Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opiate tolerance and dependence are major clinical and social problems. The anti-opiate neuropeptides FF and AF (NPFF and NPAF) have been implicated in pain modulation as well as in opioid tolerance and may play a critical role in this process, although their mechanism of action has remained unknown. Here we describe a cDNA encoding a novel neuropeptide Y-like human orphan G protein-coupled receptor (GPCR), referred to as HLWAR77 for which NPAF and NPFF have high affinity. Cells transiently or stably expressing HLWAR77 bind and respond in a concentration-dependent manner to NPAF and NPFF and are also weakly activated by FMRF-amide (Phe-Met-Arg-Phe-amide) and a variety of related peptides. The high affinity and potency of human NPFF and human NPAF for HLWAR77 strongly suggest that these are the cognate ligands for this receptor. Expression of HLWAR77 was demonstrated in brain regions associated with opiate activity, consistent with the pain-modulating activity of these peptides, whereas the expression in adipose tissue suggests other physiological and pathophysiological activities for FMRF-amide neuropeptides. The discovery that the anti-opiate neuropeptides are the endogenous ligands for HLWAR77 will aid in defining the physiological role(s) of these ligands and facilitate the identification of receptor agonists and antagonists.
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PMID:Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. 1085 Dec 42

The pain modulatory effects of (D-Tyr)L(Me-Phe)QPQRF-amide ([1DMe]NPYF), a stable analogue of neuropeptide FF were studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. According to behavioral assessments, intrathecal (i.t.) administration of [1DMe]NPYF induced mechanical antiallodynic and thermal antinociceptive effects in a parallel and dose-dependent fashion, whereas following administration in the periaqueductal gray (PAG) it produced only mechanical antiallodynia. I.t. or PAG administration of FLFQPQRF, a non-amidated form of NPFF, or intraplantar injection of [1DMe]NPYF into the neuropathic paw had no effects. Electrophysiological results indicated that administration of [1DMe]NPYF suppressed responses of nociceptive spinal dorsal horn neurons in a submodality selective way and without an effect on their spontaneous activity; PAG administration predominantly suppressed brush-evoked responses and i.t. administration heat-evoked responses. The descending inhibitory effect by conditioning electrical stimulation of the PAG was enhanced by i.t. administration of [1DMe]NPYF. The reversibility of [1DMe]NPYF-induced effects by naloxone (1 mg/kg subcutaneously) depended on the submodality of test stimulation and the route of drug administration. The amplitude of the innocuous H-reflex was not changed by [1DMe]NPYF administered i.t. in control rats. The present results indicate that [1DMe]NPYF produces a selective attenuation of pain in neuropathic animals due to naloxone-sensitive or -insensitive central mechanisms depending on the submodality of pain and route of drug administration. The amide-group is essential for the [1DMe]NPYF-induced attenuation of pain.
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PMID:Modulation of pain by [1DMe]NPYF, a stable analogue of neuropeptide FF, in neuropathic rats. 1133 3

The two mammalian neuropeptides NPFF and NPAF have been shown to have important roles in nociception, anxiety, learning and memory, and cardiovascular reflex. Two receptors (FF1 and FF2) have been molecularly identified for NPFF and NPAF. We have now characterized a novel gene designated NPVF that encodes two neuropeptides highly similar to NPFF. NPVF mRNA was detected specifically in a region between the dorsomedial and ventromedial hypothalamic nuclei. NPVF-derived peptides displayed higher affinity for FF1 than NPFF-derived peptides, but showed poor agonist activity for FF2. Following intracerebral ventricular administration, a NPVF-derived peptide blocked morphine-induced analgesia more potently than NPFF in both acute and inflammatory models of pain. In situ hybridization analysis revealed distinct expression patterns of FF1 and FF2 in the rat central nervous system. FF1 was broadly distributed, with the highest levels found in specific regions of the limbic system and the brainstem where NPVF-producing neurons were shown to project. FF2, in contrast, was mostly expressed in the spinal cord and some regions of the thalamus. These results indicate that the endogenous ligands for FF1 and FF2 are NPVF- and NPFF-derived peptides, respectively, and suggest that the NPVF/FF1 system may be an important part of endogenous anti-opioid mechanism.
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PMID:Identification and characterization of novel mammalian neuropeptide FF-like peptides that attenuate morphine-induced antinociception. 1148 30

In vertebrates, peripheral chemosensory neurons express large families of G protein-coupled receptors (GPCRs), reflecting the diversity and specificity of stimuli they detect. However, somatosensory neurons, which respond to chemical, thermal, or mechanical stimuli, are more broadly tuned. Here we describe a family of approximately 50 GPCRs related to Mas1, called mrgs, a subset of which is expressed in specific subpopulations of sensory neurons that detect painful stimuli. The expression patterns of mrgs thus reveal an unexpected degree of molecular diversity among nociceptive neurons. Some of these receptors can be specifically activated in heterologous cells by RFamide neuropeptides such as NPFF and NPAF, which are analgesic in vivo. Thus, mrgs may regulate nociceptor function and/or development, including the sensation or modulation of pain.
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PMID:A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. 1155 9

