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)

Experiments were conducted to explore the effects of Neuropeptide FF acting at spinal and supraspinal sites in models of chronic inflammatory or neuropathic pain and of acute pain. Neuropeptide FF was administered intrathecally (i.t.; 10.0, 25.0 and 50.0 nmol) or intracerebroventricularly (i.c.v.; 10.0, 12.5 and 15.0 nmol) either 24 h after inflammation-inducing injections of Freund's Complete Adjuvant in one hind paw or 7 days after unilateral sciatic nerve constriction. Evoked pain was assessed by measuring the withdrawal response threshold (in grams of pressure) to a mechanical stimulus applied to the plantar surface of the injured paw. Neuropeptide FF dose-dependently attenuated the allodynic response (i.e., withdrawal from a normally innocuous stimulus) to mechanical stimulation in the inflammatory and neuropathic model following i.t. (ED50=20.86 nmol and ED50=18.91 nmol, respectively) and i.c.v. (ED50=12.31 nmol and ED50=11.68 nmol, respectively) administration. Pretreatment with naloxone (2.0 mg/kg; s.c.) attenuated the anti-allodynic effect of i.t. or i.c.v. Neuropeptide FF in rats experiencing inflammatory, but not neuropathic pain. In contrast, Neuropeptide FF administered i.t. (10.0, 25.0 and 50.0 nmol) or i.c.v. (10.0, 12.5 and 15.0 nmol) had no effect on the response to acute thermal or mechanical stimulation. Neuropeptide FF injected i.t. or i.c.v. in inflamed or neuropathic rats did not produce any sign of motor dysfunction. These results suggest that Neuropeptide FF acting at spinal and supraspinal sites plays a role in modulating chronic, but not acute pain. Furthermore, the results suggest that the anti-allodynic effect of Neuropeptide FF is mediated indirectly by naloxone-sensitive opioid mechanisms in rats subjected to inflammatory, but not neuropathic pain.
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PMID:Neuropeptide FF attenuates allodynia in models of chronic inflammation and neuropathy following intrathecal or intracerebroventricular administration. 1106 20

1. Neuropeptides FF (NPFF) and AF (NPAF) are involved in pain modulation and opioid tolerance. These peptides were known to act through uncharacterized G protein-coupled receptors (GPCR). We describe here, using an aequorin-based assay as screening tool, that an orphan GPCR, previously designated HLWAR77, is a functional high affinity receptor for NPFF and related peptides. This receptor is further designated as NPFFR. 2. Binding experiments were performed with a new radioiodinated probe, [(125)I]-EYF, derived from the EFW-NPSF sequence of the rat NPFF precursor. Chinese hamster ovary (CHO) cell membranes expressing NPFFR bound [(125)I]-EYF with a K(d) of 0.06 nM. Various NPFF analogues and related peptides inhibited [(125)I]-EYF specific binding with the following rank order (K(i)): human NPAF (0.22 nM), SQA-NPFF (0.29 nM), NPFF (0.30 nM), 1DMe (0.31 nM), EYW-NPSF (0.32 nM), QFW-NPSF (0.35 nM), 3D (1.12 nM), Met-enk-RF-NH(2) (3.25 nM), FMRF-NH(2) (10.5 nM) and NPSF (12.1 nM). 3. The stimulatory activity of the same set of peptides was measured by a functional assay based on the co-expression of NPFFR, G(alpha 16) and apoaequorin. The rank order of potency was consistent with the results of the binding assay. 4. Membranes from NPFFR expressing CHO cells bound GTP gamma[(35)S] in the presence of SQA-NPFF. This functional response was prevented by pertussis toxin treatment, demonstrating the involvement of G(i) family members. 5. SQA-NPFF inhibited forskolin induced cyclic AMP accumulation in recombinant CHO cells in a dose dependent manner. This response was abolished as well by pertussis toxin pre-treatment. 6. RT -- PCR analysis of human tissues mRNA revealed that expression of NPFFR was mainly detected in placenta, thymus and at lower levels in pituitary gland, spleen and testis.
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PMID:Functional characterization of a human receptor for neuropeptide FF and related peptides. 1132 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

Several neuropeptide FF (NPFF)-related peptides, known as modulators of the opioid system, have been previously characterized in bovine and rodent brain. Reverse-phase high pressure liquid chromatography (HPLC) fractions of a human with normal pressure hydrocephalus cerebrospinal fluid (CSF), co-migrating with NPFF-related synthetic peptides, were characterized by capillary HPLC coupled on-line to nanospray ion trap tandem mass spectrometry. Two peptides present in the pro-NPFF(A) precursor, NPAF (AGEGLNSQFWSLAAPQRF-NH2) and NPSF (SLAAPQRF-NH2), were identified. The monitoring of NPFF-related peptides in human CSF can be helpful to understand their roles in pain sensitivity.
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PMID:Identification of neuropeptide FF-related peptides in human cerebrospinal fluid by mass spectrometry. 1248 85

