Effects of intrathecally administered nociceptin/orphanin FQ in monkeys: behavioral and mass spectrometric studies.
Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide that is an endogenous ligand for the N/OFQ peptide (NOP) receptor. The aim of this study was to investigate the behavioral responses of N/OFQ and its major fragment N/OFQ(2-17) in monkeys following i.t. administration. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was used to quantify the amounts of N/OFQ and N/OFQ(2-17) in the cerebrospinal fluid at specific time points when effects of i.t. N/OFQ were sustained and disappeared. Intrathecal administration of N/OFQ dose dependently (10-100 nmol) produced long-lasting antinociception against a noxious stimulus, 50 degrees C water, and did not elicit itch/scratching responses in monkeys. Subcutaneous pretreatment with a selective NOP receptor antagonist, (+)J-113397 [(1-[3R,4R)-1-cyclooctymethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3,-dihydro-2H-benzimidazol-2-one] (0.1 mg/kg), completely blocked i.t. N/OFQ (100 nmol)-induced antinociception. In contrast, a classic opioid receptor antagonist, naltrexone (0.01 and 1 mg/kg), failed to reverse i.t. N/OFQ-induced antinociception. MALDI-TOF-MS showed that the amount of N/OFQ(2-17) was 4-fold higher than that of N/OFQ at 1.5 h after i.t. administration of 100 nmol N/OFQ. Intrathecal N/OFQ-induced antinociception disappeared at 4.5 h, which corresponded to nearly undetectable cerebrospinal fluid levels of N/OFQ. No other metabolite of N/OFQ was detected at appreciable levels at either the 1.5- or 4.5-h time points. Although significant amounts of N/OFQ(2-17) were detected at the 1.5- and 4.5-h time points, 100 nmol N/OFQ(2-17) i.t. was inactive in changing the monkeys' nociceptive threshold. These results provide the first functional evidence of spinal N/OFQ-induced antinociception in primates and indicate that activation of spinal NOP receptors may be a potential target for spinal analgesics.
Ko
M C Holden
MC
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, USA. mko@umich.edu
Wei
Hui
H
Woods
James H
JH
Kennedy
Robert T
RT
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D007278:Injections, Spinal; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D009271:Naltrexone / Q000494:pharmacology; D018847:Opioid Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013116:Spinal Cord / Q000187:drug effects*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000700:Analgesics; D009271:Naltrexone; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin