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.

Figure 1

Schematic presentation summarizing the effects of NOP receptor activation on nociceptive processing at peripheral, spinal and supraspinal sites, and resulting analgesic effects of systemically administered NOP receptor agonists under conditions of acute, neuropathic and inflammatory pain in rodents. (A) NOP receptor agonists were largely ineffective in acute pain after systemic administration as activation of supraspinal NOP receptors counteracted spinally and peripherally mediated antinociception. Pronociceptive effects were also elicited by low concentrations of N/OFQ at peripheral and spinal sites. (B) In contrast, systemic administration of NOP receptor agonists elicited antihypersensitive effects in neuropathic pain as, here, activation of supraspinal NOP receptors did not counteract, but contributed to analgesic efficacy. In addition, peripheral, spinal and supraspinal NOP receptors were up-regulated and functionally sensitized. (C) Inhibition of nociceptive processing elicited by activation of functionally sensitized peripheral and spinal NOP receptors is hypothesized to overcome pronociceptive effects of supraspinal NOP receptor activation, thus leading to antihyperalgesic efficacy after systemic administration of NOP receptor agonists in inflammatory pain. Larger symbols indicate up-regulation/functional sensitization of NOP receptors.