Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention

Abstract

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.

A Phase‐by‐Phase Review of Migraine Pathophysiology

“…Sympathetic outflow into the meninges involving norepinephrine release has been shown in preclinical models to contribute to pronociceptive signaling through actions on dural afferents and dural fibroblasts . Activation of the kappa‐opioid system in response to stress‐induced corticotropin‐releasing hormone and dynorphin release may also play a role in stress‐induced migraine . These physiological mechanisms, involving networks which project to preganglionic parasympathetic neurons in the superior salivatory nucleus, may result in peripheral nociceptor activation through the release of neuropeptide transmitters contained within parasympathetic efferents that innervate the meninges and meningeal blood vessels (Fig.…”

Emerging Treatment Targets for Migraine and Other Headaches

“…Rats were treated with chronic sumatriptan to model medication overuse headache, which in turn made them hypersensitive to a bright light stress cue. Stress produced an increase in plasma CGRP and cephalic and peripheral allodynia, which was blocked by systemic injection of 2 different κ antagonists . Further, this hypersensitivity appears to be mediated through an upregulation of dynorphin in the amygdala, and intra‐amygdala injection of κ antagonists were also anti‐allodynic .…”

“…Stress has frequently been cited as the most common migraine trigger, but despite its prevalence, the pathophysiology of how stress actually triggers migraine is unclear. Xie et al used a preclinical model of stress‐induced headache to examine the effect of κ antagonists on cephalic pain . Rats were treated with chronic sumatriptan to model medication overuse headache, which in turn made them hypersensitive to a bright light stress cue.…”

“…Stress produced an increase in plasma CGRP and cephalic and peripheral allodynia, which was blocked by systemic injection of 2 different κ antagonists . Further, this hypersensitivity appears to be mediated through an upregulation of dynorphin in the amygdala, and intra‐amygdala injection of κ antagonists were also anti‐allodynic . The novel kappa opioid receptor antagonist, CERC‐501 (formerly known as LY2456302) is in clinical trials for mood and anxiety disorders and was shown to be safe and well‐tolerated (Table ).…”

“…Xie et al used a preclinical model of stress-induced headache to examine the effect of κ antagonists on cephalic pain. 48 Rats were treated with chronic sumatriptan to model medication overuse headache, which in turn made them hypersensitive to a bright light stress cue. Stress produced an increase in plasma CGRP and cephalic and peripheral allodynia, which was blocked by systemic injection of 2 different κ antagonists.…”