Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.
 ...
PMID:The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist. 871 89

Risperidone is a novel atypical neuroleptic with a favorable profile of side effects due to its unique pharmacological activity: it exhibits both potent dopamine D2 and 5-HT2 receptor blocking activity, as well as high affinity for alpha1 and alpha2 adrenergic receptors and histamine H1 receptor. We found that risperidone has a potent antinociceptive effect in the tailflick assay with an ED50 of 26.4 mg/kg. This effect of risperidone was antagonized by naloxone (P < 0.05). This sensitivity to naloxone indicates that at least some of the analgesic effects of risperidone are mediated by an opioid mechanism of action. beta-FNA (mu1 mu2-antagonist), naloxonazine (mu1-antagonist) and norbinaltorphamine (nor-BNI; kappa1-analgesia) reversed risperidone antinociceptive effect (P < 0.05). Naltrindole (delta-antagonist) only partially reversed risperidone antinociceptive effect. We found that the sensitivity of risperidone antinociceptive effect to selective antagonists implies involvement of mu1-, mu2- and kappa1-opioid and to a lesser extent delta-opioid mechanisms. These results suggest a possible role for risperidone both in the management of pain and in the management of opiate withdrawal and detoxification.
 ...
PMID:Augmentation of opioid induced antinociception by the atypical antipsychotic drug risperidone in mice. 919 79

This study evaluated the pain enhancing properties of the adenosine A3 receptor agonist N6-benzyl-5'-N-ethylcarboxamidoadenosine (N6-benzyl-NECA) by assessing behavioural effects following s.c. administration alone to the dorsal hindpaw of the rat, or in combination with a low concentration of formalin (0.5%). Edema formation was monitored by determining paw volume with plethysmometry. N6-benzyl-NECA (0.005-10 nmol) produced a dose-related increase in intrinsic flinching behaviours, as well as an increase in phase 2A flinch responses in the presence of formalin. Intrinsic effects were blocked by the histamine H1 receptor antagonist mepyramine and the 5-hydroxytryptamine2 (5-HT2) receptor antagonist ketanserin, but not by other 5-HT receptor antagonists or adenosine A1 or A2 receptor antagonists. N6-benzyl-NECA also produced an increase in paw volume, both alone and in the presence of formalin, with higher doses being required to produce this effect than for the flinch response. The increase in paw volume was also blocked by mepyramine and ketanserin but not by other antagonists. These results indicate both a nociceptive response and a proinflammatory response resulting in edema formation following activation of adenosine A3 receptors which is mediated by both 5-HT and histamine released most likely from mast cells.
 ...
PMID:Adenosine A3 receptor activation produces nociceptive behaviour and edema by release of histamine and 5-hydroxytryptamine. 931 54

Amitriptyline, a non-selective noradrenaline (NA) and 5-hydroxytryptamine (5-HT) reuptake inhibitor, has recently been demonstrated to produce a peripheral antinociceptive action in an inflammatory (formalin test) and a neuropathic pain model (spinal nerve ligation). In the present study, we determined whether desipramine, a selective NA reuptake inhibitor, and fluoxetine, a selective 5-HT reuptake inhibitor, could produce peripheral antinociceptive actions in these same tests. Effects on paw volume also were determined. In the 2.5% formalin test, desipramine and fluoxetine 10-300 nmol produced a dose-related reduction in phase 2 (16-60 min) flinching and biting/licking behaviours when coadministered with the formalin. Phase 1 flinch behaviours (0-12 min) were significantly reduced at the highest dose. These actions are peripherally mediated, as they were not seen when desipramine or fluoxetine (100, 300 nmol) were injected into the contralateral hindpaw. The peripheral action of desipramine and fluoxetine was not altered by coadministration of caffeine 1500 nmol. In the spinal nerve ligation model, desipramine 100 nmol, but not fluoxetine 100 nmol, produced a peripheral anti-hyperalgesic action in the hindpaw corresponding to the ligated side when thresholds were determined using a thermal paw stimulator. In paw volume experiments, desipramine, at doses which are maximally effective in behavioural tests, produced only a slight increase in paw volume, but fluoxetine (10-300 nmol) produced a robust and sustained dose-related increase in paw volume. Amitriptyline also produced minimal effects on paw volume. When coinjected with formalin, no agent significantly altered the degree of paw swelling produced by formalin. The increase in paw volume produced by fluoxetine was inhibited by ketanserin (5-HT2 receptor antagonist), mepyramine (histamine H1 receptor antagonist) and phentolamine (alpha-adrenergic receptor antagonist), but not by the other selective 5-HT receptor antagonists tested or caffeine. The pronounced peripheral pain alleviating actions in the absence of marked changes in paw volume produced by desipramine and amitriptyline, but not fluoxetine, in the formalin test and the spinal nerve ligation model suggest that these agents could be developed as cream or gel formulations to recruit a peripheral antinociceptive action in inflammatory and neuropathic pain states. Such a formulation might permit the attainment of higher and more efficacious concentrations in the region of the sensory nerve terminal, with limited systemic side effects.
Pain 1999 Aug
PMID:Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. 1076 1

