Functional plasticity of the N/OFQ‐NOP receptor system determines analgesic properties of NOP receptor agonists

Abstract

Despite high sequence similarity between NOP (nociceptin/orphanin FQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation, and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However, they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and μ-opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain. AbbreviationsCCI, chronic constriction injury; CFA, complete Freund's adjuvant; CPP, conditioned place preference; DOP, δ-opioid peptide; DRG, dorsal root ganglion; i.c.v., intracerebroventricular; i.pl., intraplantar; i.t., intrathecal; KOP, κ-opioid peptide; MOP, μ-opioid peptide; N/OFQ, nociceptin/orphaninFQ; NHP, non-human primate; NOP, nociceptin/orphaninFQ opioid peptide; NST, nocistatin; PAG, periaqueductal grey; RVM, rostral ventromedial medulla; SNL, spinal nerve ligation; WDR, wide dynamic range IntroductionIn 1994, soon after the cloning of μ-, δ-and κ-opioid receptors (MOP, DOP and KOP, respectively), several groups identified a GPCR with high homology to opioid receptors (Bunzow et al., 1994;Fukuda et al., 1994;Mollereau et al., 1994;Nishi et al., 1994;Wang et al., 1994; for receptor nomenclature see Alexander et al., 2013a), but very low affinity for opioid BJP British Journal of Pharmacology DOI:10.1111/bph.12744 www.brjpharmacol.org British Journal of Pharmacology (2014) 171 3777-3800 3777© 2014 The British Pharmacological Society ligands. Thus, this receptor was named opioid receptor like 1 (ORL1). In 1995, two groups independently identified the endogenous ORL1-ligand, ...

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

“…Spinal morphine produced a dose dependent and robust antinociceptive effect in line with previous findings (Kosson et al, 2008). A similar antinociceptive action has been promoted by the spinal injection of N/OFQ accordingly to (Schroder et al, 2014;Zeilhofer and Calò, 2003;). Compared to morphine, N/OFQ displayed similar potency but reduced maximal effects.…”

“…Moreover the action of N/OFQ was behaviorally selective; in fact the administration of analgesic doses of morphine promoted scratching responses in monkeys while N/OFQ did not. This evidence suggests the existence of relevant species differences regarding the therapeutic potential of NOP agonists as spinal analgesics (Schroder et al, 2014).…”

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

“…Given that capsaicin-sensitive nerve fibers are involved in a variety of pain conditions, the full effectiveness of BU08028 in inhibiting capsaicin-induced allodynia may indicate its clinically relevant analgesic efficacy. In addition, rodent studies have demonstrated the analgesic efficacy of NOP-related agonists across diverse pain modalities, including inflammatory pain, neuropathic pain, and sickle cell pain (18,20,22,29). Cumulative evidence supports a broad application of NOP-related agonists as analgesics.…”

“…(17)(18)(19)(20). Following spinal and systemic administration, NOP receptor agonists produce antinociception and antihypersensitivity comparable to those of MOP receptor agonists, but without reinforcing effects in nonhuman primates (21)(22)(23)(24).…”

Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

“…across a variety of pain assays. Systemic or supraspinal administration in rodents does not produce antinociception against an acute thermal stimulus (tail flick, hot plate), but may have positive effects in inflammatory, neuropathic, and chronic pain states (for reviews, see Mogil and Pasternak, 2001;Lambert, 2008;Schröder et al, 2014).…”