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)

The tachykinins are a family of peptides with putative neurotransmitter roles in the nervous system. They mediate their effects via neurokinin-1, neurokinin-2 and neurokinin-3 receptors. There has been increasing interest in the therapeutic application of the tachykinin neurokinin-1 receptor antagonists in the treatment of pain and emesis, and more recently in depression. However, the central role of neurokinin-1 receptors is not well understood. The aims of the present study were to determine the behavioural responses of guinea-pigs, and the distribution of Fos-like immunoreactivity in the guinea-pig brain, following intracerebroventricular administration of the neurokinin-1 receptor-selective agonist, [Sar9,Met(O2)11]substance P. The effects of pretreatment with the neurokinin-1 receptor antagonist, SR 140333, were also investigated. Administration of [Sar9,Met(O2)11]substance P induced increased locomotor activity, as well as face washing, grooming and wet-dog shake behaviours, all of which were inhibited by the neurokinin-1 receptor antagonist, SR 140333, indicating the involvement of neurokinin-1 receptors. In order to localize the brain regions activated by [Sar9,Met(O2)11]substance P, the distribution of neurons expressing Fos-like immunoreactivity was examined. [Sar9,Met(O2)11]substance P induced increased Fos-like immunoreactivity in widespread areas, including the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus, periaqueductal gray, area postrema and nucleus of the solitary tract. SR 140333 reduced Fos-like immunoreactivity induced by [Sar9,Met(O2)11]substance P in most areas. Thus, brain regions associated with emotion, sensation, learning and memory, autonomic regulation and emesis were activated by stimulation of neurokinin-1 receptors. The present data have added a functional domain to previous neurokinin-1 receptor localization studies by describing the extensive regions of the CNS that may be activated by stimulation of these receptors, and the potential of neurokinin-1 receptor antagonists to inhibit activation of these regions.
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PMID:Distribution of Fos-like immunoreactivity in guinea-pig brain following administration of the neurokinin-1 receptor agonist, [SAR9,MET(O2)11]substance P. 1057 26

When adrenal medullary cells are cultured in vitro, tyrosine hydroxylase (TH) mRNA, preproenkephalin (PPEnk) mRNA, and methionine enkephalin (Mek) immunoreactivity was markedly increased compared with intact adrenal medullary cells in situ, suggesting an increased biosynthesis of catecholamines and enkephalin-containing peptides. In transplanted adrenal medullary cells in vivo, TH mRNA and TH immunoreactivity are still apparent for at least 1 year after transplantation, indicating continued capacity for catecholamine biosynthesis. PPEnk mRNA levels in surviving adrenal medullary grafted cells increased, particularly in the first week after transplantation, and remained above levels found in the intact adrenal gland for at least 1 year after transplantation. These results support other studies in our laboratory, suggesting that adrenal medullary transplants reduce pain by synthesis and secretion of both catecholamines and enkephalin-containing peptides. The differences in expression of TH mRNA and PPEnk mRNA in the adrenal medulla in situ, in explants in culture and in transplants in the spinal subarachnoid space, indicate that the mechanisms regulating the expression of neurohumoral factors depend upon environmental factors extrinsic to the medullary cells themselves.
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PMID:Comparison of tyrosine hydroxylase and preproenkephalin expression in rat adrenal medullary explants in vitro and transplanted into subarachnoid space. 1068

The purposes of this study were to determine the relationship between the physical activity values obtained from the peripheral arterial disease-physical activity recall (PAD-PAR) questionnaire and (1) the free-living daily physical activity obtained from the doubly labeled water technique and (2) clinical measures of PAD severity. Fifty-one older PAD patients (age= 70 +/- 6 years) were recruited from the Vascular Clinic at the Baltimore Veterans Affairs Medical Center and from radio and newspaper advertisements. Energy expenditure of physical activity (EEPA) was determined by using doubly labeled water and indirect calorimetry techniques. PAD severity was measured by ankle/brachial index (ABI) and walking distance to maximal claudication pain determined during a graded treadmill test. In addition, patients were also characterized on body composition and total daily energy expenditure. The physical activity values obtained from the PAD-PAR questionnaire (113 +/- 37 MET-hr/wk) were not related to EEPA (542 +/- 260 kcal/day; r= -0.057, p=0.690), ABI (0.64 +/- 0.19; r=0.032, p=0.826), or distance to maximal claudication pain (376 +/- 229 m; r=-0.054, p=0.731). The authors conclude that the PAD-PAR questionnaire is not an accurate measurement of free-living daily physical activity when compared to EEPA by use of the criterion method of doubly labeled water, and the activity questionnaire measures were poorly correlated with clinical measures of PAD severity.
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PMID:Relationship between physical activity recall and free-living daily physical activity in older claudicants. 1074 5

