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Biomedical subjects

L Urban

Publications and source records attributed to L Urban.

At least 37 records · Page 2Linked to original sources
PubMed2000

Excitatory effects of galanin in the spinal cord of intact, anaesthetized rats.

The effects of intrathecal galanin on the activity of single wide dynamic range (WDR) spinal dorsal horn neurones were analyzed in anaesthetized adult rats. Abeta-, Adelta- and C-fibres were activated by transcutaneous electrical stimulation which also induced wind-up and post-discharge. Galanin dose-dependently (0. 15-15 nmol/50 microl) enhanced Adelta-and C-fibre evoked responses, post-discharge and wind-up. Application of (D-Thr(6), D-Trp(8, 9), 15-ol)-galanin (1-15), a putative antagonist, did not attenuate the enhanced effects evoked by galanin. (D-Thr(6), D-Trp(8, 9), 15-ol)-galanin (1-15) applied alone (0.3-30 nmol/50 microl) to a separate population of neurones inhibited Abeta responses but enhanced post-discharge and wind-up in a similar pattern to galanin. Thus, (D-Thr(6), D-Trp(8, 9), 15-ol)-galanin (1-15) behaved as an agonist in the present experiments. In conclusion, in the spinal cord of the anaesthetized rat, galanin has a purely pro-nociceptive role, since it enhanced responses evoked by high-threshold fibre stimulation, along with post-discharge and wind-up of WDR neurones.

Anesthesia, Inhalation↗
PubMed2000

Early recognition of hepatic portal vein gas on CT with appropriate surgical intervention improves patient survival.

Historically, hepatic portal vein gas has been linked with a dismal prognosis. However, in the last 3 decades, identification of hepatic portal vein gas has undergone a transition from late recognition on roentgenograms to earlier identification on computed tomography scan. The 5 patients in this case series were found to harbor hepatic portal vein gas identified using computed tomography scan. Eighty percent of the patients had concomitant pathology identified by computed tomography, felt to be the cause of the hepatic portal vein gas. All patients were taken to the operating room for exploration and resection of the offending pathology. All 5 patients survived. We suggest that early recognition using computed tomography scan, with appropriate operative intervention, improves the chance for patient survival when hepatic portal vein gas is identified.

Journal Article↗
PubMed2000

Repeated administration of systemic gabapentin alleviates allodynia-like behaviors in spinally injured rats.

The effect of systemic gabapentin, a novel antiepileptic and analgesic, was tested on allodynia-like behaviors in spinal cord injured rats. On the first day of treatment 30 mg/kg intraperitoneal gabapentin did not alleviate hyper-reactivity to mechanical and cold stimulation. The allodynia was significantly reduced by 100 mg/kg gabapentin, which however, produced sedation and motor impairments. Repeated administration of 30 mg/kg gabapentin once a day produced a gradually increasing anti-allodynic effect. Total alleviation of mechanical allodynia was observed in most rats after the third administration of gabapentin. Thus, build-up of the antiallodynic effect of gabapentin may develop through a time dependent mechanism or alternatively through a gradual accumulation of the effective central nervous system concentration of the drug.

Acetates↗
PubMed2000

Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain.

The anti-nociceptive and locomotor effects of the nicotinic acetylcholine receptor (nAChR) agonists (+)-epibatidine and ABT-594 were compared in the rat. Acute thermal nociception was measured using the tail flick test. Mechanical hyperalgesia was measured as paw withdrawal threshold (PWT) in response to a mechanical stimulus in two animal models of persistent pain; (1) 24 h following subplantar injections of Freund's complete adjuvant (FCA) into the left hind paw or (2) 11-15 days following a partial ligation of the left sciatic nerve. Disruption of locomotor function was assessed using an accelerating rotarod device. In all tests, (+)-epibatidine was significantly more potent than ABT-594. Both (+)-epibatidine and ABT-594 dose-dependently increased tail flick latencies but only at doses that also disrupted performance in the rotarod test. On the other hand, (+)-epibatidine and ABT-594 dose-dependently reversed inflammatory and neuropathic hyperalgesia at significantly lower doses than that needed to disrupt performance in the rotarod test. In summary, ABT-594 is less potent than (+)-epibatidine in assays of acute and persistent pain and in the rotarod assay. However, ABT-594 displayed a clearer separation between its motor and anti-hyperalgesic effects. This shows that nicotinic agonists with improved selectivity between the nicotinic receptor subtypes could provide strong analgesic effects with a much improved therapeutic window.