Neuropeptide FF, one of the mammalian PQRFamides, has been reported to affect the latency of the tail-flick response in rat. We intended to examine the nociceptive effect by the peptide PQRFamides from the comparative aspect. Using the dot immunoblot method with antiserum to FMRFamide as an assay system, a peptide (frog's nociception-related peptide, fNRP) which has the C-terminal sequence PQRFamide was isolated from the brain of the frog, Rana catesbeiana. The determined sequence, SIPNLPQRF-NH(2), is the same as that named first (frog growth hormone-releasing peptide-gene-related peptide-1: fGRP-RP-1, which is encoded in the cDNA of the fGRP precursor. Since the peptide was isolated from the frog brain, we tested another amphibian, the newt, which has a tail, by the hot beam tail-flick test. Intraperitoneal injection of fNRP significantly increased the latency of the pain response (tail-flick) 90 min after administration. The effect was blocked by simultaneous administration of 5 mM naloxone. The result provides evidence for the interaction of fNRP and opioid steps in the analgesia pathways in the newt.
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PMID:Identification of a novel frog RFamide and its effect on the latency of the tail-flick response of the newt. 1260 Jun 86

Acid sensing ion channel 3 (ASIC3) is a cation channel gated by extracellular protons. It is highly expressed in sensory neurons, including small nociceptive neurons and has been proposed to participate in pain perception associated with tissue acidosis and in mechanoperception. Neuropeptide FF (NPFF) and FMRFamide have been shown to potentiate proton-gated currents from cultured sensory neurons and acid sensing ion channel (ASIC) cDNA transfected cells. In this study, we report that another mammalian peptide neuropeptide SF (NPSF), derived from the same precursor, also considerably increases the amplitude of the sustained current of heterologously expressed ASIC3 (12-fold vs. 19- and nine-fold for FMRFamide and NPFF, respectively) with an EC(50) of approximately 50 microM. Similar effects were also observed on endogenous ASIC3-like sustained current recorded from DRG neurons although of smaller amplitudes (two-, three- and seven-fold increase for NPSF, NPFF and FMRFamide, respectively), and essentially related to a slowing down of the inactivation rate. Importantly, this modulation induced changes in neuronal excitability in response to an electrical stimulus applied during extracellular acidification. ASIC3-mediated sustained depolarisation, and its regulation by neuropeptides, could thus be important in regulating polymodal neuron excitability particularly under inflammatory conditions where the expression levels of both NPFF precursor and ASIC3 are increased.
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PMID:Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. 1266 52

Neuropeptide FF (NPFF) is involved in pain modulation, especially plasticity during inflammatory and neuropathic pain, and opiate interactions. Its nociceptive functions may be mediated by the NPFF2 receptor. To elucidate the role of the NPFF system in plasticity associated with pathologic pain, we studied the changes of NPFF mRNA and NPFF2 receptor mRNA in rat models of acute colonic inflammation, inflammatory pain, and neuropathic pain. Furthermore, we studied the mRNA levels of both NPFF and NPFF2 receptor in morphine-tolerant rats and after acute morphine injections. We found an activation of spinal NPFF and NPFF2 receptor during early inflammatory pain. Supraspinally, we found an up-regulation of NPFF2 receptor mRNA during acute colonic inflammation and neuropathic pain. Acute, but not chronic, morphine activated the genes supraspinally. The results give further evidence for the involvement of the NPFF system in pain modulation and may provide new therapeutic opportunities for pathologic pain.
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PMID:Pain- and morphine-associated transcriptional regulation of neuropeptide FF and the G-protein-coupled NPFF2 receptor gene. 1520 82

Opioids are involved in the physiological control of numerous functions of the central nervous system, particularly nociception. It appears that some endogenous neuropeptides, called anti-opioids, participate in an homeostatic system tending to reduce the effects of opioids. Neuropeptide FF (NPFF) and cholecystokinin (CCK) possess these properties and, paradoxically, the opioid peptides nociceptin and dynorphin display some anti-opioid activity. All these peptides exhibit complex properties as they are able to both counteract and potentiate opioid activity, acting rather as modulators of opioid functions. The purpose of this review is to highlight that two different mechanisms are clearly involved in the control of opioid functions by opioid-modulating peptides: a circuitry-induced mechanism for nociceptin and dynorphin, and a cellular anti-opioid mechanism for NPFF and CCK. The knowledge of these mechanisms has potential therapeutic interest in the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
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PMID:Opioid-modulating peptides: mechanisms of action. 1585 16


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