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 bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
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PMID:Potent nonpeptide antagonists of the bradykinin B1 receptor: structure-activity relationship studies with novel diaminochroman carboxamides. 1740 49

The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.
Eur J Pain 2008 Apr
PMID:Intramuscular administration of morphine reduces mustard-oil-induced craniofacial-muscle pain behavior in lightly anesthetized rats. 1776 78

Nitrogen-containing biphosphonates are a group of medications that are increasingly used in the management of Paget's disease, fibrous dysplasia, osteoporosis, multiple myeloma and metastatic prostate or breast cancer bone disease. On 2004 it was established that nitrogen-containing biphosphonates may induce jaw osteonecrosis and since then, a substantial number of publications has supported this finding. Jaw osteonecrosis may be asymptomatic, lasting for about a year or symptomatic, accompanied with mild or severe pain. Jaw osteonecrosis usually results in patients with poor dental hygiene, or subjected to invasive dental procedures. Its incidence increases with the length of nitrogen-containing biphosphonates treatment and appears to be higher for the Zometa(TM) users. It is important to early recognize this entity, since early intervention can make a significant difference to the outcome of this debilitating side effect. We here report three patients who had a positive technetium-99m methylene diphosphonate ((99m)Tc-MDP) bone scan. One of these patients also had osteomyelitis and was treated aggressively. The other two were treated in a more conservative manner. Detailed dental examination supported the scintigraphic findings. Biopsy was performed only in one patient and also offered specimens for antibiotic cultures. In discussion, jaw biopsy is a debatable procedure in the setting of jaw osteonecrosis and many consider that it should be avoided in most cases, except if it is necessary to establish the diagnosis and suggest antibiotic treatment by obtaining samples for bacterial cultures. Although axial tomography and magnetic resonance imaging are useful in defining the extent of the disease, 3-phase (99m)Tc-MDP bone scan is the most sensitive imaging modality pinpointing the disease at its early stages. In conclusion, a 3-phase (99m)Tc-MDP scan with anterior and lateral views of the skull is indicated in all symptomatic or asymptomatic patients, with a history of long-term nitrogen-containing biphosphonate treatment, since this may lead to an early detection of the disease.
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PMID:Jaw uptake of technetium-99 methylene diphosphonate in patients on biphosphonates: a word of caution. 1808 61

Inflammatory-related activation and sensitization of meningeal nociceptors is believed to play a key role in promoting the intracranial throbbing pain of migraine. We have shown recently that mast cell activation and various mast cell-derived inflammatory mediators can promote activation and sensitization of meningeal nociceptors. Mast cell tryptase has also been proposed to promote pain hypersensitivity by activating the proteinase-activated receptor 2 (PAR2) that is expressed on nociceptive neurons. In this study using in vivo single-unit recording in the trigeminal ganglion of anaesthetized rats, we found that local meningeal activation of PAR2 using the specific agonist SLIGRL-NH2 promoted sensitization of the threshold response while provoking desensitization of the suprathreshold responses. SLIGRL-NH2 also excited a subpopulation of meningeal nociceptors. Chronic mast cell depletion enhanced the sensitizing effects of PAR2 activation while curbing its desensitizing effects. Mast cell depletion did not change the PAR2-mediated excitatory effect. We propose that by enhancing the mechanical sensitivity of meningeal nociceptors local PAR2 activation could play a role in promoting the throbbing pain of migraine and that local mast cell degranulation may modulate such an effect.
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PMID:Modulation of meningeal nociceptors mechanosensitivity by peripheral proteinase-activated receptor-2: the role of mast cells. 1825 96

The possible involvement of the nitric oxide (NO)-cyclic GMP (cGMP)-protein kinase G (PKG) pathway on bovine lactoferrin (BLF)-induced spinal antihyperalgesic activity was elucidated in sciatic nerve injured rats. Intrathecal BLF reduced thermal hyperalgesia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase), 7-nitroindazole (7-NI, neuronal NO synthase inhibitor), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl-cyclase inhibitor), (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2, 9-dimethyl-1-oxo-9, 12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor) or glybenclamide (ATP-sensitive K+ channel blocker), but not NG-D-nitro-arginine methyl ester (D-NAME, an inactive enantiomer of l-NAME), d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2 (CTOP, selective mu-opioid receptor antagonist) or naloxone (nonselective opioid receptor antagonist) prevented BLF-induced antihyperalgesia. Data suggest that BLF-induced spinal antihyperalgesia could be due to activation of the NO-cGMP-PKG-K+ channel pathway and it is not mediated by mu-opioid receptor in a model of neuropathic pain.
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PMID:Involvement of the nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway in the antihyperalgesic effects of bovine lactoferrin in a model of neuropathic pain. 1840