Analgesics, Non-Narcotic↗
PubMed2000

Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons.

Expression of cannabinoid 1 (CB1) and vanilloid 1 (VR1) receptor proteins was studied in adult, cultured rat dorsal root ganglion neurons. Immunostaining of CB1 receptors alone produced labelling in 57+/-2% of the cultured dorsal root ganglion neurons (n=3 cultures). The area of the labelled cells was between 200 and 800 microm(2) with an average of 527+/-68 microm(2). VR1 immunolabelling revealed immunopositivity in 42+/-6% of the total population of dorsal root ganglion neurons. Cells showing VR1-like immunopositivity had an area between 200 and 600 microm(2). The mean area of the VR1-like immunopositive neurons was 376+/-61 microm(2). Double immunostaining with antisera raised against the CB1 and VR1 receptor proteins, showed a high degree of co-expression between CB1 and VR1 receptors. An average of 82+/-3% of the CB1-like immunopositive cells also showed VR1-like immunoreactivity (n=3 cultures) while 98+/-2% of the VR1-like immunolabelled neurons showed CB1 receptor-like immunostaining (n=3 cultures). Our data suggests that nociceptive primary sensory neurons co-express CB1 and VR1 receptors to a very high degree. We propose that this may provide an anatomical basis for a powerful combination of VR1 mediated excitation and CB1-mediated inhibition of nociceptive responses at central and peripheral terminals of nociceptive primary afferents.

Animals↗
PubMed2000

Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia.

Bradyzide is from a novel class of rodent-selective non-peptide B(2) bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with K(I) values of 0.51+/-0.18 nM (n=3) and 0.89+/-0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B(2) receptor-induced (45)Ca efflux from NG108-15 cells with a pK(B) of 8.0+/-0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC(50) value; 1.6+/-0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B(2) receptor with K(I) values of 393+/-90 nM (n=3) and 772+/-144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [(3)H]-inositol trisphosphate (IP(3)) formation with IC(50) values of 11.6+/-1.4 nM (n=3) at the rat and 2.4+/-0.3 microM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B(1) bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED(50), 0.84 micromol kg(-1); duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B(2) bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77 - 86

Administration, Oral↗
PubMed2000

GABAB receptor protein and mRNA distribution in rat spinal cord and dorsal root ganglia.

The presence of metabotropic receptors for GABA, GABAB, on primary afferent terminals in mammalian spinal cord has been previously reported. In this study we provide further evidence to support this in the rat and show that the GABAB receptor subunits GABAB1 and GABAB2 mRNA and the corresponding subunit proteins are present in the spinal cord and dorsal root ganglion. We also show that the predominant GABAB1 receptor subunit mRNA present in the afferent fibre cell body appears to be the 1a form. In frozen sections of lumbar spinal cord and dorsal root ganglia (DRG) GABAB receptors were labelled with [3H]CGP 62349 or the sections postfixed with paraformaldehyde and subjected to in situ hybridization using oligonucleotides designed to selectively hybridize with the mRNA for GABAB(1a), GABAB(1b) or GABAB2. For immunocytochemistry (ICC), sections were obtained from rats anaesthetized and perfused-fixed with paraformaldehyde. The distribution of binding sites for [3H]CGP 62349 mirrored that previously observed with [3H]GABA at GABAB sites. The density of binding sites was high in the dorsal horn but much lower in the ventral regions. By contrast, the density of mRNA (pan) was more evenly distributed across the laminae of the spinal cord. The density of mRNA detected with the pan probe was high in the DRG and distributed over the neuron cell bodies. This would accord with GABAB receptor protein being formed in the sensory neurons and transported to the primary afferent terminals. Of the GABAB1 mRNA in the DRG, approximately 90% was of the GABAB(1a) form and approximately 10% in the GABAB(1b) form. This would suggest that GABAB(1a) mRNA may be responsible for encoding presynaptic GABAB receptors on primary afferent terminals in a manner similar to that we have previously observed in the cerebellar cortex. GABAB2 mRNA was also evenly distributed across the spinal cord laminae at densities equivalent to those of GABAB1 in the dorsal horn. GABAB2 mRNA was also detected to the same degree within the DRG. Immunocytochemical analysis revealed that GABAB(1a), GABAB(1b) and GABAB2 were all present in the spinal cord. GABAB(1a) labelling appeared to be more dense than GABAB(1b) and within the superficial dorsal horn GABAB(1a) was present in the neuropil whereas GABAB(1b) was associated with cell bodies in this region. Both 1a and 1b immunoreactivity was expressed in motor neurons in lamina IX. GABAB2 immunoreactivity was expressed throughout the spinal cord and was evident within the neuropil of the superficial laminae.

