Genetic and pharmacological antagonism of NK 1 receptor prevents opiate abuse potential

Mol Psychiatry. 2018 Aug;23(8):1745-1755. doi: 10.1038/mp.2017.102. Epub 2017 May 9.

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.

MeSH terms

  • Acute Pain / drug therapy
  • Acute Pain / metabolism
  • Analgesics / pharmacology
  • Animals
  • CRISPR-Cas Systems
  • Disease Models, Animal
  • Dopamine / metabolism
  • Escherichia coli
  • Gene Knockdown Techniques
  • Male
  • Mice, Inbred ICR
  • Morphine / pharmacology
  • Neurokinin-1 Receptor Antagonists / pharmacology*
  • Nociceptive Pain / drug therapy
  • Nociceptive Pain / metabolism
  • Opioid-Related Disorders / genetics
  • Opioid-Related Disorders / metabolism
  • Opioid-Related Disorders / prevention & control*
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-1 / genetics
  • Receptors, Neurokinin-1 / metabolism*
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism
  • Reward
  • Substance P / metabolism
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism

Substances

  • Analgesics
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Substance P
  • Morphine
  • Dopamine