Altered nociception and morphine tolerance in neuropeptide <scp>FF</scp> receptor type 2 over‐expressing mice

Lin, Ya Ping; Kao, Sung‐Shuo; Day, Yuan Ji; Chang, C.C.; Chen, Jin-Chung

doi:10.1002/ejp.814

Cited by 13 publications

(6 citation statements)

References 52 publications

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“…When facing stressful condition NPFF may signal through NPFFR2 signalling to modulate anxiety‐like behaviors. This would be in line with studies showing the resistance of Npffr2 −/− mice to the single prolong stress (a stress model of post‐traumatic stress disorder)—induced increase in anxiety‐like behaviors, 21 and studies showing anxiogenic phenotypes from enhanced NPFFR2 activation either through receptor overexpression or chronic agonist treatment 23,55 …”

Section: Discussionsupporting

confidence: 72%

“…This would be in line with studies showing the resistance of Npffr2 −/− mice to the single prolong stress (a stress model of post-traumatic stress disorder)induced increase in anxiety-like behaviors, 21 and studies showing anxiogenic phenotypes from enhanced NPFFR2 activation either through receptor overexpression or chronic agonist treatment. 23,55 The high concentration of NPFF expression in the brainstem, where many other neurons are being targeted by factors that control feeding behavior and energy homeostasis control, makes NPFF also a likely player in this regulatory loop. Pharmacological studies demonstrated that NPFF family peptides administered i.c.v.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] Specifically, lack of NPFFR2 in mice led to impaired dietinduced thermogenesis and exacerbated diet-induced obesity, 20 a stronger bone phenotype 20 and resistance to the prolonged stress-induced increase in anxiety-like behaviors. 21 On the other hand, mice with NPFFR2 overexpression displayed hyperalgesia to mechanical, thermal and inflammatory pain, 23,24 and depression-and anxiety-like behaviors. 25 Lack of NPFFR1 in mice resulted in genderbiased alterations in body weight, fat composition, energy expenditure and glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Lack of neuropeptide FF signalling in mice leads to reduced repetitive behavior, altered drinking behavior, and fuel type selection

Zhang

Koller

et al. 2021

The FASEB Journal

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of neuropeptide FF signalling in mice leads to reduced repetitive behavior, altered drinking behavior, and fuel type selection

Zhang

Koller

et al. 2021

The FASEB Journal

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“…Non-peptide NPFFR2 agonists, AC-263093 (2-[(3,4-dibromophenyl) methylene]-hydrazine-carboximidamide hydrochloride) and CFMHC (2-[[4-chloro-3-(trifluoromethyl)phenyl]methylene]-Hydrazinecarboximidamidehydrochloride) were used in current study [ 26 ]. The preparation of AC-263093 and CFMHC was described previously [ 25 , 49 ]. The drugs were dissolved in a vehicle solution consisting of DMSO: Tween 20: saline at a 1:2:17 ratio.…”

Section: Methodsmentioning

confidence: 99%

NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents

Lin

Hong

et al. 2017

IJMS

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Neuropeptide FF (NPFF) belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The hypothalamic-pituitary-adrenal (HPA) axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV) and AC-263093 (intraperitoneal, IP), time-dependently (in rats) and dose-dependently (in mice) increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV), as well as corticotropin-releasing factor (CRF) antagonist, α-helical CRF(9-41) (intravenous, IV). Treatment with NPFFR2 agonist (AC-263093, IP) increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors.

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“…The main behavioural symptom of naloxone-precipitated withdrawal response, jumping, was evaluated according to previous studies (Lin, Kao, Day, Chang, & Chen, 2016). Briefly, mice were injected with increasing doses of drug at an injection interval of approximately 8 hr.…”

Section: Naloxone-precipitated Withdrawal Testmentioning

confidence: 99%

The multifunctional peptide DN‐9 produced peripherally acting antinociception in inflammatory and neuropathic pain via μ‐ and κ‐opioid receptors

Zhang

Shi

et al. 2019

British J Pharmacology

103

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Background and Purpose Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN‐9. Here, we studied the analgesic profiles and related side effects of peripheral DN‐9 in various pain models. Experimental Approach Antinociceptive effects of DN‐9 were assessed in nociceptive, inflammatory, and neuropathic pain. Whole‐cell patch‐clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN‐9 to calcium current and high‐K+‐induced intracellular calcium ([Ca2+]i) on dorsal root ganglion (DRG) neurons respectively. Side effects of DN‐9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit, and rotarod tests. Key Results DN‐9, given subcutaneously, dose‐dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN‐9 exhibited more potent ability than morphine to inhibit calcium current and high‐K+‐induced [Ca2+]i in DRG neurons. Repeated treatment with DN‐9 produced equivalent antinociception for 8 days in multiple pain models, and DN‐9 also maintained potent analgesia in morphine‐tolerant mice. Furthermore, chronic DN‐9 administration had no apparent effect on the microglial activation of spinal cord. After subcutaneous injection, DN‐9 exhibited less abuse potential than morphine, as was gastroparesis and effects on motor coordination. Conclusions and Implications DN‐9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.

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Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over‐expressing mice

Abstract: Our results suggest that neuropeptide FF R2 is mainly involved in the modulation of nociception and tolerance to morphine antinociception.

Cited by 13 publications

References 52 publications

Lack of neuropeptide FF signalling in mice leads to reduced repetitive behavior, altered drinking behavior, and fuel type selection

Lack of neuropeptide FF signalling in mice leads to reduced repetitive behavior, altered drinking behavior, and fuel type selection

NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents

The multifunctional peptide DN‐9 produced peripherally acting antinociception in inflammatory and neuropathic pain via μ‐ and κ‐opioid receptors

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