Over 2 million people in the United States suffer from prescription drug abuse of opioid analgesics. One of the leading causes for the prescription of opioids is for the treatment of trigeminovascular pain (migraine); and the majority of these treatments target the opioid receptor. These agonists have poor efficacy for trigeminovascular pain, contribute to the progression of pain from an episodic to chronic state, and serve as an entry point to prescription drug abuse. Drugs that selectively activate the ? opioid receptor have distinct properties which make them promising alternatives to currently used -based therapies. We have recently developed a novel model of trigeminovascular pain, using the known human migraine trigger nitroglycerin (NTG). Chronic intermittent treatment with NTG results in acute and chronic hyperalgesia, which is inhibited by ? agonists. In addition, we have also shown that the ? agonist SNC80 can inhibit cortical spreading depression, a ?gold standard? model of aura associated with trigeminovascular pain. The continued development of ? agonists for migraine depends upon a better understanding of where and how ? agonists inhibit trigeminovascular pain and related symptoms. ? opioid receptors are expressed in several central and peripheral regions that are important in pain processing, and emotional modulation. Which ?ORs are anatomically important for regulating trigeminovascular pathophysiology is currently unknown. A goal of this proposal will be to determine the role of central vs. peripheral ? opioid receptors in the development and treatment of trigeminovascular pain. For this purpose, we will use novel conditional knockout (cKO) mice with ? opioid receptors deleted in specific central and peripheral regions. We will examine the effects of these specific knockouts in the NTG model of trigeminovascular pain and negative affect, and on cortical spreading depression. We will also explore the mechanism by which ? agonists inhibit trigeminovascular pain. The neuropeptide, calcitonin gene related peptide (CGRP) plays a pivotal role in the induction and maintenance of trigeminovascular pain, primarily through the peripheral afferents projecting from the trigeminal ganglia. A further aim of this proposal will be to determine the expression of ?ORs on CGRP-expressing ganglia, as well as changes in CGRP release, when animals are nave, in trigeminovascular pain, and chronically treated with ? agonists. Together, these studies will provide a deeper insight into how ?ORs affect trigeminovascular pain, thus enhancing the development of novel therapeutic compounds for this disorder.

Public Health Relevance

Migraine is a debilitating disorder that affects over 30 million people in the United States. Opioids are regularly used to treat this disorder, but often result in increased pain and drug dependence. Drugs that activate the delta opioid receptor are promising alternatives, and the goal of this proposal is to develop these compounds for the treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA040688-04
Application #
9710623
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Berton, Olivier Roland
Project Start
2016-08-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Ben Aissa, Manel; Tipton, Alycia F; Bertels, Zachariah et al. (2018) Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia 38:1471-1484
Pradhan, Amynah A; Bertels, Zachariah; Akerman, Simon (2018) Targeted Nitric Oxide Synthase Inhibitors for Migraine. Neurotherapeutics 15:391-401
Moye, Laura S; Pradhan, Amynah A A (2017) Animal Model of Chronic Migraine-Associated Pain. Curr Protoc Neurosci 80:9.60.1-9.60.9
Moye, Laura S; Pradhan, Amynah A (2017) From blast to bench: A translational mini-review of posttraumatic headache. J Neurosci Res 95:1347-1354
Cahill, Catherine M; Walwyn, Wendy; Taylor, Anna M W et al. (2016) Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation. Trends Pharmacol Sci 37:963-976