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

Abstract

a b s t r a c tSevere 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 (NOP) 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 NOP peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP-112 (full NOP agonist) and UFP-113 (partial NOP 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 NOP ligands were no longer evident in rats knockout for the NOP 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 no 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 NOP system in analgesia.

Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity

“…The NOP agonists UFP-112 and UFP-113 were able to increase pain threshold after spinal injection in the rat in a dose dependent manner with a higher potency compared to the NOP endogenous ligand N/OFQ. The antinociceptive effects of NOP ligands were no longer evident in knockout rats for the NOP gene (Micheli et al, 2015) showing that the pain threshold increase induced by these compounds is mediated by the NOP receptor. In the present study, N/OFQ is tested in a range dose of 0.3-3 nmol and 0.1-3 nmol on oxaliplatin and paclitaxel induced neuropathy, respectively.…”

“…Recently, we described the antinociceptive properties of NOP agonists intrathecally administered in naïve rats; their antinociceptive potency and efficacy were compared with morphine and behaviourally selective (i.e. non associated with motor impairment) doses were selected (Micheli et al, 2015). The NOP agonists UFP-112 and UFP-113 were able to increase pain threshold after spinal injection in the rat in a dose dependent manner with a higher potency compared to the NOP endogenous ligand N/OFQ.…”

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…Furthermore, subthreshold doses of UFP-112 and morphine, when given in combination intrathecally, produced a robust antinociceptive action. Although tolerance has also been described to the effects of spinal N/OFQ in rats, no cross tolerance with morphine has been observed (Hao et al, 1997;Micheli et al, 2015). Collectively these nonhuman primate studies suggest that peptide NOP receptor agonists have the potential to be developed as innovative spinal analgesics.…”

“…This interpretation has been confirmed experimentally because the pharmacological activity of [F/G]N/OFQ(1-13)-NH 2 has been manipulated to encompass full and partial agonism to pure antagonism, using the same cells by modifying NOP receptor density as the only variable (McDonald et al, 2003a Lys 15 ] discussed above that increase peptide affinity/potency have also been combined with [F/G] to generate UFP-113 (Arduin et al, 2007), a NOP agonist with 100-fold increase in potency and longer duration of action (Table 2). After intrathecal injection, UFP-113 mimicked N/OFQ action, eliciting dose-dependent (0.001-1 nmol) antinociception in the rat paw pressure test, effects that were no longer evident in NOP(2/2) rats (Micheli et al, 2015).…”

Cebranopadol: novel dual opioid/NOP receptor agonist analgesic

“…68,[88][89][90][91] Intrathecal administration of an NOP agonist (UFP-112) is antinociceptive in mice and rhesus monkeys (Ro64-6198). 88,92 Supraspinal N/OFQ produces an anti-analgesic effect in mice and non-human primates. 93,94 N/OFQ acts on periaqueductal grey neurons in analgesic pathways; 95,96 chronic morphine leads to NOP system upregulation; 96 and administration of an NOP antagonist (J-113397) blocks the development of tolerance to morphine.…”