Animals↗
PubMed2000

Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat.

Inflammatory processes occurring within the central nervous system (CNS) can produce 'illness induced behaviours' which include fever, sleep and the development of allodynia and hyperalgesia. Here we demonstrate the effects of the pro-inflammatory mediators, bacterial endotoxin, and rat recombinant interleukin 1 beta (rrIL-1 beta) or tumour necrosis factor-alpha (rrTNF alpha) on the integration of somatosensory information at the single neuronal level, via recordings from wide-dynamic range neurones in the dorsal horn of the spinal cord in anaesthetized rats. Intrathecal administration of E. coli lipopolysaccharide (LPS, 10 and 100 microg, i.t.) enhanced the activity of dorsal horn neurones, including facilitation of neuronal post-discharge. Intrathecal administration of IL-1 beta (5-5000 pg) or TNF-alpha (5-5000 pg) enhanced dorsal horn neuronal responses, including the acute responses to C-fibre stimulation, wind-up and post-discharge, however, the effects of IL-1 beta were more robust than those of TNF alpha. Intrathecal administration of IL-1 beta (1-1000 pg) also leads to the development of mechanical allodynia and hyperalgesia. On the other hand intrathecal application of TNF alpha did not produce changes in sensitivity to mechanical stimuli. Changes in the activity of spinal wide-dynamic range neurones induced by local inflammation may provide a pathomechanism for the clinical pathology of central pain syndrome, which can accompany CNS disease or acute CNS injury.

Animals↗
PubMed1999

Distribution and developmental changes in metabotropic glutamate receptor messenger RNA expression in the rat lumbar spinal cord.

Using in situ hybridisation, the regional distribution of primary transcripts and splice variants of all metabotropic glutamate receptor subtypes (mGluR) currently known to be expressed in the spinal cord have been studied in the lumbar enlargement of the rat spinal cord. In adult animals, the messenger RNA of the mGluR subtypes 1, 5, 3, 4 and 7 were differentially expressed. The transcripts of mGluR1 and 5 were most abundant with mGluR5 messenger RNA being concentrated in the superficial dorsal horn. In contrast, the mGluR2 transcript was not detectable with the sensitivity of the method. Secondly, age related changes (postnatal days 1, 7, 12, 21) in the postnatal expression of mGluR1-5 and 7 transcripts have been investigated. mGluR1 and 7 messenger RNA showed a general decrease in spinal expression from postnatal day 1 to day 21. Quantitative densitometry showed high mGluR3 and 5 messenger RNA levels especially in the superficial dorsal horn at birth, however these levels decreased with age. In addition to changes in density, the regional distribution of mGluR3 messenger RNA was altered with postnatal development. Up to postnatal day 12, mGluR3 messenger RNA expression was almost exclusively restricted to the spinal grey matter, but with postnatal day 21 a strong additional expression in the white matter occurred. Distribution of mGluR4 messenger RNA showed little change in the dorsal horn, however motoneuronal expression emerged during development. These changes may suggest different roles for mGluRs in the maturation of spinal transmission of the rat nervous system.

Aging↗
PubMed1998

2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N - methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models.

A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f (2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benz yl- N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (Ki = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.

Analgesics↗
PubMed1998

mGluR activation reveals a tonic NMDA component in inflammatory hyperalgesia.