To study the participation of histamine H(1) receptors in pain perception, histamine H(1) receptor knockout mice were examined for pain threshold by means of three different kinds of nociceptive tasks. These included assays for thermal nociception (hot-plate, tail-flick, paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (abdominal constriction, formalin test, capsaicin test) which evoked pain by the activation in nociceptive Adelta and C fibers. The mutant mice lacking histamine H(1) receptors showed significantly fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests. Sensitivity to noxious stimuli in histamine H(1) receptor knockout mice significantly decreased when compared to wild-type mice. This data indicates that histamine plays an important role in both somatic and visceral pain perceptions through histamine H(1) receptors. The difference in the effect of histamine H(1) receptors antagonist, the active (D-) and inactive (L-) isomers of chlorpheniramine on ICR mice further substantiates the evidence of the role of histamine H(1) receptors on pain threshold.
 ...
PMID:Role of histamine H(1) receptor in pain perception: a study of the receptor gene knockout mice. 1072 Jun 38

Histamine activates pain-transmitting nerve fibres, releases pain-related neuropeptides, and is painful when injected into the skin. Histamine agonists mimic these effects, suggesting that histamine plays a role in mediating the signal transduction of tissue damage or other painful stimulus. Certain 'antihistamines' (histamine H1 receptor antagonists) and other antihistaminics are 'analgesic' in preclinical or clinical models. Potential sites of action of these agents include the brain and spinal cord and a specific histamine receptor subtype might be involved (three subtypes have been identified). However, it is possible that other mechanisms account for the analgesic effect.
 ...
PMID:Antihistamines as analgesics. 1135 May 29

The tricyclic compound (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN 1869) is a novel, selective histamine H(1) receptor antagonist. It is orally available, well tolerated, easily enters the central nervous system (CNS) but no adverse effects are seen in mice at 300 mg/kg. ReN 1869 at 0.01-10 mg/kg is antinociceptive in tests of chemical nociception in rodents (formalin, capsaicin, phenyl quinone writhing) but not in thermal tests (hot plate and tail flick). ReN 1869 amplifies the analgesic action of morphine but does not show tolerance after chronic dosing. Moreover, the compound is effective against inflammation of neurogenic origin (antidromic nerve stimulation, histamine-evoked edema) but not in carrageenan-induced inflammation. We suggest that ReN 1869, via H(1) blockade, counteracts the effect of histamine liberated from activated mast cells and inhibits pain transmission in the dorsal spinal cord. ReN 1869 represents a new class of antihistamines with pain-relieving properties that probably is mediated centrally through histamine H(1) receptors but alternative mechanisms of action cannot be excluded.
 ...
PMID:ReN 1869, a novel tricyclic antihistamine, is active against neurogenic pain and inflammation. 1179 Mar 77

We previously reported that histamine H(1) receptor gene knockout mice (H1KO) showed lower spontaneous nociceptive threshold to pain stimuli when compared to wild-type mice. The objective of the present study was to examine the antinociceptive effect of intrathecally-administered morphine in H1KO mice. The antinociceptive effects of morphine were examined using assays for thermal (tail-flick, hot-plate, paw-withdrawal), mechanical (tail-pressure) and chemical nociception (formalin and capsaicin tests) using H1KO and wild-type mice. In these nociceptive assays, intrathecally-administered morphine produced significant antinociceptive effects in wild-type mice. The antinociceptive effect produced by intrathecally administered morphine was enhanced in the knockout mice. We also examined the effect of an histamine H(1) receptor antagonist, an active (d-) isomer of chlorpheniramine, on morphine-induced antinociception in ICR mice. The intrathecal co-administration of d-chlorpheniramine enhanced the effect of morphine in all nociceptive assays examined. The pharmacological experiments using d-chlorpheniramine further substantiate the evidence for the histamine H(1) receptor-mediated suppression of morphine-induced antinociception. These results suggest that existing H(1) receptors play an inhibitory role in morphine-induced antinociception at the spinal cord level.
 ...
PMID:Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice. 1212 9

The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.
 ...
PMID:Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists. 1217 73

We characterized the effect of a novel selective histamine H1 receptor antagonist, (R)-1-(3-(10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN-1869), on the responses of dorsal horn neurons in anesthetized rats after carrageenan induced-inflammation and peripheral neuropathy (L5/6 spinal nerve ligation; SNL). ReN-1869 was administered systemically (0.1-4 mg/kg), and drug effects were assessed using a wide range of peripheral electrical and natural stimuli (brush, von Frey filaments, and heat). Comparisons were made between unoperated naive groups and either carrageenan inflamed or SNL rats. ReN-1869 produced little effect on the electrically evoked responses (wind-up, Abeta-, Adelta-, and C-fiber-evoked responses); however, it significantly attenuated neuronal responses to noxious heat in carrageenan and SNL rats. A robust effect was seen with the low-threshold mechanical punctate (von Frey 9 g) stimuli, which were selectively inhibited by ReN-1869 after tissue and nerve injury. These inhibitory actions were in marked contrast to the naive animal group, where only nonsignificant effects were observed. To investigate whether the actions of ReN-1869 are mediated via the antagonism of histamine H1 receptors, the effects of this novel compound were compared with that of another H1 receptor antagonist, mepyramine (1-20 mg/kg). Systemic mepyramine produced strong inhibitions of the 9-g von Frey-evoked responses in carrageenan and SNL rats. The similar pharmacological profile of these two compounds suggests for a similar mechanism of action. We propose that ReN-1869 may represent a novel agent for the treatment of certain modalities of persistent pain states, in particular for the treatment of mechanical allodynia.
 ...
PMID:ReN-1869 [(R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid], a novel histamine H1 receptor antagonist, produces potent and selective antinociceptive effects on dorsal horn neurons after inflammation and neuropathy. 1498 22


1 2 3 4 Next >>