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)

We isolated a cDNA encoding an orphan G protein-coupled receptor, TGR7, which has been recently reported to correspond to MrgD. To search for ligands for TGR7, we screened a series of small molecule compounds by detecting the Ca2+ influx in Chinese hamster ovary cells expressing TGR7. Through this screening, we found that beta-alanine at micromolar doses specifically evoked Ca2+ influx in cells expressing human, rat, or mouse TGR7. A structural analogue, gamma-aminobutyric acid, weakly stimulated cells expressing human or rat TGR7, but another analogue, glycine, did not. In addition, beta-alanine decreased forskolin-stimulated cAMP production in cells expressing TGR7, suggesting that TGR7 couples with G proteins Gq and Gi. In guanosine 5'-O-3-thiotriphosphate binding assays conducted using a membrane fraction of cells expressing TGR7, beta-alanine specifically increased the binding of guanosine 5'-O-3-thiotriphosphate. When a fusion protein composed of TGR7 and green fluorescent protein was expressed in cells, it localized at the plasma membrane but internalized into the cytoplasm after treatment with beta-alanine. In addition, we found that beta-[3H]alanine more efficiently bound to TGR7-expressing cells than to control cells. From these results, we concluded that TGR7 functioned as a specific membrane receptor for beta-alanine. Quantitative PCR analysis revealed that TGR7 mRNA was predominantly expressed in the dorsal root ganglia in rats. By in situ hybridization and immunostaining, we confirmed that TGR7 mRNA was co-expressed in the small diameter neurons with P2X3 and VR1, both in rat and monkey dorsal root ganglia. Our results suggest that TGR7 participates in the modulation of neuropathic pain.
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PMID:Identification of a G protein-coupled receptor specifically responsive to beta-alanine. 1503 33

A recent review calls attention to the discrepant results resulting from studies that have examined the nociceptive or antinociceptive properties of orphanin-FQ/nociceptin (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-ArgLys-Leu-Ala-Asn-Gln; OFQ/N), the heptadecapeptide isolated from rat (nociceptin) and pig (orphanin FQ) brain that binds with high affinity to the opioid 'orphan' receptor (a seven transmembrane protein with sequence homology to opioid receptors), but exhibits only low affinity binding with conventional opioid ligands. Some of the discrepancy might result from differences in species, test, route of administration or time-course. We undertook a comprehensive examination of the effects of spinal (i.t.) or supraspinal (i.c.v.) administration of OFQ/N in mice and rats. Mice treated with OFQ/N either i.t. or i.c.v. demonstrated no significant nociceptive effect in the hot plate, warm-water or radiant heat tail-flick tests (except for the highest and most sedative dose of 10 nmol i.c.v. in the mouse warm-water tail-flick test). Pretreatment with the opioid antagonist naloxone or with peptidase inhibitors did not enhance the nociceptive effects of OFQ/N peptide in the warm-water tail-flick test. The motor activity in mice administered OFQ/N i.c.v. decreased significantly compared to controls. Rats administered i.c.v. or i.t. OFQ/N displayed no significant difference from vehicle-treated animals in similar noxious stimulus tests and OFQ/N-treated rats did not exhibit allodynia in a paw-withdrawal test. Overall, OFQ/N was ineffective in significantly altering response to noxious stimuli, regardless of whether the peptide was given at supraspinal or spinal sites in mice or in rats. In addition, i.c.v. or i.t. application of antisense or mismatch ODN to the orphan receptor did not modify tail-flick latency in either mice or rats, arguing against a tonic nociceptive tone mediated via the OFQ/N receptor.
Eur J Pain 1998
PMID:Orphanin-FQ/nociceptin: lack of anti nociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests following intracerebroventricular or intrathecal administration to mice or rats. 1510 88

