Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys.
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.


CONCLUSIONS
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.
Ko
Mei-Chuan
MC
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5632, USA. mko@umich.edu
Naughton
Norah N
NN
D000700:Analgesics; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000523:psychology; D007278:Injections, Spinal; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D018847:Opioid Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D011537:Pruritus / Q000139:chemically induced; D011957:Receptors, Opioid / Q000819:agonists*; D013373:Substance P / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000097629:Nociceptin
D000700:Analgesics; D000701:Analgesics, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013373:Substance P; D000097629:Nociceptin