Arizona Health Sciences

Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential.

TitleGenetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential.
Publication TypeJournal Article
Year of Publication2017
AuthorsSandweiss AJ, McIntosh MI, Moutal A, Davidson-Knapp R, Hu J, Giri AK, Yamamoto T, Hruby VJ, Khanna R, Largent-Milnes TM, Vanderah TW
JournalMol Psychiatry
Date Published2017 May 09
ISSN1476-5578
Abstract

Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a μ/δ opioid agonist and NK1R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist-NK1R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.Molecular Psychiatry advance online publication, 9 May 2017; doi:10.1038/mp.2017.102.

DOI10.1038/mp.2017.102
Alternate JournalMol. Psychiatry
PubMed ID28485408
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Rajesh Khanna, Ph.D.
Tally Largent-Milnes, Ph.D.
Todd Vanderah, Ph.D.