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

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 posit

SUBMITTER: Sandweiss AJ 

PROVIDER: S-EPMC5680162 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature