Neuropeptide FF, pain and analgesia

Roumy, M.; Zajac, Jean‐Marie

doi:10.1016/s0014-2999(97)01604-x

Cited by 223 publications

(133 citation statements)

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“…Among these peptides, NPFF, which belongs to the RF-amide peptide family, was shown (among other actions) to regulate blood pressure 7 , prolactin release 8 and nociceptive signal processing 9 . Prolactin-releasing peptide (PrRP) has recently been identified as an additional member of the mammalian RF-amide peptide family, following its isolation as the natural agonist of the previously orphan GPR10 (ref.…”

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The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

et al. 2005

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Prolactin-releasing peptide (PrRP) and its receptor G protein-coupled receptor 10 (GPR10) are expressed in brain areas involved in the processing of nociceptive signals. We investigated the role of this new neuropeptidergic system in GPR10-knockout mice. These mice had higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice, differences that were suppressed by naloxone treatment. In addition, potentiation of morphine-induced antinociception and reduction of morphine tolerance were observed in mutants. Intracerebroventricular administration of PrRP in wild-type mice promoted hyperalgesia and reversed morphine-induced antinociception. PrRP administration had no effect on GPR10-mutant mice, showing that its effects are mediated by GPR10. Anti-opioid effects of neuropeptide FF were found to require a functional PrRP-GPR10 system. Finally, GPR10 deficiency enhanced the acquisition of morphine-induced conditioned place preference and decreased the severity of naloxone-precipitated morphine withdrawal syndrome. Altogether, our data identify the PrRP-GPR10 system as a new and potent negative modulator of the opioid system.Opiate drugs, the prototype of which is morphine, are used largely for the treatment of severe pain. However, the prolonged use of opiate drugs induces a behavioral adaptation that results in the development of tolerance and dependence 1 . Although these adaptive mechanisms have been known for decades, the underlying pathophysiological pathways have not been fully clarified. It has been proposed that the opioid receptor signaling pathway is adaptively regulated at the cellular level, although more recently a growing contribution of the plasticity of neuronal networks involving opioidergic neurons has been recognized. In support of this latter hypothesis, a number of neuropeptides, including cholecystokinin (CCK) 2 , neuropeptide FF (NPFF) 3 and nociceptin (orphanin FQ) 4 , have been proposed as modulators of the opioid system. These various peptidergic pathways are collectively designated as an anti-opioid system. However, the action of individual peptides on the opioid pathway and on the processing of nociceptive signals is complex and some aspects remain controversial, particularly as the behavioral consequences can vary depending on the injection site of these peptides and the precise experimental setup 5,6 . Among these peptides, NPFF, which belongs to the RF-amide peptide family, was shown (among other actions) to regulate blood pressure 7 , prolactin release 8 and nociceptive signal processing 9 . Prolactin-releasing peptide (PrRP) has recently been identified as an additional member of the mammalian RF-amide peptide family, following its isolation as the natural agonist of the previously orphan GPR10 (ref. 10) (also known as hGR3 in human or UHR-1 in rat). Intracerebroventricular (i.c.v.) administration of PrRP affects feeding behavior 11 , blood pressure 12 and neuroendocrine processes, such as corticotropin-releasing hormone (CRH) 13 and oxytocin 14 release.In a...

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The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

et al. 2005

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“…Neuropeptide FF (NPFF, FLFQPQRFamide) is a mammalian amidated neuropeptide, originally isolated from bovine brain and characterized as a modulator of endogenous opioid functions [1,2]. Two precursors, proNPFF A and proNPFF B encoding peptides possessing the PQRFamide sequence, have been cloned in mammals [3,4].…”

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“…These pharmacological effects are mediated by two G-protein-coupled receptors, NPFF 1 and NPFF 2 , cloned in human and rat [22][23][24][25]. Pharmacological characterization of these receptors in recombinant cell lines showed a better selectivity of peptides deduced from proNPFF A sequence for NPFF 2 receptors binding, whereas proN-PFF B -derived peptides displayed a greater affinity for NPFF 1 receptors [26].…”

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“…Pharmacological characterization of these receptors in recombinant cell lines showed a better selectivity of peptides deduced from proNPFF A sequence for NPFF 2 receptors binding, whereas proN-PFF B -derived peptides displayed a greater affinity for NPFF 1 receptors [26]. Autoradiographic studies performed on rat CNS with highly selective radioligands revealed the localization of both receptors in central nervous areas implicated in pain transmission [27].…”

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confidence: 99%

“…Autoradiographic studies performed on rat CNS with highly selective radioligands revealed the localization of both receptors in central nervous areas implicated in pain transmission [27]. The existence of two peptidergic systems of neurotransmission, mediated through NPFF 1 and NPFF 2 receptor stimulation by peptides generated by proNPFF B and proNPFF A processing, respectively, could explain the complex pharmacological effects of NPFF.…”

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Identification of proNeuropeptide FF_A peptides processed in neuronal and non‐neuronal cells and in nervous tissue