The aim of the present study was to investigate the effect of a micro-opioid receptor agonist DAMGO (Tyr-d-Ala-Gly-NMe-Phe-Gly-ol) on the excitability of trigeminal root ganglion (TRG) neurons, projecting onto the superficial layer of the cervical dorsal horn, by using the perforated-patch technique and to determine whether TRG neurons show the expression of mRNA or functional protein for micro-opioid receptors by using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. TRG neurons projecting onto the superficial layer of the cervical dorsal horn were retrogradely labeled with Fluorogold (FG). The cell diameter of FG-labeled TRG neurons was small (<30 microm). Under voltage-clamp (V(h)=-60 mV), voltage-dependent K(+) currents were recorded in the TRG neurons and isolated by blocking Na(+) and Ca(2+) currents with appropriate ion replacement. Separation of the K(+) current components was achieved by the response to variation in the conditioning voltage. Two distinct K(+) current components, a transient (I(A)) and sustained (I(K)), were identified. DAMGO significantly increased I(A) by 57% (20 microM) and in a dose-dependent manner (1-50 microM). Similarly, I(K) was also enhanced by DAMGO administration (42%, 20 microM). The augmentation of both I(A) and I(K) was antagonized by a micro-opioid receptor antagonist, CTOP (d-Phe-Cys-Thr-d-Trp-Orn-Thr-Pen-Thr-NH(2)). Hyperpolarization of the membrane potential was elicited by DAMGO (20 microM) and the response was associated with a decrease in the input resistance. DAMGO induced hyperpolarization was blocked by CTOP. DAMGO-sensitive I(A) and I(K) currents were antagonized by K(+) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA). In the presence of both 4-AP and TEA, no significant changes in membrane potential induced by DAMGO application were observed. In the presence of BaCl(2), DAMGO evoked hyperpolarization with decreased resistance was observed. The firing rate of action potentials and the first spike duration induced by depolarizing step pulses were decreased in the presence of DAMGO. RT-PCR analysis demonstrated the expression of mRNA for micro-opioid receptors in the trigeminal ganglia. The micro-opioid receptor immunoreactivity was expressed in the small diameter FG-labeled TRG neurons. These results suggest that the activation of micro-opioid receptors inhibits the excitability of rat small diameter TRG neurons projecting on the superficial layer of the cervical dorsal horn and this inhibition is mediated by potentiation of voltage-dependent K(+) currents. We therefore concluded that modulation of nociceptive transmission in the trigeminal system, resulting in the functional activation of micro-opioid receptors, occurs at the level of small TRG cell bodies and/or their primary afferent terminals, which contribute to opioid analgesia in the trigeminal pain.
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PMID:Opioidergic modulation of excitability of rat trigeminal root ganglion neuron projections to the superficial layer of cervical dorsal horn. 1512 Aug 59

Opioid analgesics with restricted access to the central nervous system represent a new approach to the treatment of severe pain with an improved safety profile. The objective of this study was to investigate the peripheral and central components of the antinociceptive actions of the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared with those of the centrally penetrating mu-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. In the tail-flick test in rats, the 6-amino acid conjugates were 45- to 1170-fold more potent than morphine after i.c.v. administration and 19- to 209-fold after s.c. administration. They showed potencies similar to fentanyl after s.c. administration and were more potent after i.c.v. application. The time course of action was different between s.c. and i.c.v. administration, with significant long-lasting effects after i.c.v. administration. Systemic administration of the peripherally selective opioid antagonist naloxone methiodide antagonized the effects after s.c. but not after i.c.v. administration in the tail-flick test. Subcutaneous 6-amino acid derivatives also elicited antihyper-analgesic effects in the formalin test in rats, which were reversed by systemically administered naloxone methiodide. Although morphine exerts its analgesic effects by central and peripheral mechanisms, the investigated new opioids interact primarily with peripheral opioid receptors after s.c. administration. The present data indicate that the 6-amino acid conjugates of 14-O-methyloxymorphone have limited access to the central nervous system and can mediate antinociception at peripheral sites. Also, they might find clinical application when the central actions of opioids are unwanted.
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PMID:Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. 1538 36

