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

Jennifer Y. Xie, Milena De Felice, Caroline M. Kopruszinski, Nathan Eyde, Justin Lavigne, Bethany Remeniuk, Pablo Hernandez, Xu Yue, Naomi Goshima, Michael Ossipov, Tamara King, John M. Streicher, Edita Navratilova, David William Dodick, Hugh Rosen, Ed Roberts, Frank Porreca

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)780-794
Number of pages15
JournalCephalalgia
Volume37
Issue number8
DOIs
StatePublished - Jul 1 2017

Fingerprint

kappa Opioid Receptor
Narcotic Antagonists
Migraine Disorders
Hyperalgesia
Secondary Headache Disorders
Sumatriptan
Therapeutics
Headache
Dynorphins
Head
Opioid Peptides
Wounds and Injuries
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Amygdala
Neck

Keywords

  • amygdala
  • Kappa opioid receptor antagonists
  • migraine
  • prophylaxis
  • stress

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Xie, J. Y., De Felice, M., Kopruszinski, C. M., Eyde, N., Lavigne, J., Remeniuk, B., ... Porreca, F. (2017). Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention. Cephalalgia, 37(8), 780-794. https://doi.org/10.1177/0333102417702120

Kappa opioid receptor antagonists : A possible new class of therapeutics for migraine prevention. / Xie, Jennifer Y.; De Felice, Milena; Kopruszinski, Caroline M.; Eyde, Nathan; Lavigne, Justin; Remeniuk, Bethany; Hernandez, Pablo; Yue, Xu; Goshima, Naomi; Ossipov, Michael; King, Tamara; Streicher, John M.; Navratilova, Edita; Dodick, David William; Rosen, Hugh; Roberts, Ed; Porreca, Frank.

In: Cephalalgia, Vol. 37, No. 8, 01.07.2017, p. 780-794.

Research output: Contribution to journalArticle

Xie, JY, De Felice, M, Kopruszinski, CM, Eyde, N, Lavigne, J, Remeniuk, B, Hernandez, P, Yue, X, Goshima, N, Ossipov, M, King, T, Streicher, JM, Navratilova, E, Dodick, DW, Rosen, H, Roberts, E & Porreca, F 2017, 'Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention', Cephalalgia, vol. 37, no. 8, pp. 780-794. https://doi.org/10.1177/0333102417702120
Xie JY, De Felice M, Kopruszinski CM, Eyde N, Lavigne J, Remeniuk B et al. Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention. Cephalalgia. 2017 Jul 1;37(8):780-794. https://doi.org/10.1177/0333102417702120
Xie, Jennifer Y. ; De Felice, Milena ; Kopruszinski, Caroline M. ; Eyde, Nathan ; Lavigne, Justin ; Remeniuk, Bethany ; Hernandez, Pablo ; Yue, Xu ; Goshima, Naomi ; Ossipov, Michael ; King, Tamara ; Streicher, John M. ; Navratilova, Edita ; Dodick, David William ; Rosen, Hugh ; Roberts, Ed ; Porreca, Frank. / Kappa opioid receptor antagonists : A possible new class of therapeutics for migraine prevention. In: Cephalalgia. 2017 ; Vol. 37, No. 8. pp. 780-794.
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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.",
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AU - Eyde, Nathan

AU - Lavigne, Justin

AU - Remeniuk, Bethany

AU - Hernandez, Pablo

AU - Yue, Xu

AU - Goshima, Naomi

AU - Ossipov, Michael

AU - King, Tamara

AU - Streicher, John M.

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AU - Dodick, David William

AU - Rosen, Hugh

AU - Roberts, Ed

AU - Porreca, Frank

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N2 - 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.

AB - 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.

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