A Novel Target for Migraine Prevention Through Modulation of Stress Receptors
By Dara Jamieson, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Jamieson reports she is a consultant for Roche.
SYNOPSIS: Kappa opioid receptors (KORs) modulate response to stress, a common migraine trigger, so KOR blockade may be a novel preventive treatment for migraine as well as other stress-related diseases.
SOURCE: Xie JY, De Felice M, Kopruszinski CM, et al. Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention. Cephalalgia 2017; Jan 1:333102417702120. doi: 10.1177/0333102417702120. [Epub ahead of print].
Stress, or relief from stress, is one of the most commonly reported migraine triggers, but the mechanism underlying the correlation is poorly understood. Kappa opioid receptors (KORs), present in multiple structures in the cerebrum and brainstem, are involved in the modulation of reward-seeking behavior, mood disorders (including anxiety and depression), and cognitive functioning. Dynorphin, an endogenous opioid peptide that is a potent modulator of pain response and stress behavior, interacts with KORs. This study used an “injury-free” rodent model to test the preventive effect of KOR blockade on stress-induced cephalic pain. Excessively frequent use of an acute pain medication for migraine (i.e., a triptan) in rats was used to develop a medication overuse headache (MOH) model that simulated an increased frequency of migraine attacks. Using surgically implanted minipumps, rats were primed with sumatriptan, causing a state of “latent sensitization” characterized by the presence of multiple known migraine markers, including increased trigeminal ganglion cells that expressed the migraine-related neuropeptide calcitonin gene-related peptide (CGRP), increased sensitivity to migraine triggers, stress-induced cutaneous allodynia, and increased levels of CGRP detected in jugular blood. The role of CGRP blockade in migraine treatment is well known since stress-induced cephalic (i.e., periorbital) and extracephalic (i.e., hind-paw) allodynia in rats with prior exposure to sumatriptan is blocked by CGRP antibodies. After priming with sumatriptan for seven days, followed by a 14-day, drug-free period, the rats then underwent two days of an hour-long exposure to bright light as an environmental stressor used to trigger a migraine response. Markers of migraine in the rat (i.e., allodynia, tail-flick test, and intrajugular CGRP), in addition to neurochemical (plasma CGRP release, dynorphin, KOR phosphorylation) and immunohistochemical (KOR phosphorylation) markers of environmental stress, were assessed in the presence or absence of systemic or intra-amygdala blockade of KOR signaling. The stressor of bright light exposure resulted in a significant elevation of dynorphin levels and in the activation and phosphorylation of the KOR receptors in the bilateral central nuclei of the amygdala (CeA) of sumatriptan-primed rats, as compared to saline-primed rats. Long-acting (nor-binaltorphimine) or short-acting (CYM51317) KOR antagonists were given systemically either during the sumatriptan priming period or immediately before the bright-light stress challenge. Systemic KOR blockade prevented both the migraine physiological markers of stress-induced allodynia and the increased plasma CGRP. Oral administration of CYM51317 blocked stress-induced periorbital and hind-paw cutaneous allodynia. The long-acting KOR antagonist was injected into the right or the left CeA with a lateralized therapeutic effect. Nor-binaltorphimine injection in the right, but not in the left, CeA blocked bright light stress-induced cutaneous allodynia, regardless of whether extracerebral allodynic thresholds were measured in the right or the left hind-paws.
Xie et al developed a sumatriptan-primed rat model, overlapping migraine and triptan-associated MOH, and used the model to test the hypothesis that modulation of KORs could mediate the migraine markers of stress-induced cutaneous allodynia and increased plasma CGRP. They discovered a lateralized effect of the antagonism of the KOR circuit as blockade of KOR signaling in the right, but not left, CeA-inhibited, stress-induced cephalic and extracephalic allodynia. The authors suggested that this dynorphin/KOR signaling pathway in the right CeA may modulate stress responses, including migraine triggering. A prior observation that the right, but not the left, amygdala appears to be activated in pain states may explain the laterality in this stress-mediating circuit. There are restrictions to this model that it does not ideally replicate migraines, as the sumatriptan-priming trigger also mirrors MOH. However, the response to the bright light stress stimulus appeared to produce physiological stress and migraine. Migraine is too complicated to be prevented by a single mechanism or circuit blockade, as evidenced by the many different categories of preventive medications (e.g., seizure, blood pressure, and antidepressant medications) and the multitude of techniques used for prevention with relatively disappointing success. Currently, antibodies to CRGP are being evaluated in human clinical trials as a parenteral preventive migraine medication. Whether prevention of migraine in the future uses a cocktail of many medications or a precision medicine approach predicting the individual patients response to a particular treatment, more effective medications are necessary. Exploration of new therapeutic targets for the acute or preventive treatment of migraine is crucial. Based on current animal models, KOR antagonists, especially if orally effective, may represent an ideal novel class of medications for migraine prevention. Only further investigation with animal models and human clinical trials will determine whether the KOR circuit is a viable therapeutic target for migraine prevention or just an interesting mirage.
Kappa opioid receptors (KORs) modulate response to stress, a common migraine trigger, so KOR blockade may be a novel preventive treatment for migraine as well as other stress-related diseases.
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