Received for publication April 13, 2006.
Revised June 7, 2006.
Accepted for publication June 8, 2006.

Effects of Intrathecally Administered Nociceptin/Orphanin FQ in Monkeys: Behavioral and Mass Spectrometric Studies

Abstract

Nociceptin/Orphanin FQ (N/OFQ) is a heptadecapeptide that is an endogenous ligand for the 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 intrathecal (i.t.) administration. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) 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. I.t. administration of N/OFQ dose-dependently (10-100 nmol) produced long-lasting antinociception against a noxious stimulus, 50 °C water, and did not elicit itch/scratching responses in monkeys. Subcutaneous pretreatment with a selective NOP receptor antagonist, (+)J-113397 (0.1 mg/kg), completely blocked i.t. N/OFQ (100 nmol)-induced antinociception. In contrast, a classical opioid receptor antagonist, naltrexone (0.01 and 1 mg/kg), failed to reverse i.t. N/OFQ-induced antinociception. MALDI-TOFMS 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. I.t. 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, i.t. N/OFQ(2-17) 100 nmol 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.

Key words: analgesics, mass spectrometry, monkeys, opioid receptors, orphanin FQ, spinal