Korean J Physiol Pharmacol.  2019 Nov;23(6):427-448. 10.4196/kjpp.2019.23.6.427.

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

• Park JY
• Chae S
• Kim CS
• Kim YJ
• Yi HJ
• Han E
• Joo Y
• Hong S
• Yun JW
• Kim H
• Shin KH

• KMID: 2461036
• DOI: http://doi.org/10.4196/kjpp.2019.23.6.427

Abstract

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K⁺ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.

Keyword

Antidepressive agents; Depression; Neuropeptide; Receptors, drug

MeSH Terms

Amygdala
Antidepressive Agents
Brain
Brain Stem
Calcium Channels
Depression*
Habenula
Models, Animal
Neurons
Neuropeptides
Opioid Peptides*
Receptors, Drug
Septal Nuclei
Antidepressive Agents
Calcium Channels
Neuropeptides
Opioid Peptides
Receptors, Drug

Figure

• 

  Fig. 1 Electrophysiological effects of nociceptin/orphanin FQ (N/OFQ) on ion channels in neuronal cell body and axon terminals. Nociceptin opioid peptide (NOP) receptor activation by N/OFQ stimulates G protein-coupled inwardly rectifying K+ channels (GIRK) and voltage sensitive M-type K+ channels, but inhibits voltage sensitive transient outward A-type K+ channels in neuronal cell body. Presynaptic NOP receptor activation in axon terminals inhibits voltage sensitive calcium channels and delayed rectifier K+ channels. N/OFQ inhibits neuronal excitability and neurotransmitter release from axon terminals by activation of GIRK and inhibition of voltage sensitive calcium channels, respectively. For example, release of norepinephrine, dopamine, 5-hydroxytryptamine (serotonin), acetylcholine, and glutamate from their terminals are known to be inhibited by N/OFQ. This scheme is modified using Motifolio Scientific Illustration Toolkits for Presentations and Publications (www.motifolio.com).

• 

  Fig. 2 Inhibitory effects of nociceptin/orphanin FQ (N/OFQ) on noradrenergic neurotransmission. Nociceptin opioid peptide (NOP) receptor is distributed on norepinephrine (NE) neurons in the locus coeruleus (LC) and their terminals in the basolateral amygdala (BLA) and prefrontal cortex (PFC). N/OFQ inhibits activity of noradrenergic LC neurons and leads to diminish NE release in the BLA and PFC. There is also evidence that N/OFQ reduces NE release by acting on NOP receptor at axon terminals in the BLA and PFC, but the NE release in the BLA and PFC following NOP receptor activation is regulated in a rather different manner. Intraperitoneal injection of NOP receptor antagonist J-113397 increases NE release and the simultaneous infusion of N/OFQ into the BLA blocks the effects of J-113397 indicating that NOP receptor in the BLA appears to exert tonic inhibitory effects on NE release. On the contrary, local injection of NOP receptor agonist NCNH2 into the LC decreases NE release in the PFC and this effect is partially restored by co-administration of NOP receptor antagonist [Nphe1]NC(1–13)NH2 and NCNH2 into the LC. Interestingly, injection of [Nphe1]NC(1–13)NH2 into the LC is without effect on NE release in the PFC per se. Thus, NOP in the LC seems not to exert tonic inhibition of NE release in the PFC. In vitro studies using brain slice and synaptosome demonstrate that N/OFQ also diminishes the release of NE in the frontal cortex. This scheme is modified using Motifolio Scientific Illustration Toolkits for Presentations and Publications (www.motifolio.com).

• 

  Fig. 3 Inhibition of dopamine (DA) release by nociceptin/orphanin FQ (N/OFQ) in the ventral tegmental area (VTA). N/OFQ inhibits DA release in the VTA and its terminals via both direct and indirect hyperpolarization of DA neurons. N/OFQ activates NOP receptors localized on DA neurons directly followed by a decrease in its neuronal activity. GABAergic terminals in the VTA are largely apposed by enkephalinergic nerve terminals and release of GABA is often presynaptically inhibited by enkephalin. N/OFQ is known to block released enkephalin (Enk) via anti-opioid effects, and thus reduced enkephalinergic tone could increase GABA release in the VTA. Therefore, DA neuronal activity in the VTA is suppressed by direct inhibitory effect of N/OFQ along with enhanced GABAergic neurotransmission indirectly. δ, delta-opioid receptors; GABAA, γ-aminobutyric acid A receptors. This scheme is modified using Motifolio Scientific Illustration Toolkits for Presentations and Publications (www.motifolio.com).

• 

  Fig. 4 Regulation of 5-hydroxytryptamine (5-HT) release by nociceptin/orphanin FQ (N/OFQ) in the dorsal raphe nucleus (DR) and frontal cortex (FC). N/OFQ and nociceptin opioid peptide (NOP) receptor are found in the DR and its terminals in the frontal cortex, medial and lateral septum, hippocampus, striatum, and nucleus accumbens. Although it is not clear whether N/OFQ is present in 5-HT neurons in the DR, NOP receptor in the DR is supposed to be located on 5-HT neurons because the injection of 5,7-dihydroxytryptamine, neurotoxin which preferentially destroys 5-HT neurons, into rat DR significantly reduces [3H]nociceptin binding and [3H]citalopram binding. N/OFQ seems to exert biphasic effect on 5-HT neurons in the DR: 5-HT neurons in the DR is tonically inhibited by nearby GABAergic interneurons. Low doses of N/OFQ are found to stimulate 5-HT neurons, and it is likely that low doses of N/OFQ hyperpolarize GABA neurons, thereby disinhibiting 5-HT neurons in the DR. On the contrary, high doses of N/OFQ inhibits 5-HT neurons by activating inwardly rectifying K+ channels through NOP receptor. This effect appears to predominate over GABAergic disinhibition effects on 5-HT neurons in the DR. This scheme is modified using Motifolio Scientific Illustration Toolkits for Presentations and Publications (www.motifolio.com).

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