# Investigation and Modulation of the Central Mu-Opioid Mechanism in Migraine (in vivo)

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $633,966

## Abstract

Abstract
Episodic migraine (EM) sufferers can develop a progressive state of their disease with more than 15
attacks per month. This state is referred to as chronic migraine (CM), a disorder that significantly impacts
a patient’s daily life with more frequent sensory and emotional suffering and potential for substance abuse,
especially opiates. Built on rigorous scientific data from our initial R01 on EM, our next goal is to expand
the investigation and modulation of endogenous µ-opioid neurotransmission to more complex CM patients.
We will investigate how this µ-opioid dysfunction impacts other crucial central neurotransmitters (D2/D3
dopamine) and systems (sensory and reward), leading to a worsening of pain/emotional suffering. The
endogenous μ-opioid and D2/D3 dopamine are arguably two of the most crucial molecular mechanisms
responsible for pain and emotional regulation; they are the primary targets for the action of the most potent
exogenous analgesic and psychotic drugs available. Our initial EM study using PET with [11C] carfentanil,
a selective μ-opioid receptor (μOR) radiotracer, has demonstrated a decrease in μOR availability (non-
displaceable binding potential [BPND]) in the brains of EM patients during attacks. Notably, our preliminary
data shows that with the progression to CM, there is a further increase in μ-opioid (peptide) release in the
amygdala that correlates with attack severity and allodynia. The EM attacks were also accompanied by
an increase in DA D2/D3 BPND measured by [11C]raclopride in the basal ganglia, and the longer the
history and recurrence of attacks, the lower the ictal endogenous DA release. We were the first group to
demonstrate that a non-invasive neuromodulatory method targeting the primary motor cortex (M1),
transcranial direct current stimulation (tDCS), can immediately modulate the µOR system. We further
developed a M1 high-definition tDCS montage (M11 HD-tDCS) that significantly reversed μOR BPND in
more frequent EM patients and reduced CM-specific clinical endpoints (e.g., moderate/severe days per
month). Built on solid and persuasive data from our prior R01 in EM, our renewal project expands its
relevance by directly evaluating and modulating crucial neurotransmitters, systems/symptoms associated
with pain suffering in the most resilient migraine, CM: Aim1. Demonstrate with PET that patients who
progress to CM display higher dysfunction than EM in endogenous μ-opioid and D2/D3 dopamine
neurotransmission that correlates with their attack frequency and severe pain suffering; Aim2. Evaluate
the impact of CM on the neuronal systems’ connectivity and BOLD signal variability and their association
with dysfunction in neurotransmission and worsening of attacks; Aim3. Investigate whether 20 daily
lab/home-based unilateral and bilateral M11-2 HD-tDCS modulation have different effects on the molecular,
system, and clinical states in CM patients.

## Key facts

- **NIH application ID:** 10375812
- **Project number:** 2R01NS094413-06A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ALEXANDRE DASILVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $633,966
- **Award type:** 2
- **Project period:** 2015-09-30 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375812

## Citation

> US National Institutes of Health, RePORTER application 10375812, Investigation and Modulation of the Central Mu-Opioid Mechanism in Migraine (in vivo) (2R01NS094413-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375812. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*