Impact of chronic migraine attacks and their severity on the endogenous μ-opioid neurotransmission in the limbic system

Hassan Jassar; Thiago D. Nascimento; Niko Kaciroti; Marcos F. DosSantos; Theodora Danciu; Robert A. Koeppe; Yolanda R. Smith; Marcelo E. Bigal; Frank Porreca; Kenneth L. Casey; Jon-Kar Zubieta; Alexandre F. DaSilva

NeuroImage: Clinical (Jan 2019)

Impact of chronic migraine attacks and their severity on the endogenous μ-opioid neurotransmission in the limbic system

Hassan Jassar,
Thiago D. Nascimento,
Niko Kaciroti,
Marcos F. DosSantos,
Theodora Danciu,
Robert A. Koeppe,
Yolanda R. Smith,
Marcelo E. Bigal,
Frank Porreca,
Kenneth L. Casey,
Jon-Kar Zubieta,
Alexandre F. DaSilva

Affiliations

Hassan Jassar: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
Thiago D. Nascimento: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
Niko Kaciroti: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA; Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48104, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
Marcos F. DosSantos: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
Theodora Danciu: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48104, USA
Robert A. Koeppe: PET Physics Section, Division of Nuclear Medicine, Radiology Department, University of Michigan, Ann Arbor, MI 48109-5030, USA
Yolanda R. Smith: Department of Obstetrics and Gynecology, Medical School, University of Michigan, Ann Arbor, MI 48109-0276, USA
Marcelo E. Bigal: Ventus Therapeutics, Montreal, Canada
Frank Porreca: Department of Pharmacology, University of Arizona, Tucson, AZ 85724-5050, USA
Kenneth L. Casey: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
Jon-Kar Zubieta: Department of Psychiatry and Behavioral Heal, Stony Brook University, Stony Brook, NY 11794, USA
Alexandre F. DaSilva: Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48104, USA; Corresponding author at: Headache & Orofacial Pain Effort Lab (H.O.P.E.), Biologic & Materials Sciences Department School of Denstistry, University of Michigan, 1011 N University Ave, room 1014A, Ann Arbor, MI 48109-1078, USA.

Journal volume & issue: Vol. 23

Abstract

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Objective: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous μ-opioid neurotransmission. Background: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. Methods: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the μ-opioid receptor availability and the clinical data. Results: μOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower μOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower μOR BPND values indicate either a decrease in μOR concentration or an increase in endogenous μ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in μOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). Conclusions: Increased endogenous μ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous μ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313 Keywords: Migraine, PET, Opioid, Central pain, MRI, Thermal pain threshold

Published in NeuroImage: Clinical

ISSN: 2213-1582 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General): Computer applications to medicine. Medical informatics; Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system
Website: http://www.journals.elsevier.com/neuroimage-clinical/

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