Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys

J Pain. 2009 May;10(5):509-16. doi: 10.1016/j.jpain.2008.11.006. Epub 2009 Feb 23.

Abstract

Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide for the NOP receptors. Depending on the doses, intrathecal administration of N/OFQ has dual actions (ie, hyperalgesia and antinociception) in rodents. However, the pharmacological profile of intrathecal N/OFQ is not fully known in primates. The aim of this study was to investigate behavioral effects of intrathecal N/OFQ over a wide dose range and to compare its effects with ligands known to produce hyperalgesia or antinociception in monkeys. Intrathecal N/OFQ from 1 fmol to 1 nmol did not produce any hyperalgesic or scratching responses. In contrast, intrathecal substance P 100 nmol produced hyperalgesia, and intrathecal DAMGO 10 nmol produced antinociception. At the dose range between 10 nmol and 1 micromol, intrathecal N/OFQ dose-dependently produced thermal antinociception against a noxious stimulus in 2 intensities. More importantly, N/OFQ in combined with intrathecal morphine dose-dependently potentiated morphine-induced antinociception without inhibiting morphine-induced itch/scratching. Taken together, this study is the first to provide a unique functional profile of intrathecal N/OFQ over a wide dose range in primates. Intrathecal N/OFQ produces thermal antinociception without anti-morphine actions or scratching responses, indicating that N/OFQ or NOP receptor agonists represent a promising target as spinal analgesics.

Perspective: Intrathecal administration of N/OFQ only produced thermal antinociception, not hyperalgesia, in monkeys. In addition, intrathecal N/OFQ does not have anti-morphine actions or itch/scratching responses. This study strongly supports the therapeutic potential of N/OFQ or NOP receptor agonists as spinal analgesics for clinical trials.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics*
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / administration & dosage
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / adverse effects
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Female
  • Hyperalgesia / psychology
  • Injections, Spinal
  • Macaca mulatta
  • Male
  • Morphine / adverse effects
  • Morphine / pharmacology
  • Opioid Peptides / administration & dosage
  • Opioid Peptides / adverse effects
  • Opioid Peptides / therapeutic use*
  • Pain Measurement / drug effects
  • Pruritus / chemically induced
  • Receptors, Opioid / agonists*
  • Substance P / administration & dosage
  • Substance P / adverse effects
  • Substance P / pharmacology

Substances

  • Analgesics
  • Analgesics, Opioid
  • Opioid Peptides
  • Receptors, Opioid
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Substance P
  • Morphine
  • nociceptin