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)

Drugs antagonizing glycine at the N-methyl-D-aspartate (NMDA) receptor have been developed to improve efficacy, increase specificity, and, perhaps, reduce side effects. The purpose of this study was to examine the effect of intrathecally (IT) administered acea-1021, a glycine receptor antagonist at the NMDA receptor complex, in a rat model of postoperative pain. Rats with IT catheters were anesthetized and underwent a plantar incision. Two hours later, withdrawal threshold to punctate stimulation was determined by applying calibrated von frey filaments adjacent to the wound. In another group, the response frequency to a plastic disk, a blunt, nonpunctate mechanical stimulus applied directly on the incision also was measured. In unincised rats, NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), Or kainate (KA) was administered it 30 minutes after acea-1021 or vehicle. Spontaneous nociceptive behaviors (SNB) caused by it excitatory amino acids (EAAS) were counted. In the vehicle-treated group, the median withdrawal threshold for punctate stimulation decreased from 522 mn before incision to 61 mn or less for 4 hours after incision. In 3 separate groups, the median withdrawal threshold increased to 61, 118, and 332 mn 30 minutes after it administration of 10, 30, and 60 nmol of acea-1021, respectively. In 3 other groups, it administration of 10, 30, and 60 nmol of acea-1021 decreased the response frequency to the blunt mechanical stimulus from 95 +/- 13 or greater to 78 +/- 40%, 67 +/- 37%, and 22 +/- 27% 30 minutes after drug injection, respectively. Sixty nmol of acea-1021 inhibited SNBS caused by IT NMDA, KA, and AMPA. IT administration of acea-1021 decreased incision-induced pain behaviors in this rat model. Acea-1021 blocked SNB by NMDA, KA, and AMPA. These data, coupled with previous studies, suggest that inhibition of pain behaviors by it acea-1021 is produced by blockade of spinal non-NMDA receptors.
J Pain 2000
PMID:Effect of intrathecal ACEA-1021 in a rat model for postoperative pain. 1462 11

Accumulating preclinical data suggest that compounds that block the excitatory effect of glutamate on the kainate subtype of glutamate receptors may have utility for the treatment of pain, migraine, and epilepsy. In the present study, the in vitro pharmacological properties of the novel glutamate antagonist 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) are described. In functional assays in human embryonic kidney (HEK)293 cells expressing homomeric GLU(K5) or GLU(K6) receptors, NS3763 is shown to display selectivity for inhibition of domoate-induced increase in intracellular calcium mediated through the GLU(K5) subtype (IC(50) = 1.6 microM) of kainate receptors compared with the GLU(K6) subtype (IC(50) > 30 microM). NS3763 inhibits the GLU(K5)-mediated response in a noncompetitive manner and does not inhibit [(3)H]alpha-amino-3-hydroxy-5-tertbutylisoxazole-4-propionic acid binding to GLU(K5) receptors. Furthermore, NS3763 selectively inhibits l-glutamate- and domoate-evoked currents through GLU(K5) receptors in HEK293 cells and does not significantly inhibit alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- or N-methyl-d-aspartate-induced currents in cultured mouse cortical neurons at 30 microM. This is the first report on a selective and noncompetitive GLU(K5) antagonist.
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PMID:In vitro characterization of 5-carboxyl-2,4-di-benzamidobenzoic acid (NS3763), a noncompetitive antagonist of GLUK5 receptors. 1498 18

Using a rat formalin-induced conditioned place avoidance (F-CPA) model and Fos immunohistochemistry, the present study observed the effect of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxozole propionic acid/kainite (AMPA/KA) receptors on pain-related aversion. Adult Sprague-Dawley rats were implanted with cannula in the anterior cingulate cortex (ACC) or the lateral ventricle. Before (10 min) the injection of formalin into a hindpaw on days 2 and 4 of place-conditioning trials, vehicle (0.01 M PBS), the NMDA receptors antagonist, 2-amino-5-phosphonovalerate (AP5), or the AMPA/KA receptors antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), was injected through the cannula. F-CPA was effectively eliminated by both intracerebroventricular (icv) and intra-ACC microinjection of AP5. In contrast, the intra-ACC or icv injection of DNQX failed to alter the conditioning scores of F-CPA compared with vehicle control group (P >0.05). Intra-ACC or icv injection of AP5 or DNQX had no effect on formalin-induced acute nociceptive behaviors. Fos immunoreactivity in the ACC was activated by retrieval of pain-related aversion, and this activation was significantly suppressed by preadministration of AP5, but not DNQX (P <0.001). These results suggest that NMDA receptors in the ACC are preferentially involved in the processing of the affective dimension of pain.
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PMID:NMDA receptors in the anterior cingulate cortex mediate pain-related aversion. 1538 Apr 91

