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 have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oral-to-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.
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PMID:Effect of leuprolide acetate in treatment of abdominal pain and nausea in premenopausal women with functional bowel disease: a double-blind, placebo-controlled, randomized study. 963 30

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-i mine hydrogen maleate (MK-801) was examined on c-fos-like immunoreactivity (c-fos-LI) in urethane-anesthetized Sprague-Dawley rats using a polyclonal antibody. C-fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema. lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C-fos-positive cells were counted at three representative levels corresponding to obex, -2.05 mm and -6.45 mm in 18 tissue sections (50 microm). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose-dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK-801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 microl artificial CSF) reduced significantly and dose-dependently (12%, 36% and 47%, respectively) the c-fos-LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c-fos-LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.
Pain 1998 May
PMID:The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. 969 79

Proton-gated channels expressed by sensory neurons are of particular interest because low pH causes pain. Two proton-gated channels, acid-sensing ionic channel (ASIC) and dorsal root ASIC (DRASIC), that are members of the amiloride-sensitive ENaC/Degenerin family are known to be expressed by sensory neurons. Here, we describe the cloning and characterization of an ASIC splice variant, ASIC-beta, which contains a unique N-terminal 172 aa, as well as unique 5' and 3' untranslated sequences. ASIC-beta, unlike ASIC and DRASIC, is found only in a subset of small and large diameter sensory neurons and is absent from sympathetic neurons or the central nervous system. The patterns of expression of ASIC and ASIC-beta transcripts in rat dorsal root ganglion neurons are distinct. When expressed in COS-7 cells, ASIC-beta forms a functional channel with electrophysiological properties distinct from ASIC and DRASIC. The pH dependency and sensitivity to amiloride of ASIC-beta is similar to that described for ASIC, but unlike ASIC, the channel is not permeable to calcium, nor are ASIC-beta-mediated currents inhibited by extracellular calcium. The unique distribution of ASIC-beta suggests that it may play a specialized role in sensory neuron function.
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PMID:A sensory neuron-specific, proton-gated ion channel. 970 31

Capsaicin (CAP) excites small sensory neurons, causing pain, neurogenic inflammation, and other visceral reflexes. These effects have been proposed to be the result of CAP activation of a nonselective cation current. It is generally assumed that CAP binds to an extracellular domain of the membrane receptor. However, the exact binding site is not known because of the lipophilic nature of CAP. To determine whether the binding domain is extracellular or intracellular, we tested the effect of a synthetic water-soluble CAP analog, DA-5018.HCl, on current activation. CAP activated the 45 pS (at -60 mV) nonselective cation channel from either side of the membrane. However, DA-5018.HCl, which had a greater potency and efficacy than CAP, activated the channels only from the cytosolic side of the patch membrane in a capsazepine, a CAP receptor antagonist, reversible manner. When applied extracellularly, DA-5018. HCl did not, but CAP did, activate whole-cell currents in sensory neurons, as well as in oocytes expressing vanilloid receptor 1, a recently cloned CAP receptor. Hydrogen ions, reported as a possible endogenous activator of cation current, failed to elicit any current when acidic medium (pH 5.0-6.0) was applied intracellularly, indicating that H+ does not mediate the CAP effect. These results indicate that CAP and its analog bind to the cytosolic domain of the CAP receptor and suggest that an endogenous CAP-like substance other than H+ may be present in the cell.
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PMID:Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel. 988 May 73

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.
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PMID:Effect of coadministration of caffeine and either adenosine agonists or cyclic nucleotides on ketorolac analgesia. 1045 27

Excess hydrogen ions induce sustained nociceptor excitation as well as pain, and this has been suggested, with evidence from sensory ganglion cells, to result from gating a slowly inactivating sodium/calcium inward current. In the rat skin-nerve preparation, isolated receptive fields of pH-sensitive C-fibre terminals were exposed to low-pH solutions of various sodium concentrations. The pH responses showed a good correlation with log [Na+]e, which supports the above model. Amiloride has previously been shown to block a pH-induced Na+ current involved in sensory transduction in hamster taste cells; however, it has been shown to act differently in cutaneous nociceptors. Amiloride induced a dose-dependent increase in and prolongation of the nociceptive pH responses, with a prominent acceleration of the onset. The latter could be mimicked by replacing external sodium with sucrose, thus impeding sodium-proton antiport. Together, the findings indicate functional expression of amiloride-sensitive Na+/H+-antiporters, which enable the nociceptive nerve endings to extrude invading H+. Intracellular acidification may thus compete with Na+/H+ exchange, and pHi may be decisive in the transduction of nociception and pain from tissue acidosis.
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PMID:The pH response of rat cutaneous nociceptors correlates with extracellular [Na+] and is increased under amiloride. 1045 75

