Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.
We have recently shown that Neuropeptide S (NPS) can promote arousal and induce anxiolytic-like effects after central administration in rodents. Another study reported a number of natural polymorphisms in the human NPS receptor gene. Some of these polymorphisms were associated with increased risk of asthma and possibly other forms of atopic diseases, but the physiological consequences of the mutations remain unclear. One of the polymorphisms produces an Asn-Ile exchange in the first extracellular loop of the receptor protein, and a C-terminal splice variant of the NPS receptor was found overexpressed in human asthmatic airway tissue. We sought to study the pharmacology of the human receptor variants in comparison with the murine receptor protein. Here, we report that the N107I polymorphism in the human NPS receptor results in a gain-offunction characterized by an increase in agonist potency without changing binding affinity in NPSR Ile 107 . In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn 107 . The mouse NPS receptor, which also carries an Ile residue at position 107, displays an intermediate pharmacological profile. Structureactivity relationship studies show that the amino terminus of NPS is critical for receptor activation. The altered pharmacology of the Ile 107 isoform of the human NPS receptor implies a mechanism of enhanced NPS signaling that might have physiological significance for brain function as well as peripheral tissues that express NPS receptors.Neuropeptide S (NPS) is the endogenous ligand of an orphan G protein-coupled receptor (GPCR). The NPS receptor (NPSR) belongs to the subfamily of peptide GPCRs and is widely expressed in the brain, with highest levels found in hypothalamus, amygdala, endopiriform nucleus, cortex, subiculum, and nuclei of the thalamic midline. In contrast, the NPS precursor mRNA is found in only a few brain structures (Xu et al., 2004). Highest levels of NPS precursor expression were detected in a novel nucleus located in between the noradrenergic locus coeruleus and Barrington's nucleus in the pontine area of the rat brain stem. Other brain regions of high NPS precursor expression include the lateral parabrachial nucleus, sensory principle 5 nucleus, and a few scattered neurons in the amygdala and dorsomedial hypothalamic nucleus. In addition, we found high expression of NPS and NPSR mRNA in endocrine tissues, including thyroid, mammary, and salivary glands, but did not observe significant levels in rat lung tissue.Central administration of NPS promotes behavioral arousal and suppresses all stages of sleep in rodents. Furthermore, NPS was found to produce anxiolytic-like effects in a battery of four different tests that measure behavioral responses of rodents to novelty or stress. NPS was shown to induce transient increases of intracellular Ca 2ϩ , indicating that it might have excitatory effects at the cellular level (Xu et al., 2004).Recently, a number of polymorphisms in the human NPS rece...
Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca 2ϩ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPSinduced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.Neuropeptide S (NPS) and its receptor, NPSR, are a recently identified transmitter system that modulates a number of brain functions . NPS is a small peptide of 20 amino acids that occurs in all tetrapod vertebrates but is absent from fish (Reinscheid, 2007). Activation of NPSR produces transient increases in intracellular Ca 2ϩ and cAMP and thus increases cellular excitability (Reinscheid et al., 2005). Expression of NPS precursors and receptors is found in specific brain areas that have been associated with arousal, emotional processing, energy, and hormonal homeostasis, as well as learning and memory (Xu et al., 2004(Xu et al., , 2007. In the rat, NPS precursor transcripts are expressed in only a few brainstem structures; in particular, in a previously uncharacterized nucleus situated between the noradrenergic locus coeruleus and Barrington's nucleus. Besides the pericoerulear region, NPS mRNA is only found in the lateral parabrachial nucleus and the principle sensory 5 nucleus of the rat brainstem. A few scattered cells expressing NPS precursor transcripts are also detected in the amygdala and hypothalamus. In the brainstem, the majority of NPSexpressing neurons coexpress other excitatory transmitters, such as glutamate, acetylcholine, or corticotropin-releasing factor (Xu et al., 2007). NPSR mRNA is found at high levels in hypothalamus, thalamus, amygdala, various cortical regions, and the parahippocampal formation. Central administration of NPS was shown to produce profound arousal that is independent of novelty (Xu et al., 2004).
