynia were prevented by right CeA
U0126, a
mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous
allodynia and increased plasma CGRP in an injury-free model of functional cephalic
pain with features of
migraine and
medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive
therapeutics for
migraine.