The presence of a neuropeptide AF and FF receptor (NPFF-R2) mRNA in human adipose tissue (Elshourbagy, N. A., Ames, R. S., Fitzgerald, L. R., Foley, J. J., Chambers, J. K., Szekeres, P. G., Evans, N. A., Schmidt, D. B., Buckley, P. T., Dytko, G. M., Murdock, P. R., Tan, K. B., Shabon, U., Nuthulaganti, P., Wang, D. Y., Wilson, S., Bergsma, D. J., and Sarau, H. M. (2000) J. Biol. Chem. 275, 25965-25971) suggested these peptides, principally recognized for their pain modulating effects, may also impact on adipocyte metabolism, an aspect that has not been explored previously. Our aim was thus to obtain more insights into the actions of these peptides on adipocytes, an approach initially undertaken with a functional genomic assay. First we showed that 3T3-L1 adipocytes express both NPFF-R1 and NPFF-R2 transcripts, and that NPAF binds adipocyte membranes with a nanomolar affinity as assessed by surface plasmon resonance technology. Then, and following a 24-h treatment with NPFF or NPAF (1 microm), we have measured using real-time quantitative reverse transcriptase-PCR the mRNA steady state levels of already well characterized genes involved in key pathways of adipose metabolism. Among the 45 genes tested, few were modulated by NPFF ( approximately 10%) and a larger number by NPAF ( approximately 27%). Interestingly, NPAF increased the mRNA levels of beta2- and beta3-adrenergic receptors (AR), and to a lesser extent those of beta1-ARs. These variations in catecholamine receptor mRNAs correlated with a clear induction in the density of beta2- and beta3-AR proteins, and in the potency of beta-AR subtype-selective agonists to stimulate adenylyl cyclase activity. Altogether, these data show that NPFF-R1 and NPFF-R2 are functionally present in adipocytes and suggest that besides their well described pain modulation effects, NPAF and to a lesser extent NPFF, may have a global impact on body energy storage and utilization.
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PMID:Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness. 1214 60

Studies have suggested that NPFF-like peptides and their receptors play important roles in physiological and pathological conditions. Here, we show, using multiple expression modalities, that the type 2 NPFF receptor (hNPFF2) is expressed in regions of the primate spinal cord and brainstem mediating pain sensation. In situ hybridization using an NPFF2 riboprobe, and immunohistochemistry using a novel NPFF2 antibody, demonstrated strong NPFF2 expression in the superficial layer of the dorsal horn, and in the spinal trigeminal nucleus of the brainstem of the African green monkey (AGM). In addition, autoradiography using a radiolabeled NPFF analog ([125I]1DMe) revealed dense binding signal in the superficial layer of the dorsal horn in the spinal cord. The distribution pattern of hNPFF2 in the AGM spinal cord and the lower level of the brainstem are consistent with a hypothesized potential role for NPFF peptides in modulation of sensory input, opioid analgesia and morphine tolerance through spinal and supraspinal mechanisms.
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PMID:Neuropeptide FF receptor 2 (NPFF2) is localized to pain-processing regions in the primate spinal cord and the lower level of the medulla oblongata. 1284 72

The brain substrates involved in the pharmacological effects of neuropeptide FF (NPFF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) including interactions with opioid systems, were investigated with the [14C]-2-deoxyglucose ([14C]-2-DG) autoradiography technique in mouse. The changes in cerebral activity were mapped after i.p. administration of 1DMe ([D-Tyr1,(NMe)Phe3]NPFF; 70 mg/kg), a neuropeptide FF analogue partially resistant to peptidases, alone or in combination with morphine (15 mg/kg). 1DMe induced a rapid decrease in the cerebral activity in the thalamus, the pontine reticular nuclei and the cerebellar cortex, brain regions involved in the control of motor activity and/or the processing of sensory data. This decrease, observed when 1DMe was administered 5 min before [14C]-2-DG, was reversed by morphine, which was devoid of significant effect at this time. When administered 30 min before the radioisotope, 1DMe was without effect, whereas morphine induced a significant increase in cerebral glucose utilization in the caudate putamen, the primary somatosensory cortex, the thalamus, the superior colliculus, the pontine reticular nuclei and the spinal cord. The association of morphine and 1DMe significantly increased cerebral glucose utilization in the same regions as morphine alone and also in three additional regions: the auditory cortex, the inferior colliculus and the dorsomedial periaqueductal gray. Following systemic administration, 1DMe and morphine modulated cerebral activity in brain regions involved in pain transmission and motor control, but their effects were temporally shifted, as were their effects on horizontal locomotor activity. However, neuropeptide FF-induced changes in brain activity were modulated in part by opioid receptors activation.
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PMID:Functional consequences of neuropeptide FF receptors stimulation in mouse: a cerebral glucose uptake study. 1520 62