Neuropeptide S (NPS) has been associated with a number of complex brain functions, including anxiety-like behaviors, arousal, sleep-wakefulness regulation, drug-seeking behaviors, and learning and memory. In order to better understand how NPS influences these functions in a neuronal network context, it is critical to identify transmitter systems that control NPS release and transmitters that are co-released with NPS. For this purpose, we generated several lines of transgenic mice that express enhanced green-fluorescent protein (EGFP) under control of the endogenous NPS precursor promoter. NPS/EGFP-transgenic mice show anatomically correct and overlapping expression of both NPS and EGFP. A total number of ∼500 NPS/EGFP-positive neurons are present in the mouse brain, located in the pericoerulear region and the Kölliker-Fuse nucleus. NPS and transgene expression is first detectable around E14, indicating a potential role for NPS in brain development. EGFP-positive cells were harvested by laser-capture microdissection, and mRNA was extracted for expression profiling by using microarray analysis. NPS was found co-localized with galanin in the Kölliker-Fuse nucleus of the lateral parabrachial area. A dense network of orexin/hypocretin neuronal projections contacting pericoerulear NPS-producing neurons was observed by immunostaining. Expression of a distinct repertoire of metabotropic and ionotropic receptor genes was identified in both NPS neuronal clusters that will allow for detailed investigations of incoming neurotransmission, controlling neuronal activity of NPS-producing neurons. Stress-induced functional activation of NPS-producing neurons was detected by staining for the immediate-early gene c-fos, thus supporting earlier findings that NPS might be part of the brain stress response network.
The neuropeptide orphanin FQ/nociceptin (OFQ/N) has been shown to counteract several effects of endogenous and exogenous opioids, and it has been proposed as an opioid-modulating agent involved in the development of morphine tolerance and dependence. However, conflicting results have been obtained from animal models using different protocols to induce morphine tolerance. Here, we report that both genetic and pharmacological blockade of OFQ/N signaling can effectively prevent development of morphine tolerance. OFQ/N knockout mice injected daily with low doses of morphine (10 mg/kg) fail to develop tolerance even after 3 weeks of treatment, whereas their wild-type litter mates show profound tolerance starting after 10 days. Likewise, coadministration of morphine together with the synthetic N/OFQ peptide antagonist, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), is able to block tolerance development in normal mice. These data indicate that release of endogenous OFQ/N after morphine administration might produce a gradual decline of analgesic potency, i.e., tolerance. Interestingly, tolerant and nontolerant groups of mice receiving repeated daily low morphine doses did not differ in their withdrawal behavior after naloxone injection. In contrast, mice receiving escalating doses of morphine developed analgesic tolerance independent of their OFQ/N genotype, whereas withdrawal symptoms were attenuated in OFQ/N-deficient animals. These results indicate that the endogenous OFQ/N system is differentially involved in morphine tolerance development and establishment of opiate dependence, depending on the specific morphine dosage regimen. Furthermore, it suggests that OFQ/N antagonists could provide a novel therapeutic strategy to attenuate morphine tolerance development.Morphine and related opioids are still the most powerful and widely used drugs in the clinical management of severe pain. However, long-term use of opioids is limited by the development of tolerance and dependence. Tolerance is a gradual loss in drug effect upon repeated administration, requiring increasing doses to maintain analgesia. Dependence reflects a change in neuronal homeostasis that results in withdrawal symptoms upon cessation of drug administration. Studies on knockout mice have shown that activation of -opioid (MOP) receptors is responsible for morphine-induced analgesia, tolerance, and dependence (Matthes et al., 1996). However, the mechanisms of adaptive changes downstream of MOP activation are still poorly understood. Therefore, elucidating the molecular and neurobiological mechanisms of opioid tolerance has been compared with the "search for the Holy Grail" (Kieffer and Evans, 2002).The search for physiological correlates of opioid tolerance has indicated a number of protein kinases, ion channels, second messenger-synthesizing enzymes, glutamate receptors, cytoskeletal proteins, and neurotrophic factors to be involved (Nestler, 1997;Williams et al., 2001). In addition,...
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