Metabotropic glutamate receptors (mGluRs) have been shown to contribute to nociceptive processing in the spinal cord. We have investigated the pharmacology of the mGluR agonist (1S,3R)-ACPD during inflammatory hyperalgesia in an in vitro preparation of the juvenile rat hemisected spinal cord. Superfusion of (1S,3R)-ACPD produced a concentration-dependent ventral root depolarization in naive and hyperalgesic animals with no significant difference in EC50 values (55.5 +/- 6.36 microM and 51.0 +/- 5.76 microM, respectively, n = 4). However, the amplitude of the maximum response was significantly enhanced by 23% in hyperalgesic compared with naive animals. The NMDA receptor antagonist D-AP5 reversed this effect, leaving the (1S,3R)-ACPD dose-response curve unchanged in naive animals. These results suggest a tonic NMDA component in the spinal cord during inflammatory hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed1998

The effects of SDZ NKT 343, a potent NK1 receptor antagonist, on cutaneous responses of primate spinothalamic tract neurones sensitized by intradermal capsaicin injection.

Substance P, acting through neurokinin I receptors, is involved in the processing of nociceptive information in the spinal cord. Sensitization of spinothalamic tract neurons occurs to low-intensity stimuli following capsaicin injection. The current study tested the effects of the novel neurokinin I receptor antagonist, SDZ NKT 343, on the sensitization of spinothalamic tract cells by capsaicin in monkeys. Spinothalamic tract cells from the lumbar enlargement with receptive fields in the hindpaw were isolated and recorded before and after intradermal injection of capsaicin. The background activity and responses to brushing, pressing and pinching the skin were assessed. Thirty minutes after capsaicin injection there was an increase in background activity and responses to brush and pressure applied to the receptive field. Infusion of SDZ NKT 343 (for 30-45 min) significantly reversed the increased response to brushing without affecting the increased background activity or the increased response to pressure. Thus, blockade of neurokinin 1 receptors reduces the sensitized responses to innocuous mechanical stimuli but not to noxious mechanical stimuli.

Action Potentials↗
PubMed1998

Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation.

Metabotropic glutamate receptors are thought to play a role in the development and maintenance of spinal hyperexcitability resulting in hyperalgesia and pain. In this study we have used in situ hybridization to investigate the distribution of metabotropic glutamate receptors mGluR1-7 messenger RNA in the rat spinal cord in a model of inflammatory hyperalgesia. Hyperalgesia was induced in nine-day-old rats by exposure of the left hindpaw to an ultraviolet light source. Lumbar portions of spinal cords were removed from control and ultraviolet-treated animals. In situ hybridization with specific oligonucleotide probes was used to localize metabotropic glutamate receptor messenger RNAs. mGluR1, 3-5 and 7 subtype messenger RNA was detected in the gray matter of the spinal cord with distribution being specific for the different subtypes. A significant increase in the expression of mGluR3 messenger RNA was seen in cells of the dorsal laminae in both sides of the lumbar spinal cord. This increase was most pronounced in laminae II, III and IV but gradually decreased and disappeared by the third day of inflammation. In parallel with this, behavioural experiments revealed mechanical hyperalgesia in both hindlimbs after ultraviolet irradiation. There was no change in mGluR3 messenger RNA expression in the thoracic segments. No changes have been detected in the levels of expression of mGluR 1,2,4,5,7 subtype messenger RNA in spinal cords taken from hyperalgesic animals. These observations show that during ultraviolet irradiation induced inflammation, the synthesis of mGluR3 messenger RNA is altered suggesting that regulation of metabotropic glutamate receptor expression may be instrumental in plastic changes within the spinal cord during the development of hyperalgesia and pain.

Amino Acid Sequence↗
PubMed1998

Selective neurokinin-1 receptor antagonists are anti-hyperalgesic in a model of neuropathic pain in the guinea-pig.

Neuropathic pain is poorly managed by conventional analgesic therapy, such as non-steroidal anti-inflammatory drugs and opiates. The development of animal models of peripheral neural damage has aided in our understanding of the pathology and pharmacology of neuropathic pain. This report is the first clear demonstration using selective neurokinin-1 receptor antagonists of a potentially novel therapeutic approach to the treatment of neuropathic pain resulting from peripheral nerve damage in a guinea-pig model. The neurokinin-1 receptor antagonists, SDZ NKT 343 and LY 303,870 significantly reduced mechanical hyperalgesia following oral and intrathecal administration. (R,R)-SDZ NK T343, the enantiomer of SDZ NKT 343 did not show anti-hyperalgesic activity. RPR 100,893 showed significant anti-hyperalgesic activity only following intrathecal administration suggesting poor absorption or low level penetration of the blood-brain barrier. These results imply that neurokinin-1 receptor antagonists offer a new class of anti-hyperalgesic drugs with a largely central site of action in neuropathic pain.

