Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GPR7 and GPR8 are orphan G protein-coupled receptors that are highly similar to each other. These receptors are expressed predominantly in brain, suggesting roles in central nervous system function. We have purified an endogenous peptide ligand for GPR7 from bovine hypothalamus extracts. This peptide, termed neuropeptide B (NPB), has a C-6-brominated tryptophan residue at the N terminus. It binds and activates human GPR7 or GPR8 with median effective concentrations (EC(50)) of 0.23 nM and 15.8 nM, respectively. In situ hybridization shows distinct localizations of the prepro-NPB mRNA in mouse brain, i.e., in paraventricular hypothalamic nucleus, hippocampus, and several nuclei in midbrain and brainstem. Intracerebroventricular (i.c.v.) injection of NPB in mice induces hyperphagia during the first 2 h, followed by hypophagia. Intracerebroventricular injection of NPB produces analgesia to s.c. formalin injection in rats. Through EST database searches, we identified a putative paralogous peptide. This peptide, termed neuropeptide W (NPW), also has an N-terminal tryptophan residue. Synthetic human NPW binds and activates human GPR7 or GPR8 with EC(50) values of 0.56 nM and 0.51 nM, respectively. The expression of NPW mRNA in mouse brain is confined to specific nuclei in midbrain and brainstem. These findings suggest diverse physiological functions of NPB and NPW in the central nervous system, acting as endogenous ligands on GPR7 andor GPR8.
 ...
PMID:Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8. 1271 37

Adrenocorticotropin (ACTH) and alpha-melanocyte stimulating hormone (alpha-MSH) are peptides which present many physiological effects related to pigmentation, motor and sexual behavior, learning and memory, analgesia, anti-inflammatory and antipyretic processes. The 13 amino acid residues of alpha-MSH are the same initial sequence of ACTH and due to the presence of a tryptophan residue in position 9 of the peptide chain, fluorescence techniques could be used to investigate the conformational properties of the hormones in different environments and the mechanisms of interaction with biomimetic systems like sodium dodecyl sulphate (SDS) micelles, sodium dodecyl sulphate-poly(ethylene oxide) (SDS-PEO) aggregates and neutral polymeric micelles. In buffer solution, fluorescence parameters were typical of peptides containing tryptophan exposed to the aqueous medium and upon addition of surfactant and polymer molecules, the gradual change of those parameters demonstrated the interaction of the peptides with the microheterogeneous systems. From time-resolved experiments it was shown that the interaction proceeded with conformational changes in both peptides, and further information was obtained from quenching of Trp fluorescence by a family of N-alkylpyridinium ions, which possess affinity to the microheterogeneous systems dependent on the length of the alkyl chain. The quenching of Trp fluorescence was enhanced in the presence of charged micelles, compared to the buffer solution and the accessibility of the fluorophore to the quencher was dependent on the peptide and the alkylpyridinium: in ACTH(1-21) highest collisional constants were obtained using ethylpyridinium as quencher, indicating a location of the residue in the surface of the micelle, while in alpha-MSH the best quencher was hexylpyridinium, indicating insertion of the residue into the non-polar region of the micelles. The results had shown that the interaction between the peptides and the biomimetic systems where driven by combined electrostatic and hydrophobic effects: in ACTH(1-24) the electrostatic interaction between highly positively charged C-terminal and negatively charged surface of micelles and aggregates predominates over hydrophobic interactions involving residues in the central region of the peptide; in alpha-MSH, which presents one residual positive charge, the hydrophobic interactions are relevant to position the Trp residue in the non-polar region of the microheterogeneous systems.
 ...
PMID:Interaction of adrenocorticotropin peptides with microheterogeneous systems--a fluorescence study. 1901 30

The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/-) and knockout (-/-) mice. Comparisons were made with SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviours in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT-/- mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT-/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/- mice.
 ...
PMID:Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice. 1927 75

In 'arthritic' rats a decrease in total tryptophan and an increase in free tryptophan levels was observed in serum after morphine administration (10 mg kg, s.c.). These changes were maximum within 15 and 30 min after injection. A decrease in total and an increase in free tryptophan levels in serum were observed 30 min after naloxone administration (1 mg/kg, i.m.). An increase in tryptophan and 5-hydroxyindoleacetic acid levels was also observed in the brain after morphine and naloxone. These observations suggest that the rise in 5-hydroxytryptamine synthesis provoked by morphine may be partly related to an increase in the availability of tryptophan from blood. However, the analgesia induced by the opiate appears unlikely to be directly related to this effect.
 ...
PMID:Changes in total and free tryptophan levels in serum following acute morphine administration in arthritic rats. 2048 29

G-protein coupled receptor 35 (GPR35) is a former "orphan receptor" expressed in brain and activated by either kynurenic acid or zaprinast. While zaprinast has been studied as a phosphodiesterase inhibitor, kynurenic acid (KYNA) is a tryptophan metabolite and has been proposed as the endogenous ligand for this receptor. In the present work, we showed that GPR35 is present in the dorsal root ganglia and in the spinal cord and in order to test the hypothesis that GPR35 activation could cause analgesia, we administered suitable doses of zaprinast or we increased the local concentration of KYNA by administering a precursor (kynurenine) or by inhibiting its disposal from the CNS (with probenecid). We used the "writhing test" induced by acetic acid i.p. injection in mice. KYNA and kynurenine plasma and spinal cord levels were measured with HPLC techniques. Kynurenine (30, 100, 300 mg/kg s.c.) increased plasma and spinal cord levels of KYNA and decreased the number of writhes in a dose dependent manner. Similarly, probenecid was able to increase KYNA levels in plasma and spinal cord, to reduce the number of writes and to amplify kynurenine effects. Furthermore, zaprinast had antinociceptive effects in the writhing test without affecting KYNA levels. In agreement with its affinity for GPR35 receptor (approximately 10 times higher than that of KYNA), zaprinast action occurred at relatively low doses. No additive actions were obtained when kynurenine and zaprinast were administered at maximally active doses. Our results suggest that GPR35 could be an interesting target for innovative pharmacological agents designed to reduce inflammatory pain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
 ...
PMID:G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effects of kynurenic acid and zaprinast. 2111 Sep 87


<< Previous 1 2 3 4