We hypothesized that glutamate (Glu) released from the peripheral terminals of primary afferents contributes to the generation of mechanical hyperalgesia following peripheral nerve injury. Nerve injury was performed on rats with a lumbar 5 spinal nerve lesion (L5 SNL), which was preceded by L5 dorsal rhizotomy (L5 DR) to avoid the potential central effects induced by L5 SNL through the L5 dorsal root. Mechanical hyperalgesia, as evidenced by a reduction in paw withdrawal threshold (PWT), was short-lasting (<6 days) after L5 DR, but persistent (>42 days) after L5 SNL preceded by L5 DR. When an intraplantar injection into the affected hind paw was given immediately before L5 SNL, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (20 nmol), group-I metabotropic Glu (mGlu) receptor antagonist DL-amino-3-phosphonopropionic acid (DL-AP3; 70 nmol), and selective group-II mGlu receptor agonist 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 20 nmol) delayed the onset of PWT reduction for 1-4 days. However, this onset was not affected by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4,-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX; 100 nmol). When the same injection was given after L5 SNL-induced mechanical hyperalgesia had been established, MK-801 reversed the PWT reduction for 30-75 min, whereas NBQX, DL-AP3, or APDC had no effect. These results suggest that the manipulation of the peripheral Glu receptors reduces neuropathic pain, by blocking NMDA and group-I mGlu receptors and by stimulating group-II mGlu receptor during the induction phase of neuropathic pain, but only by blocking the NMDA receptor during its maintenance phase.
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PMID:Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. 1545 Mar 64

Transmission of noxious-stimulus-evoked inputs in the spinal and trigeminal systems is mediated primarily through excitatory glutamatergic synapses using alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors. Glutamatergic synapses exhibit multiple forms of short-lasting and long-lasting synaptic plasticity. Persistent enhancement of nociceptive transmission, known as "central sensitization," is a form of lasting plasticity that is similar mechanistically to long-term potentiation of glutamatergic transmission in other regions of the central nervous system. This potentiation of AMPA/kainate transmission is dependent upon the activity of NMDA receptors, which become enhanced following noxious peripheral stimulation as a result of several convergent mechanisms. Central sensitization is thus an expression of increased synaptic gain at glutamatergic synapses in central nociceptive-transmission neurons and thereby contributes importantly to pain hypersensitivity. In addition, recent evidence has revealed a new player in the mechanisms underlying pain hypersensitivity following nerve injury--microglia. Understanding of the roles of microglia may lead to new strategies for the diagnosis and management of neuropathic pain.
J Orofac Pain 2004
PMID:Cellular neuroplasticity mechanisms mediating pain persistence. 1563 15

Non-steroidal anti-inflammatory agents (NSAIDs) are widely used for pain relief. However, they have been associated with harmful and sometimes fatal side effects. Usually, the target organs are the GI tract and liver. In this study, we have investigated the physicochemical requirements of 21 NSAIDs for glucuronidation and cytotoxicity by quantitative structure-toxicity relationships (QSTRs) in isolated rat hepatocytes. Furthermore, we have investigated the contrast in physicochemical variables that correlated with NSAID-induced hepatocyte cytotoxicity when glucuronidation was inhibited with borneol. The competitive inhibition of hepatocyte p-nitrophenol glucuronidation by NSAIDs was determined by HPLC. Glucuronidation-inhibited hepatocytes were more susceptible to NSAID-induced cytotoxicity. Also, we found a parabolic correlation between lipophilicity and the inhibition of glucuronidation for a subset of NSAIDs. For NSAIDs with a benzoic acid moiety, cytotoxicity also correlated parabolically with lipophilicity, but correlated linearly with the HOMO-LUMO gap, and the first-order valence connectivity index. The cytotoxicity of NSAIDs with a phenylacetic acid (or propionic acid) substructure also correlated with lipophilicity, but not with the HOMO-LUMO gap. Our findings indicated that the inhibition of glucuronidation resulted in increased NSAID cytotoxicity, suggesting that acyl-glucuronide metabolites were acutely less cytotoxic. Also, comparative QSTRs revealed that benzoic acid NSAIDs may form cytotoxic radical metabolites (parameterized by the HOMO-LUMO gap) or alter mitochondrial respiration (parameterized by the connectivity index), whereas phenylacetic acid derived NSAIDs may form different cytotoxic metabolites, since they did not correlate with these parameters. In summary, we have used QSTRs as a tool to distinguish the cytotoxic mechanism of two groups of NSAIDs, which, if analyzed together as one group, did not reveal such mechanism-based differences.
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PMID:Application of quantitative structure-toxicity relationships for acute NSAID cytotoxicity in rat hepatocytes. 1573 39

The post-operative pain state results from a barrage of primary afferent inputs exposed to products of tissue damage such as bradykinin and prostaglandins and the central sensitization by the continuing inputs. This provides the rationale for preemptive analgesia, whereby the blockade of primary afferent inputs prior to injury may result in a reduction of post-operative pain. 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl) propionic acid (zaltoprofen) is a unique compound that inhibits cyclooxygenase (COX) and exhibits anti-bradykinin activity. The present study evaluated the preemptive analgesic effect of zaltoprofen in a post-operative pain model produced by plantar incision. When orally, but no intrathecally, administered 30 min prior to incision, zaltoprofen significantly increased the withdrawal threshold 2 h and 1-3 days after incision at 10 mg/kg. While the bradykinin B1 antagonist des-Arg10-HOE-140, the selective COX-1 inhibitor SC-560, and the selective COX-2 inhibitor celecoxib did not affect post-operative pain, the B2 antagonist HOE-140 dose-dependently relieved the post-operative pain at 2-200 microg/kg with a time course similar to that of zaltoprofen. The B2 receptor mRNA was expressed in the hindpaw and the expression did not change before and 24 h after surgery. These results suggest that zaltoprofen produces the preemptive analgesic effect peripherally by blocking the B2 pathway.
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PMID:Preemptive analgesia by zaltoprofen that inhibits bradykinin action and cyclooxygenase in a post-operative pain model. 1574 Aug 5

