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

Cephalalgia ◽  
2017 ◽  
Vol 37 (8) ◽  
pp. 780-794 ◽  
Author(s):  
Jennifer Y Xie ◽  
Milena De Felice ◽  
Caroline M Kopruszinski ◽  
Nathan Eyde ◽  
Justin LaVigne ◽  
...  
Keyword(s):  
Environmental Stress ◽  
Stress Responses ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Endogenous Opioid Peptide ◽  
Opioid Receptor Antagonists ◽  
Cephalic Pain ◽  
The Right

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.

scholarly journals Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats

2019 ◽  
Author(s):  
Sarah Page ◽  
Maria M Mavrikaki ◽  
Tania Lintz ◽  
Daniel Puttick ◽  
Edward Roberts ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Time Course ◽  
Kappa Opioid Receptor ◽  
Tail Flick ◽  
Receptor Antagonists ◽  
Kappa Opioid ◽  
Duration Of Action ◽  
Opioid Receptor Antagonists ◽  
Opioid Receptor Agonists ◽  
Self Stimulation

Abstract Background New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. Methods We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). Results In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. Conclusions These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

scholarly journals Discovery ofN-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

2013 ◽  
Vol 56 (11) ◽  
pp. 4551-4567 ◽  
Author(s):  
Chad M. Kormos ◽  
Chunyang Jin ◽  
Juan Pablo Cueva ◽  
Scott P. Runyon ◽  
James B. Thomas ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Receptor Antagonists ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonists

scholarly journals Alcohol Drinking Alters Stress Response to Predator Odor via Extended Amygdala Kappa Opioid Receptor Signaling in Male Mice

2019 ◽  
Author(s):  
Lara S. Hwa ◽  
Sofia Neira ◽  
Meghan E. Flanigan ◽  
Christina M. Stanhope ◽  
Melanie M. Pina ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Stress Responses ◽  
Alcohol Drinking ◽  
Kappa Opioid Receptor ◽  
Predator Odor ◽  
Stria Terminalis ◽  
Receptor Signaling ◽  
Kappa Opioid ◽  
Bed Nucleus ◽  
Heavy Alcohol

AbstractMaladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST compared to drinking or stress alone. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal from heavy drinking. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.Impact StatementHeavy alcohol drinking primes dynorphin / kappa opioid systems in the bed nucleus of the stria terminalis to alter stress responses in mice.

scholarly journals Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

2020 ◽  
Author(s):  
Elyssa B. Margolis ◽  
Tanya L. Wallace ◽  
Lori Jean Van Orden ◽  
William J. Martin
Keyword(s):  
Opioid Receptor ◽  
Therapeutic Potential ◽  
Outward Current ◽  
Complete Recovery ◽  
Kappa Opioid Receptor ◽  
Dopamine Neurons ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonists ◽  
Neurobehavioral Disorders ◽  
Circuit Function

AbstractActivation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively). JNJ-67953964 showed an IC50 of 0.3 ± 1.3 nM. PF-04455242 (IC50 = 19.6 ± 16 nM) exhibited partial antagonist activity (∼60% maximal blockade). In 50% of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within disorder-relevant circuits implicated in neurobehavioral disorders.

Kappa opioid receptor antagonists

Peptides 1994 ◽  
1995 ◽  
pp. 607-608
Author(s):  
G. Orosz ◽  
A. Z. Rónai ◽  
E. Kátay ◽  
K. Medzihradszky
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Receptor Antagonists ◽  
Kappa Opioid ◽  
Opioid Receptor Antagonists
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