Recently a cDNA clone, vanilloid receptor subtype-1 (VR1), was isolated and found to encode an ion channel that is activated by both capsaicin, the pain producing compound in chili peppers, and by noxious thermal stimuli. Subsequently, two related cDNAs have been isolated, a stretch inactivating channel with mechanosensitive properties and a vanilloid receptor-like protein that is responsive to high temperatures (52-53 degrees C). Here, we report the isolation of a vanilloid receptor 5'-splice variant (VR.5'sv) which differs from VR1 by elimination of the majority of the intracellular N-terminal domain and ankyrin repeat elements. Both VR.5'sv and VR1 mRNA were shown to be expressed in tissues reportedly responsive to capsaicin including dorsal root ganglion, brain, and peripheral blood mononuclear cells. Functional expression of VR.5'sv in Xenopus oocytes and mammalian cells showed no sensitivity to capsaicin, the potent vanilloid resiniferatoxin, hydrogen ions (pH 6.2), or noxious thermal stimuli (50 degrees C). Since VR.5'sv is otherwise identical to VR1 throughout its transmembrane spanning domains and C-terminal region, these results support the hypothesis that the N-terminal intracellular domain is essential for the formation of functional receptors activated by vanilloid compounds and noxious thermal stimuli.
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PMID:Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. 1064 39

Trimebutine (2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate, hydrogen maleate) relieves abdominal pain in humans. In the present study, the antinociceptive action of systemic (S)-N-desmethyl trimebutine, a stereoisomer of N-monodesmethyl trimebutine, the main metabolite of trimebutine in humans, was studied in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) stimulus was used. Experiments were performed two weeks after surgery when the pain-related behaviour has fully developed. (S)-N-desmethyl trimebutine (1, 3, 10 mg/kg s.c.) produced dose-dependent antinociceptive effects on the nerve-injured and the contralateral hindpaw. The effect of the lowest dose (1 mg/kg s.c.) of (S)-N-desmethyl trimebutine on the nerve-injured paw was equal to that seen after a ten time stronger dose on the contralateral paw. The effect of (S)-N-desmethyl trimebutine (1 mg/kg) was not naloxone reversible. The results suggest that systemic (S)-N-desmethyl trimebutine may be useful in the treatment of some aspects of neuropathic pain.
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PMID:Antinociceptive effect of (S)-N-desmethyl trimebutine against a mechanical stimulus in a rat model of peripheral neuropathy. 1067 Aug 31

Nocistatin, a new heptadecapeptide encoded in the bPNP-3 gene, has a powerful biological activity connected with the mechanisms of pain transmission. It does not bind to the opioid receptors but to another brain receptor with high affinity. In order to substantiate these novel biological data with a structural basis, we have undertaken a conformational study in solution. Proton nmr data in helicogenic solvents are consistent with a well-defined helical structure that is consistent with the nmr parameters of the C-terminal octapeptide, a shorter fragment that retains allodynia-blocking activity.
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PMID:Solution structure of nocistatin, a new peptide analgesic. 1067 30

Intrathecal (i.t.) administration of spermine (0.1-10000 fmol), an endogenous polyamine, produced the behavioural response mainly consisting of biting and/or licking of the hindpaw along with a slight hindlimb scratching directed toward the flank in mice, which peaked at 5-15 min and almost disappeared at 30 min after an injection. The behaviour induced by spermine (10 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-0.5 mg/kg). The characteristic behaviour was also inhibited dose-dependently by i.t. co-administration of ifenprodil (62.5-4000 pmol), a competitive antagonist of the polyamine recognition site on N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and D(-)-2-amino-5-phosphonovaleric acid (D-APV) (0.5-2 nmol) and 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (7. 8-500 pmol), the competitive NMDA receptor antagonists, and (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cycloheptene-5, 10-imine hydrogen maleate (MK-801) (0.5-4 nmol), an NMDA ion-channel blocker, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist. Both (2S, 3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicy clo [2.2.2]octane-3-amine] (CP-96,345), a non-peptidic neurokinin-1 (NK-1) receptor antagonist, and CP-96,344, its inactive 2R,3R enantiomer, inhibited spermine-induced behavioural response in a dose-dependent manner. However, [Tyr(6), D-Phe(7), D-His(9)]-substance P(6-11) (sendide) and [D-Phe(7), D-His(9)]-substance P(6-11), the selective antagonists for NK-1 receptors, were without affecting spermine-induced behaviour. These results indicate that spermine-induced behaviour is mediated through the polyamine recognition site on NMDA receptor ion-channel complex without the involvement of substance P system in the mouse spinal cord.
Pain 2000 May
PMID:Intrathecally administered spermine produces the scratching, biting and licking behaviour in mice. 1077 60


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