The possible roles of the NPFF system in pain processing are summarized from the viewpoints of (1) biological activities of NPFF, (2) anatomical distribution of NPFF and its receptor(s) and (3) the regulation of NPFF and receptor(s) in animal models of pain. NPFF and NPFF analogues were found to have analgesic, pronociceptive and morphine modulating activities. Since the isolation of NPFF, several other RF-NH2 peptides have been identified and some of them were found to have nociceptive or morphine modulating activity. Depending on the pharmacological doses and locations of administration, NPFF may exhibit the biological activities of other structurally related RF-NH2 peptides thus complicating NPFF bioactivity studies and their interpretation. Acid sensing ion channels were found to respond to RF-NH2 peptides including NPFF, raising the possibility that interaction of NPFF and acid sensing ion channels can modulate nociceptive activity. NPFF and NPFF receptor mRNAs are highly expressed and localized in the superficial layers of the dorsal cord, the two genes are also in dorsal root ganglia though at much lower level. The spinal NPFF system is up-regulated by peripheral inflammation in the rat. Furthermore, immunohistochemically, NPFF receptor 2-protein was demonstrated to be increased in the primary afferents in the spinal cord of rats with peripheral inflammation. Regulation and localization of spinal NPFF systems, taken together with the analgesic bioactivity of intrathecally administered NPFF, strongly suggest involvement of spinal NPFF system in pain processing.
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PMID:Modulatory roles of the NPFF system in pain mechanisms at the spinal level. 1644 6

FMRFamide and related peptides typically exert their action through G-protein coupled receptors. However, two ionotropic receptors for these peptides have recently been identified. They are both members of the epithelial amiloride-sensitive Na+ channel and degenerin (ENaC/DEG) family of ion channels. The invertebrate FMRFamide-gated Na+ channel (FaNaC) is a neuronal Na+-selective channel which is directly gated by micromolar concentrations of FMRFamide and related tetrapeptides. Its response is fast and partially desensitizing, and FaNaC has been proposed to participate in peptidergic neurotransmission. On the other hand, mammalian acid-sensing ion channels (ASICs) are not gated but are directly modulated by FMRFamide and related mammalian peptides like NPFF and NPSF. ASICs are activated by external protons and are therefore extracellular pH sensors. They are expressed both in the central and peripheral nervous system and appear to be involved in many physiological and pathophysiological processes such as hippocampal long-term potentiation and defects in learning and memory, acquired fear-related behavior, retinal function, brain ischemia, pain sensation in ischemia and inflammation, taste perception, hearing functions, and mechanoperception. The potentiation of ASIC activity by endogenous RFamide neuropeptides probably participates in the response to noxious acidosis in sensory and central neurons. Available data also raises the possibility of the existence of still unknown FMRFamide related endogenous peptides acting as direct agonists for ASICs.
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PMID:FMRFamide-gated sodium channel and ASIC channels: a new class of ionotropic receptors for FMRFamide and related peptides. 1651 45

The tetra-peptide FMRF-NH(2) is a cardioexcitatory peptide in the clam. Using the antibody against this peptide, FMRF-NH(2)-like immunoreactive material was detected in mammalian CNS. Subsequently, mammalian FMRF-NH(2) immunoreactive peptides were isolated from bovine brain and characterized to be FLFQPQRF-NH(2) (NPFF) and AGEGLSSPFWSLAAPQRF-NH(2) (NPAF). The genes encoding NPFF precursor proteins and NPFF receptors 1 and 2 are expressed in all vertebrate species examined to date and are highly conserved. Among many biological roles suggested for the NPFF system, the possible modulatory role of NPFF in nocicetion and opiate analgesia has been most widely investigated. Pharmacologically, NPFF-related peptides were found to exhibit analgesia and also potentiate the analgesic activity of opiates when administered intrathecally but attenuate the opiate induced analgesia when administered intracerebroventricularly. RF-NH(2) peptides including NPFF-related peptides were found to delay the rate of acid sensing ion channels (ASIC) desensitization resulting in enhancing acid gated currents, raising the possibility that NPFF also may have a pain modulatory role through ASIC. The genes for NPFF as well as NPFF-R2, preferred receptor for NPFF, are highly unevenly expressed in the rat CNS with the highest levels localized to the superficial layers of the dorsal spinal cord. These two genes are also present in the dorsal root ganglia (DRG), though at low levels in normal rats. NPFF and NPFF-R2 mRNAs were found to be coordinately up-regulated in spinal cord and DRG of rats with peripheral inflammation. In addition, NPFF-R2 immunoreactivity in the primary afferents was increased by peripheral inflammation. The findings from the early studies on the analgesic and morphine modulating activities suggested a role for NPFF in pain modulation and this possibility is further supported by the distribution of NPFF and its receptor and the regulation of the NPFF system in vivo.
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PMID:Modulatory role of neuropeptide FF system in nociception and opiate analgesia. 1785 90


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