Review ArticleABSTRACT
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid endogenous opioid-like neuropeptide and the N/OFQ-NOP receptor system is widely represented throughout the rodent, primate and human. Administration of N/OFQ has been consistently shown to inhibit spontaneous locomotion as well as motor activity stimulated by pharmacological agents. Endogenous N/OFQ also inhibits motor behaviour since pharmacological or genetic blockade of N/OFQ transmission increases locomotor performance. The motor depressant action of endogenous N/OFQ has been related to N/OFQ ability to inhibit dopaminergic transmission along the nigrostriatal pathway. However, in a recent work we have observed either increase or decrease of Dopamine (DA) levels monitored with Differential Pulse Voltammetry (DPV) in the Substance Nigra (SN) of anaesthetized rats, depending on the amount of N/OFQ injected.
On the other hand, what appears more consistent as an effect of N/OFQ is the [negative] influence upon serotoninergic activities. Indeed, in earlier studies performed with DPV we have shown that microinjection of N/OFQ in the Substantia Nigra Reticulata (SNr) inhibits local serotonin (5-HT) release in anaesthetized rats. Thus, our hypothesis is that continuous motor activity may cause release of endogenous N/OFQ which therefore may act upon DA and subsequently upon 5-HT release in the basal ganglia, as previously observed in the SN, resulting in impaired locomotion. To prove this hypothesis, a specific study will be undertaken in awake rats prepared for voltammetry-electrophysiology recordings. These rodents will be freely moving and subjected to behavioral tests (i.e. the rotarod or the forced swimming test). Concomitant voltammetric and electrophysiological measurements of the dopaminergic and serotonergic activities will be performed at two different levels: cell bodies (i.e. SNr, RDN) and relevant nerve terminals i.e. amygdale, hippocampus, cortex.
Abbreviations: FQ (N/OFQ): Nociceptin/ Orphanin; DA: Dopamine; DPV: Differential Pulse Voltammetry; SN: Substance Nigra; SNr: Substantia Nigra Reticulata; CMS: Chronic Mild Stress; I.C.V: Intra-Cerebroventricularly; TH: Tyrosine Hydroxylase; DPV: Differential Pulse Voltammetry; DLS: Dorsolateral Striatum; FST: Forced Swimming Test; SSRI: Selective Serotonin Reuptake Inhibitor
Introduction
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid endogenous opioid-like neuropeptide [1] that activates a G-protein coupled nociceptin opioid peptide receptor [2,3], named NOP [4].The N/OFQ-NOP receptor system is widely represented throughout the rodent [5,6], primate [7] and human [8] CNS. Established neurobehavioral techniques as well as radio-imaging technologies have been applied to investigate this system in animals and humans, in particular on the role of N/OFQ in the control of feeding, body weight homeostasis, stress, depression, anxiety, and in drug and alcohol dependence [9] and for reviews [10,11]. In rodents the N/OFQ receptor system is widely expressed in cortical and subcortical motor areas [5] and is involved in the modulation of a number of biological actions [12] for a review [13]. Previous works demonstrated that Intra-Cerebroventricular (I.C.V.) administration of N/OFQ has been consistently shown to inhibit spontaneous locomotion [14,15] as well as motor activity stimulated by pharmacological agents [16,17].
Alternatively other experiments showed that Nociceptin administered Intra-Cerebroventricularly (I.C.V.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate but was able to reduce morphine-induced DA and metabolites release in the shell of the nucleus accumbens, therefore possibly acting mainly as modulator of neurochemical and behavioral influence of drugs of abuse [18,19]. Endogenous N/OFQ also inhibits motor behaviour since pharmacological or genetic blockade of N/OFQ transmission increases locomotor performance on the rotarod [20]. Early pharmacological evidence also supports a role for the N/OFQ-NOP receptor system in the modulation of mood related behaviours in rodents, i.e. two chemically unrelated NOP receptor antagonists, the peptide [Nphe’]N/OFQ(l-13)NH2 and the non-peptide J-l 13397, reduced the immobility time of mice in the forced swimming test (FST); [21] test that has been proved to be of utility to predict the clinical efficacy of antidepressants in rodents [22].
Later, these results were obtained also with the NOP receptor peptide antagonist UFP-101, i.e. in rodents administered i.c.v. it was followed by reduction of the immobility time and by increase of the climbing behaviour in rats submitted to the forced swimming test. These data were further supported with genetic observations, i.e. by challenging knockout mice [23] in the forced swimming and tail suspension tests [24]. Additionally, chronic treatment with UFP-101 produced antidepressant-like effects in rats subjected to a validated animal model of depression: the Chronic Mild Stress (CMS) [25]. The neurochemical substrate involved in the motor depressant action of endogenous N/OFQ and ii) the antidepressant-like action of NOP receptor antagonists is still matter of investigation. The motor depressant action of endogenous N/OFQ has been related to N/OFQ ability to inhibit dopaminergic transmission along the nigrostriatal pathway, since NOP receptor antagonists evoked striatal Dopamine (DA) release in the rat [20]. However, the influence of N/OFQ upon DA system is controversial as other works have shown that: a. Nociceptin administered Intra-Cerebroventricularly (I.C.V.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate [18].
b. Orphanin FQ when applied to the ventral tegmental area of anesthetized rats by reverse dialysis at a probe concentration of 1 mM (but not at 0.1 mM) significantly reduced dopamine levels sampled with a second dialysis probe in the nucleusaccumbens. In contrast, the receptor-inactive analogue, des-Phe1 Orphanin FQ (1 mM), produced a small but significant increase in nucleus accumbens dialysate dopamine levels [26].
c. In vivo microdialysis studies have shown a large increase ofdopamine release (in the order of 350-390% of control values)in striatum when treating conscious rats with nociceptin at themicro molar concentration [27].