Bradykinin interacts with the bradykinin B2 receptor on dorsal root ganglion (DRG) neurons, setting off a series of reactions inside the cells that ultimately make the vanilloid receptor 1 more sensitive to a normal stimulus by activating various enzymes coupled with second messenger signaling cascades. Zaltoprofen, a propionic acid derivative non-steroidal anti-inflammatory drug (NSAID), was proved to inhibit bradykinin-induced pain responses in vivo experimental systems more potently than indomethacin or other NSAIDs, but the molecular mechanisms underlying its action are not yet fully understood. Currently it appears unlikely that zaltoprofen binds to specific sites on the protein of the bradykinin B2 receptor, hence we have examined the effect of zaltoprofen on bradykinin-induced responses of adult DRG neurons to investigate possible interaction sites. Compared with several other NSAIDs, such as indomethacin, loxoprofen and diclofenac, zaltoprofen most potently inhibits bradykinin-enhancement of capsaicin-induced 45Ca2+ uptake into DRG neurons. Zaltoprofen also significantly inhibits bradykinin-induced 12-lipoxygenase (12-LOX) activity and the slow bradykinin-induced onset of substance P release from DRG neurons. These data indicate zaltoprofen may produce its analgesic effects through the inhibition of bradykinin B2 receptor-mediated bradykinin responses of not only cyclooxygenases (COXs) but also bradykinin induced 12-LOX inhibitors.
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PMID:Zaltoprofen inhibits bradykinin-induced responses by blocking the activation of second messenger signaling cascades in rat dorsal root ganglion cells. 1585 30

Prostacyclin, one of the cyclooxygenase metabolites, causes various biological effects, including vasodilation and antithrombogenicity, and is also involved in several pathophysiological effects, such as inflammatory pain and bladder disorders. The prostacyclin receptor (IP receptor) agonists iloprost, cicaprost, and carbacyclin have been useful for clarifying the role of the IP receptor signaling, since the endogenous ligand, prostacyclin, is very unstable. On the other hand, only a few IP receptor antagonists have been reported to date. Here, we characterized the biological activities of 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (compound A) in various in vitro systems. Compound A inhibited the accumulation of the second messenger cyclic AMP in the UMR-108 rat osteosarcoma cell line and primary cultured rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner up to 10 microM, without affecting other eicosanoid receptors. Functionally, the IP receptor plays an important role in DRG neuron sensitization, which is measured by release of the neurotransmitter substance P. Although the effects of iloprost or Lys-bradykinin, an inflammatory peptide, alone on substance P release were limited, stimulation of the neurons with both these ligands induced substantial amounts of substance P release. This synergistic effect was suppressed by compound A. Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost-induced sensitization of sensory neurons. Furthermore, these findings suggest that IP receptor antagonist administration may be effective for abnormal neural activities of unmyelinated sensory afferents. Compound A should prove useful for further investigations of the IP receptor in various biological processes.
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PMID:A prostacyclin receptor antagonist inhibits the sensitized release of substance P from rat sensory neurons. 1610 42

A 12-month-old boy diagnosed with propionic acidemia underwent gastrostomy. The patient's general state was good and he was alert, but with reduced muscular tone (unstable when seated with support, floppy head) and with dystonic movements in all extremities. An electroencephalogram showed slightly slowed brain activity. The patient was being treated with a low protein diet, phenobarbital, L-carnitine, L-isoleucine, and biotin. Surgery was carried out in satisfactory conditions with general anesthesia without opioids combined with infiltration of the surgical wound with local anesthetic. Recovery from anesthesia was rapid and free of complications. Propionic acidemia is caused by mitochondrial propionyl coenzyme carboxylase deficiency. Most patients have episodes of severe metabolic ketoacidosis as a result of excessive protein intake, delayed development, vomiting, gastroesophageal reflux, lethargy, hypotonia, and convulsions. The anesthetic approach involves avoiding triggers of metabolic acidosis (such as fasting, dehydration, hypoxemia, and hypotension) and preventing airway complications. Agents that metabolize propionic acid (such as succinylcholine, benzylisoquinoline neuromuscular blocking agents, and propofol) are not used, as they can exacerbate acidemia. We also believe that using local or regional anesthesia in combination with general anesthesia without opiates is safe and effective for controlling pain during surgery and postoperative recovery, as that combination avoids respiratory depression in these patients, who are highly sensitive to opiates.
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PMID:[Infant boy with propionic acidemia: anesthetic implications]. 1620 Sep 24


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