Administration, Oral↗
PubMed1998

Spinal neurokinin NK1 receptor down-regulation and antinociception: effects of spinal NK1 receptor antisense oligonucleotides and NK1 receptor occupancy.

To define the effects of antisense oligonucleotides on spinal neurokinin 1 (NK1) receptor function in nociceptive processing, several antisense oligonucleotides directed against the NK1 receptor mRNA were intrathecally injected into rats via an implanted catheter, and their effect on the behavioural response to formalin injected into the paw was assessed. We observed that there was no significant reduction of pain behaviour or immunostaining of spinal NK1 receptors after repeated daily intrathecal treatment with an antisense oligonucleotide. However, spinal application of substance P (SP) in the antisense oligonucleotide-treated animals resulted in a profound and long-lasting reduction in the behavioural response to formalin injection, and a parallel reduction in the NK1 receptor immunoreactivity normally observed in spinal dorsal horn. Intrathecal SP in the control groups, i.e., rats treated with an oligonucleotide containing four mismatched bases, the corresponding sense oligonucleotide, a mixture of the sense and the antisense oligonucleotides, in each case had no effect. The effects of SP were blocked by NK1 receptor antagonists and were not mimicked by NMDA. The mechanism underlying these effects is not clear. It may be due to partial degradation of the internalised receptors, which cannot be replaced by newly synthesised receptors because of the action of the NK1 antisense oligonucleotide.

Animals↗
PubMed1997

Signal changes in the spinal cord of the rat after injection of formalin into the hindpaw: characterization using functional magnetic resonance imaging.

Changes in metabolism and local circulation occur in the spinal cord during peripheral noxious stimulation. Evidence is presented that this stimulation also causes signal intensity alterations in functional magnetic resonance images of the spinal cord during formalin-induced pain. These results indicate the potential of functional magnetic resonance imaging in assessing noninvasively the extent and intensity of spinal cord excitation in this well characterized pain model. Therefore, the aim of this study was to establish functional magnetic resonance imaging as a noninvasive method to characterize temporal changes in the spinal cord after a single injection of 50 microl of formalin subcutaneously into the hindpaw of the anesthetized rat. This challenge produced a biphasic licking activity in the freely moving conscious animal. Images of the spinal cord were acquired within 2 min, enabling monitoring of the site and the temporal evolution of the signal changes during the development of formalin-induced hyperalgesia without the need of any surgical procedure. The time course of changes in the spinal cord functional image in the isoflurane-anesthetized animal was similar to that obtained from behavioral experiments. Also, comparable physiological data, control experiments, and the inhibition of a response through application of the local anesthetic agent lidocaine indicate that the signal changes observed after formalin injection were specifically related to excitability changes in the relevant segments of the lumbar spinal cord. This approach could be useful to characterize different models of pain and hyperalgesia and, more importantly, to evaluate effects of analgesic drugs.

Animals↗
PubMed1996

Leukemia inhibitory factor induces mechanical allodynia but not thermal hyperalgesia in the juvenile rat.

Systemic administration or local injection to the rat hindpaw of leukemia inhibitory factor induced a prolonged, dose dependent, mechanical hypersensitivity of the hindpaw flexion withdrawal reflex. Mechanical stimuli which were innocuous prior to leukemia inhibitory factor administration, evoked a rapid hindpaw withdrawal reflex indicative of mechanical allodynia. Pre-administration of anti-leukemia inhibitory factor antibodies prevented this behavioural hypersensitivity. Hindpaw sensitivity to a noxious thermal stimulus was unaffected by leukemia inhibitory factor administration. Anti-leukemia inhibitory factor had no effect upon hindpaw withdrawal thresholds when injected alone nor influenced the mechanical hypersensitivity produced by a subcutaneous injection of nerve growth factor. Injection of the closely related cytokine ciliary neurotrophic factor did not affect mechanical or thermal reflex withdrawal thresholds. Elevation of the neuroactive cytokine leukemia inhibitory factor following peripheral nerve injury may be a contributory factor to the pathogenesis of neuropathic pain.

Age Factors↗