Increases in neuronal activity in response to tissue or nerve injury can lead to prolonged functional changes in the spinal cord resulting in an enhancement/sensitization of nociceptive processing. To assess the contribution of alpha-calcium-calmodulin kinase II (alpha-CaMKII) to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a point mutation in the alpha-CaMKII gene at position 286 (threonine to alanine). The mutated protein is unable to autophosphorylate and thus cannot function independently of calcium and calmodulin. Responses to acute noxious stimuli did not differ between alpha-CaMKII T286A mutant and wild type mice. However, the ongoing pain produced by formalin injury was significantly reduced in the mutant mice, as was formalin-evoked spinal Fos-immunoreactivity. In contrast, the decreased mechanical and thermal thresholds associated with nerve injury, Complete Freund's Adjuvant-induced inflammation or formalin-evoked tissue injury were manifest equally in wild-type and mutant mice. Double-labeling immunofluorescence studies revealed that in the mouse alpha-CaMKII is expressed in the superficial dorsal horn as well as in a population of small diameter primary afferent neurons. In summary, our results suggest that alpha-CaMKII, perhaps secondary to an N-methyl-D-aspartate-mediated calcium increase in postsynaptic dorsal horn nociresponsive neurons, is a critical contributor to the spontaneous/ongoing component of tissue-injury evoked persistent pain.
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PMID:The contribution of autophosphorylated alpha-calcium-calmodulin kinase II to injury-induced persistent pain. 1546 94

On nociceptive neurons, one important mechanism to generate pain signals is the activation of P2X(3) receptors, which are membrane proteins gated by extracellular ATP. In the presence of the agonist, P2X(3) receptors rapidly desensitize and then recover slowly. One unique property of P2X(3) receptors is the recovery acceleration by extracellular Ca(2+) that can play the role of the gain-setter of receptor function only when P2X(3) receptors are desensitized. To study negatively charged sites potentially responsible for this action of Ca(2+), we mutated 15 non-conserved aspartate or glutamate residues in the P2X(3) receptor ectodomain with alanine and expressed such mutated receptors in human embryonic kidney cells studied with patch clamping. Unlike most mutants, D266A (P2X(3) receptor numbering) desensitized very slowly, indicating that this residue is important for generating desensitization. Recovery appeared structurally distinct from desensitization because E111A and D266A had a much faster recovery and D220A and D289A had a much slower one despite their standard desensitization. Furthermore, E161A, E187A, or E270A mutants showed lessened sensitivity to the action of extracellular Ca(2+), suggesting that these determinants were important for the effect of this cation on desensitization recovery. This study is the first report identifying several negative residues in the P2X(3) receptor ectodomain differentially contributing to the general process of receptor desensitization. At least one residue was important to enable the development of rapid desensitization, whereas others controlled recovery from it or the facilitating action of Ca(2+). Thus, these findings outline diverse potential molecular targets to modulate P2X(3) receptor function in relation to its functional state.
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PMID:Identification of negative residues in the P2X3 ATP receptor ectodomain as structural determinants for desensitization and the Ca2+-sensing modulatory sites. 1547 63

The descending pain control system is activated by opioid peptides mainly at the midbrain periaqueductal gray (PAG). Although activation of presynaptic opioid receptors has been reported to inhibit gamma-aminobutyric acid (GABA) release, the exact electrophysiological mechanisms are controversial. To elucidate the mechanisms involved in the opioid modulation of presynaptic GABA release, we isolated single PAG neurons with functionally intact synaptic terminals by a mechanical dissociation in the absence of enzyme. With the conventional whole-cell recording mode under the voltage-clamp conditions, the spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were recorded. Bicuculline completely and reversibly blocked mIPSCs. A specific mu-opioid agonist, [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), reversibly reduced the frequency of mIPSCs without any alteration of amplitude. The inhibitory effect of DAMGO was blocked by N-ethylmaleimide. Blockade of presynaptic Ca(2+) influx by cadmium or depletion of extracellular Ca(2+) did not alter the DAMGO inhibition. In addition, K(+) channels blockers, Ba(2+) or 4-aminopyridine, did not affect the DAMGO effect. The present study indicates that activation of presynaptic mu-opioid receptors coupled to G-proteins inhibits GABA release through unknown intracellular mechanisms downstream of Ca(2+) influx.
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PMID:Opioid inhibition of GABAergic neurotransmission in mechanically isolated rat periaqueductal gray neurons. 1548 97

Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4-17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.
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PMID:The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships. 1559 48

Patients with gout are at a high risk for drug-induced complications associated with the use of nonsteroidal anti-inflammatory drugs due to the baseline renal and hepatic abnormalities, metabolic disturbances, and concomitant diseases, such as arterial hypertension or type 2 diabetes mellitus. In this connection, it is expedient to use safer selective cycloxygenase-2 (COG-2) inhibitors. However, there are only single reports dealing with studies of the effectiveness and safety of selective COG-2 inhibitors in gout. The study was undertaken to evaluate the effectiveness and safety of the selective COG-2 inhibitor nimesulide (nimesile) in acute gouty arthritis (GA). Twenty male patients (whose mean age was 51.1 +/- 8.4 years) with PA were examined. Seven patients were found to have monoarthritis of 1 metatarsophalangeal joint, oligoarthritis was present in 9 patients and 4 patients had polyarthritis. The history of arthritis was as long as 6 days in 16 patients and 21-30 days in 4. Nimesulide was given in a dose of 200 mg/day for at least 14 days. The time course of changes in the objective and subjective symptoms of arthritis was studied. The tolerability of the drug was evaluated by its effect on renal (the levels of creatinine and urea, creatinine clearance) and hepatic (alanine transferase (ALT), aspartate transferase (AST), gamma-glutamyltranspeptidase (gamma-GTP)) functions, and blood pressure (BP) [24-hour BP monitoring (24-h BPM) before and after treatment. There were clear positive changes in the major parameters of arthritis: the swelling index was 4.5 +/- 2.7 and 0.5 +/- 0.5 scores before and after treatment, respectively; hyperemia, 3.5 +/- 2.5 and 0.1 +/- 0. 1 scores; articular index, 3.6 +/- 2.0 and 0.7 +/- 0.6 scores; pain (visual analogue scale) when resting, 53.8 +/- 17.6 and 4.7 +/- 4.6 scores, and that when moving, 68.3 +/- 16.0 and 9.0 +/- 8.8 mm, respectively. Negative changes in the levels of creatinine and uric acid and a reduction in creatinine clearance were not observed. There were no increases in the levels of ACT, ALT, gamma-GTP. 24-h BPM did not reveal any significant changes in the mean 24-hour, mean diurnal and nocturnal variables of BP. The 24-hour BP profile became better in some patients. Thus, nimesulide is an effective and safe drug for the treatment of PA.
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PMID:[The effectiveness and safety of nimesulide (nimesile) in patients with gouty arthritis]. 1573 21

The aim of this study was to determine neutrophil elastase levels (NE) in periapical exudates and to evaluate its relationship with clinical signs and symptoms of endodontically involved teeth. A total of 42 teeth with periapical periodontitis of 37 patients were clinically examined and spontaneous pain, swelling, pain on palpation or percussion, sinus tract formation and pus discharge were recorded. Additionally, periapical lesion size was measured on periapical radiographs. Periapical exudate samples were obtained during routine root canal treatment by using paper points. Enzyme levels were determined by spectrophotometric assays using the NE specific substrate N-methoxysuccinil-Ala-Ala-Pro-Val-p-nitroanilide. The teeth with signs and symptoms showed higher NE levels than the teeth without symptoms (p<0.05). The differences were significant when NE levels were presented as total amounts instead of concentration. This study demonstrated that NE in periapical lesions related with clinical symptoms and total enzyme amount may be more reliable mode of data presentation.
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PMID:Neutrophil elastase levels in periapical exudates of symptomatic and asymptomatic teeth. 1585 27


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