Finally, in his review [28] reported about both facilitatory and inhibitory motor actions of N/OFQ and that both these effects were abolished in animals in which tyrosine hydroxylase (TH) activity was inhibited, indicating that endogenous DA is critical for both events [14]. In particular, [29] previously noted that the facilitatory effects of low doses of N/OFQ were abolished by haloperidol treatment, proposing a role for D2 receptors. Again, in more recent work, we have observed either increase or decrease of DA levels monitored with differential pulse voltammetry (DPV) in the Substancia Nigra (SN) of anaesthetized rats, depending on the amount of N/OFQ injected locally into the SN [30]. On the other hand, what appears more consistent as an effect of N/OFQ is the [negative] influence upon serotoninergic activities. Indeed, in earlier studies performed with DPV we have shown that microinjection of N/OFQ in the Substantia Nigra Reticulata (SNr) inhibits local serotonin (5-HT) release in anaesthetized rats [31,30].
Facilitation of serotonergic transmission in the SNr enhances locomotion in rodents [32,33] and both dopaminergic and serotonergic transmission is increased in the SNr and striatum during continuous motor execution [34,35]. Moreover, some authors have suggested that the antidepressant action of NOP receptor antagonists is due to blockade of N/OFQ inhibition of central serotonergic transmission at two different levels: at the dorsal raphe nucleus (RDN) neurons, where N/OFQ causes hyperpolarization by increasing a K+ conductance [36,28], and at cortical serotonergic nerve terminals, where N/OFQ inhibits 5-HT release [37,38]. It has been observed that local injection of N/OFQ into the hippocampus markedly decreased exploratory locomotor activity including vertical movements (rearing) in rats [39]. Furthermore it has been shown that it elicits hypo locomotion in rats submitted to elevated plus maze and in the conditioned defensive burying test [40].
Thus, our hypothesis is that continuous motor activity may cause release of endogenous N/OFQ which therefore may act upon DA and subsequently upon 5-HT release in the basal ganglia, as previously observed in the SN, resulting in impaired locomotion. To prove this hypothesis, a specific study will be undertaken in awake rats prepared for voltammetry – electrophysiology recordings as already described [41,42]. In addition , these rodents will be freely moving and therefore subjected to behavioral tests (i.e. the rotarod or the forced swimming test) by employing a telemetric system that allows to correlate on line and with high-time resolution both neurochemical and behavioural parameters [43,44]. Furthermore, concomitant voltammetric and electrophysiological changes of the dopaminergic and serotonergic systems will be performed at two different levels: cell bodies (i.e. SNr, RDN) and relevant nerve terminals i.e. amygdale, hippocampus, cortex, as previously described [40,45,46].
Project Strategy
Animals: The difference between strains of rats has to be taken into consideration as it appears that combined behaviouralvoltammetric investigations suggest that “behavioural despair” is the process interesting Wistar rats when submitted to FST while “learning to be immobile” is the process involving Sprague-Dawley CD rats [47].
Voltammetric Analysis and Behavior: Voltammetric analysis of 5-HT and DA release [48,44,31] will be performed in the SNr and dorsolateral striatum (DLS) of awake rats at rest and during performance on the rotarod. Then, the effect of selective NOP receptor agonists and antagonists (either injected into the SNr or given systemically) on nigral and striatal 5-HT and DA release will be investigated. Among agonists, N/OFQ will be tested while among antagonists, the peptide compound UFP-101 [49] and the non-peptide compound J-l 13397 [48] will be used. This will allow correlation between changes of 5-HT and DA release and motor effects of NOP receptor ligands. A telemetric system will be implemented to transmit data from the electrodes to the recording system [40,43].
Concomitant Electrophysiological Analysis performed in the cell bodiesand relevant terminal brain areas of anaesthetised rats [7] will give information on the effect of N/OFQ or NOP receptor blockade on cell firing. The feasibility of telemetric electrophysiological monitoring in conscious rats would be also assessed in order to correlate these outcomes with the biochemical data gathered in rotarod-behaving animals. In the attempt to verify the putative antidepressant action of NOP receptor antagonists the correlation between cortical 5-HT levels and the behavioural effects induced by the NOP antagonist UFP-101 will be analysed in rats subjected to the forced swimming test (FST) as previously described [50]. Briefly, in conscious rats previously prepared for voltammetric analysis in the cerebral cortex, an i.c.v. administration of UFP-101 at 1 and 10 nmol/rat will be performed 5 min before the FST. Three behavioral parameters, previously shown to be reliable and validated for the detection of antidepressant drug effects in the rat FST, will be scored:
a. Immobility time
b. Swimming time
c. Climbing time
Real time in vivo voltammetric measurement of 5-HT levels in the cerebral cortex will be assessed in rats before, during and after the FST, in order to correlate the behavioural effects induced by central administration of UFP-101 with 5-HT levels in the cerebral cortex.
Conclusion
It is known that the generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ receptor system. Furthermore it has been shown that UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. The present experiments will possibly further support the involvement of the N/OFQ-NOP receptor system in mood modulation so that it can be proposed as another potential targets for antidepressant drug development.
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