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Dopaminergic Regulation of Reward System Connectivity Underpins Pain and Emotional Suffering in Migraine

Authors Kim DJ, Jassar H, Lim M, Nascimento TD, DaSilva AF

Received 10 December 2020

Accepted for publication 17 February 2021

Published 9 March 2021 Volume 2021:14 Pages 631—643

DOI https://doi.org/10.2147/JPR.S296540

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Michael Schatman


Dajung J Kim, Hassan Jassar, Manyoel Lim, Thiago D Nascimento, Alexandre F DaSilva

Headache and Orofacial Pain Effort (H.O.P.E.), Biologic and Material Sciences & Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA

Correspondence: Alexandre F DaSilva
Headache and Orofacial Pain Effort Lab (H.O.P.E.), Biologic and Material Sciences & Prosthodontics, University of Michigan School of Dentistry, 1011 N University Avenue, Ann Arbor, MI, 48109, USA
Tel +1 734 615 3807
Fax +1 734 763 3453
Email [email protected]

Purpose: It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues.
Patients and Methods: We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [11C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed.
Results: Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS).
Conclusion: Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.

Keywords: dopamine, nucleus accumbens, functional connectivity, migraine, reward system, craniofacial pain

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