Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Severe pain occurs in the context of many diseases and conditions and is a leading cause of disability. Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOD) receptor. This peptidergic system controls pain transmission and in particular spinally administered N/OFQ has robust antinociceptive properties. The aim of this study was to investigate the spinal antinociceptive properties of NOD peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP-112 (full NOD agonist) and UFP-113 (partial NOD agonist) were administered intrathecally (i.t.) by spinal catheterization. Acute injection of UFP-112 induced antinociceptive response at lower dosages (0.03-1 nmol i.t.) compared to morphine and similar to N/OFQ. UFP-113 was effective in a 0.001-1 nmol i.t. dose range. The antinociceptive effects of NOD ligands were no longer evident in rats knockout for the NOD gene, while those of morphine were maintained. The continuous spinal infusion (by osmotic pumps) of 0.1 nmol/h UFP-112 and UFP-113 showed antinociceptive action comparable to 1-3 nmol/h morphine or N/OFQ. The antinociceptive effect of morphine progressively decreased and was 110 longer significant after 6 days of treatment. Similar results were obtained with N/OFQ, UFP-112, and UFP-113. The acute i.t, injection of morphine in animals tolerant to N/OFQ and UFP-112 evoked analgesic effects. Neither morphine nor N/OFQ induced antinociceptive effects in morphine- and UFP-113-tolerant rats. In conclusion this study highlights the analgesic efficacy and potency of UFP-112 and UFP-113 underlining the relevance of NOD system in analgesia. (C) 2015 Elsevier B.V All rights reserved.