Acidosis is associated with inflammation and ischemia and activates cation channels in sensory neurons. Inflammation also induces expression of FMRFamidelike neuropeptides, which modulate pain. We found that neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe amide) and FMRFamide (Phe-Met-Arg-Phe amide) generated no current on their own but potentiated H+-gated currents from cultured sensory neurons and heterologously expressed ASIC and DRASIC channels. The neuropeptides slowed inactivation and induced sustained currents during acidification. The effects were specific; different channels showed distinct responses to the various peptides. These results suggest that acid-sensing ion channels may integrate multiple extracellular signals to modify sensory perception.
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PMID:Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. 1079 98

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

Methionine-enkephalin (Met-Enk) induces notable alterations in immune and central nervous system functions. The present study was conducted in order to compare peripheral and central effects of Met-Enk on nonspecific immunity, open field behavior and pain perception in the rat. The results showed that 0.2 mg/kg of Met-Enk given intraperitoneally (i.p.) increased concanavalin A (Con-A)-induced paw edema and enhanced basal and phorbol myristate acetate (PMA)-stimulated H(2)O(2) production of peritoneal macrophages. Met-Enk-induced immunopotentiation was antagonized by anti-Met-Enk antibodies (anti-Met-Enk-Ig) and quaternary naltrexone (qNtx). Met-Enk injected i.p. produced an increase of horizontal and vertical locomotor activity in the open field that was reversed by i. p. administration of anti-Met-Enk-Ig and qNtx. The dose of 0.2 mg/kg of Met-Enk applied i.p. did not affect the number of writhes in the test of analgesia. Intracerebroventricular (i.c.v.) injection of Met-Enk, given in a dose that was previously shown to be immunostimulatory, enhanced only basal H(2)O(2) production of peritoneal macrophages, and anti-Met-Enk-Ig antagonized this effect. Besides, i.c.v. treatment with anti-Met-Enk-Ig increased and decreased H(2)O(2) production of peritoneal macrophages under basal and stimulated conditions, respectively. Met-Enk and anti-Met-Enk-Ig injected i.c.v. did not influence activity in the open field and pain sensitivity. Thus, the i.c.v. dose of Met-Enk that was sufficient to modulate immune functions did not influence behavior. It may be concluded that Met-Enk modulated nonspecific immune responses and open field behavior by peripheral mechanisms.
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PMID:Peripheral effects of methionine-enkephalin on inflammatory reactions and behavior in the rat. 1096 31

This study examined a mechanism responsible for the enhanced antihyperalgesic and antinociceptive effects of the mu opioid receptor agonist (ORA) [D-Ala(2), NMePhe(4), Gly(5)-ol]enkephalin (DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats with inflammatory injury induced by injection of complete Freund's adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier, microinjection of the mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in the RVM antagonized both the marginal enhancement of the potency of DAMGO and its antinociceptive effect. The delta opioid receptor antagonist naltriben (NTB) was without effect. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancement of the potency of DAMGO, whereas it did not antagonize DAMGO's antinociceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpaw and induced hyperalgesia in the contralateral, uninjured hindpaw. These results suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the delta opioid receptor, which can interact in a synergistic or additive manner with an exogenously administered mu opioid receptor agonist. Indeed, the levels of [Met(5)]enkephalin and [Leu(5)]enkephalin were increased in the RVM and in other brainstem nuclei in CFA-treated rats. This increase most likely presents a compensatory neuronal response of the CNS of the injured animal to mitigate the full expression of inflammatory pain and to enhance the antinociceptive and antihyperalgesic effects of exogenously administered mu opioid receptor analgesics.
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PMID:Contribution of endogenous enkephalins to the enhanced analgesic effects of supraspinal mu opioid receptor agonists after inflammatory injury. 1126 27

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

We have previously shown that beta-endorphin (END) is contained and released from memory-type T-cells within inflamed tissue and that it is capable to control pain (J Clin Invest 100(1) (1997) 142). Methionine-enkephalin (MET) and Dynorphin-A (DYN) are endogenous opioids with preference for delta- and kappa-opioid receptors, respectively. Both MET and DYN are produced and contained within immune cells. The goal of this study was to determine the release characteristics of MET and DYN in a rat model of localized hindpaw inflammation and to examine the antinociceptive role of MET and DYN in a Freund's adjuvant induced model of inflammatory pain. We found that corticotropin-releasing factor (CRF) can stimulate the release of both MET and DYN from lymphocytes. This release is dose-dependent and reversible by the selective CRF antagonist alpha-helical-CRF. Furthermore, CRF (1.5 ng) produces analgesia when injected into the inflamed paw, which is reversible by direct co-administration of antibodies to MET. Lymphocyte content of MET was 7.0+/-1.4 ng/million cells, whilst DYN content was ~30-fold lower. Both END and DYN, but not MET, were released by IL-1. Consistently, IL-1 produced peripheral analgesic effects which were not reversed by antibodies to MET. These results indicate that both MET and DYN play a role in peripheral analgesia but have different characteristics of release. These studies further support a role of the immune system in the control of inflammatory pain. This may be particularly important in patients suffering from compromised immune systems as with cancer and AIDS.
Pain 2001 Sep
PMID:Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. 1151 79

Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.
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PMID:Sulfur in human nutrition and applications in medicine. 1189 44


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