The effect of dipeptide Tyr-Pro, present in representatives of most families of opioid peptides, and two its analogs, Tyr-Pro-NH2 and Tyr-Pro-OMe, on analgesic activity was studied in different tests (tail-flick test, tail pinch (Haffner's) test, formalin test, and acetic acid writing test) describing different organization levels of pain sensitivity. Intraperitoneal administration of the dipeptide decreased the pain threshold in all above-mentioned tests. Coadministration of the dipeptide and naloxone or naloxone methiodide insignificantly decreased the dipeptide analgesic effect in the tail-flick and acetic acid writing tests. Its analogs Tyr-Pro-NH2 and Tyr-Pro-OMe demonstrated a similar analgesic activity in the tail-flick test and a higher activity in the acetic acid writing test. Administration of individual amino acids (Tyr or Pro) or their mixture had no effect on the pain threshold.
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PMID:[Analgesic activity of dipeptide Tyr-Pro]. 1849 63

A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
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PMID:Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands. 1881 Nov 33

Maintaining physiological pH is required for survival, and exposure to alkaline chemicals such as ammonia (smelling salts) elicits severe pain and inflammation through unknown mechanisms. TRPV1, the capsaicin receptor, is an integrator of noxious stimuli including heat and extracellular acidic pH. Here, we report that ammonia activates TRPV1, TRPA1 (another polymodal nocisensor), and other unknown receptor(s) expressed in sensory neurons. Ammonia and intracellular alkalization activate TRPV1 through a mechanism that involves a cytoplasmic histidine residue, not used by other TRPV1 agonists such as heat, capsaicin or low pH. Our studies show that TRPV1 detects both acidic and basic deviations from homeostatic pH.
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PMID:TRPV1 is activated by both acidic and basic pH. 1912 93

It has been reported that proteinase-activated receptor 2 (PAR2) receptor activation enhances the animal's pain response and PAR2 coexpresses with P2X3 in dorsal root ganglion neurons. However, whether PAR2 activation has a direct impact on P2X3 currents is still not clear. In this study, we performed the patch-clamp experiments in cultured dorsal root ganglion neurons and found that when incubated with trypsin or the PAR2 agonist SL-NH2 for a short time (3 min), instead of increasing, P2X3 currents amplitude decreased significantly. Meanwhile, the opening of P2X3 ion channel accelerated. Protein kinase A inhibitor H89 could not reverse above phenomenon, but played a synergistic effect on the contrary. These results suggest that the enhanced pain response caused by PAR2 activation is not through direct increase of the P2X3 current amplitude, and the acceleration of P2X3 opening may participate in the enhanced pain response in a long-time view. Moreover, protein kinase A does not participate in the inhibition of P2X3 currents caused by PAR2 activation.
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PMID:Acute PAR2 activation reduces alpha, beta-MeATP sensitive currents in rat dorsal root ganglion neurons. 2011 42

Stings by bees and wasps, including Brazilian species, are a severe public health problem. The local reactions observed after the envenoming includes typical inflammatory response and pain. Several studies have been performed to identify the substances, including peptides that are responsible for such phenomena. The aim of the present study is to characterize the possible nociceptive (hyperalgesic) and edematogenic effects of some peptides isolated from the venoms of the honeybee (Apis mellifera) and the social wasps Polybia paulista and Protonectarina sylveirae, in addition to characterize some of the mechanisms involved in these phenomena. For this purpose, different doses of the peptides mellitin (Apis mellifera), Polybia-MP-I, N-2-Polybia-MP-I (Polybia paulista), Protonectarina-MP-NH2 and Protonectarina-MP-OH (Protonectarina sylveirae) were injected into the hind paw of mice. Hyperalgesia and edema were determined after peptide application, by using an electronic von Frey apparatus and a paquimeter. Carrageenin and saline were used as controls. Results showed that melittin, Polybia-MP-I, N-2-Polybia-MP-I, Protonectarina-MP-NH(2) and Protonectarina-MP-OH peptides produced a dose- and time-related hyperalgesic and edematogenic responses. Both phenomena are detected 2 h after melittin, Polybia-MP-I, N-2-Polybia-MP-I injection; their effects lasted until 8 h. In order to evaluate the role of prostanoids and the involvement of lipidic mediators in hyperalgesia induced by the peptides, indomethacin and zileuton were used. Results showed that zileuton blocked peptide-induced hyperalgesia and induced a decrease of the edematogenic response. On the other hand, indomethacin did not interfere with these phenomena. These results indicate that melittin, Polybia-MP-I, N-2-Polybia-MP-I, Protonectarina-MP-NH(2), and Protonectarina-MP-OH peptides could contribute to inflammation and pain induced by insect venoms.
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PMID:Hyperalgesic and edematogenic effects of peptides isolated from the venoms of honeybee (Apis mellifera) and neotropical social wasps (Polybia paulista and Protonectarina sylveirae). 2017 46


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