Bonnard

Burlet‐Schiltz

Monsarrat

et al. 2003

European Journal of Biochemistry

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Peptides which should be generated from the neuropeptide FF (NPFF) precursor were identified in a neuronal (human neuroblastoma SH-SY5Y) cell line and in COS-7 cells after transient transfection of the human proNPFF A cDNA and were compared with those detected in the mouse spinal cord. After reverse-phase high performance liquid chromatography of soluble material, NPFF-related peptides were immunodetected with antisera raised against NPFF and identified by using on-line capillary liquid chromatography/ nanospray ion trap tandem mass spectrometry. Neuronal and non-neuronal cells generated different peptides from the same precursor. In addition to NPFF, SQA-NPFF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) and NPAF were identified in the human neuroblastoma while only NPFF was clearly identified in COS-7 cells. In mouse, in addition to previously detected NPFF and NPSF, SPA-NPFF (Ser-Pro-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Pheamide), the homologous peptide of SQA-NPFF, were characterized. These data on intracellular processing of proNeuropeptide FFA are discussed in regard to the known enzymatic processing mechanisms. There is a large body of evidence that NPFF exhibits antiopioid properties; in rodents, morphine-induced analgesia decreased following administration of NPFF or NPFF analogues and increased, as stress-induced analgesia, in response to anti-NPFF antibody administration [6][7][8]. In contrast, intrathecal injections of NPFF analogues induced a long-lasting analgesia [9,10] by increasing opioid peptide release in the spinal cord through the functional blockade of presynaptic delta-opioid autoreceptors [11,12]. Recent data provided evidence that opioid and NPFF endogenous systems exert a tonic activity, NPFF counteracting tonic opioid analgesia under resting conditions [13]. NPFF is also implicated in morphine tolerance, morphine abstinence and also in several physiological processes, such as body thermoregulation, food intake and blood pressure regulation [7,[14][15][16][17][18][19][20][21].These pharmacological effects are mediated by two G-protein-coupled receptors, NPFF 1 and NPFF 2 , cloned in human and rat [22][23][24][25]. Pharmacological characterization of these receptors in recombinant cell lines showed a better selectivity of peptides deduced from proNPFF A sequence for NPFF 2 receptors binding, whereas proN-PFF B -derived peptides displayed a greater affinity for NPFF 1 receptors [26]. Autoradiographic studies performed on rat CNS with highly selective radioligands revealed the localization of both receptors in central nervous areas implicated in pain transmission [27]. The existence of two peptidergic systems of neurotransmission, mediated through NPFF 1 and NPFF 2 receptor stimulation by peptides generated by proNPFF B and proNPFF A processing, respectively, could explain the complex pharmacological effects of NPFF.The characterization of NPFF-related peptides generated by NPFF precursors processing is essential to identify peptides candidate to the role of neurotransmitter. This study f...

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Dual localization of neuropeptide FF receptors in the rat dorsal horn

Gouardères

Roumy

Advokat

et al. 2000

Synapse

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Although neuropeptide FF (NPFF) is generally considered an anti-opioid, its intrathecal administration produces analgesia. In the present study, the stable analog 1DMe ([D.Tyr(1), (NMe)Phe(3)]neuropeptide FF) was used in quantitative autoradiographic experiments in combination with surgical and chemical lesions to precisely localize NPFF receptors in the rat spinal cord. Ligation of lumbar dorsal spinal roots revealed the presence of NPFF receptors in dorsal root fibers and it induced a significant accumulation of [(125)I]1DMe-specific binding on the side peripheral to the ligature, demonstrating that a population of NPFF receptors is synthesized in dorsal root ganglia and migrates anterogradely towards primary afferent nerve endings. Complete mid-thoracic spinal cord transection failed to modify the [(125)I]1DMe labeling density in the dorsal horn, indicating that NPFF receptors are not located on the descending fiber terminals. In contrast, unilateral microinjections of kainic acid into the dorsal horn dramatically reduced [(125)I]1DMe-specific binding in the superficial layers, revealing localization of a population of NPFF receptors on the spinal intrinsic neurons. NPFF receptor binding was not modified during the development of spinal opioid tolerance. The pre- and postsynaptic localization of spinal NPFF receptors provide further support for heterogeneity in the pain modulation by NPFF and related agonists.

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Neuropeptide FF, pain and analgesia

Cited by 223 publications

References 76 publications

The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

Identification of proNeuropeptide FF_A peptides processed in neuronal and non‐neuronal cells and in nervous tissue

Dual localization of neuropeptide FF receptors in the rat dorsal horn

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Neuropeptide FF, pain and analgesia

Cited by 223 publications

References 76 publications

The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

Identification of proNeuropeptide FFA peptides processed in neuronal and non‐neuronal cells and in nervous tissue

Dual localization of neuropeptide FF receptors in the rat dorsal horn

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Identification of proNeuropeptide FF_A peptides processed in neuronal and non‐neuronal cells and in nervous tissue