Biomedical subjects

G Geisslinger

Publications and source records attributed to G Geisslinger.

At least 19 recordsLinked to original sources

PubMed2007

The partial 5-hydroxytryptamine1A receptor agonist buspirone does not antagonize morphine-induced respiratory depression in humans.

Based on experiments in rats, serotonin receptor 5-hydroxytryptamine (5-HT)(1A) agonists have been proposed as a potential therapeutic strategy for the selective treatment of opioid-induced respiratory depression. We investigated the clinical applicability of this principle in healthy volunteers. Twelve subjects received 0.43 mg/kg morphine (30 mg for 70 kg body weight) administered intravenously (i.v.) over approximately 2 h. At the start of the morphine infusion, they received in a randomized, double-blind cross-over design 60 mg p.o. buspirone or placebo. Respiratory depression (hypercapnic challenge) and pain (electrical stimuli: 5 Hz sinus 0-20 mA; chemical stimuli: 200 ms gaseous CO(2) pulses applied to the nasal mucosa) were assessed at baseline, at the end of the morphine infusion, and a third time after antagonizing the opioid effects by i.v. administration of 2 mg naloxone. The linear relationship between the minute ventilation and the CO(2) concentration in the inspired air of 1.07+/-0.27 l/mm Hg CO(2) at baseline conditions became shallower (0.45+/-0.23 l/mm Hg CO(2)) after morphine administration (P<0.001), indicating respiratory depression, which was significantly reversed by naloxone (0.95+/-0.43 l/mm Hg CO(2); P=0.001). Co-administration of buspirone had no effect on morphine-induced respiratory depression (slope 0.45+/-0.23 l/mm Hg CO(2) under morphine plus placebo versus 0.38+/-0.25 l/mm Hg CO(2) under morphine plus buspirone; P=0.7). Significant morphine-induced analgesia was observed in both pain models and was reversed by naloxone but unaffected by buspirone. Buspirone significantly increased the nausea induced by morphine (P=0.011). Oral co-administration of a high dose of the clinically available 5-HT(1A) agonist buspirone cannot be advised as a remedy for opioid-induced respiratory depression. This is indicated by its lack of anti-respiratory depressive effects and by the buspirone-associated increase of morphine-induced nausea.

Adult↗

PubMed2006

Nickel release, a possible indicator for the duration of antiplatelet treatment, from a nickel cardiac device in vivo: a study in patients with atrial septal defects implanted with an Amplatzer occluder.

UNLABELLED: The present study was undertaken to evaluate the safety and release of nickel after implantation of a nickel device (Amplatzer occluder) in patients with an atrial septal defect (ASD) receiving antiplatelet therapy. METHODS: Blood and urine samples were obtained from 24 patients with ASD before occluder implantation (baseline) and during a 12-month post closure period. Antiplatelet drugs were administered for the initial 6-month period post implantation. The nickel content in the specimens was determined using electrothermal atomic absorption spectroscopy. The clinical, sonographic and magnetic resonance imaging follow-ups were carried out 1 week, 1 month, 6 months and 12 months post implantation. RESULTS: Mean baseline concentrations of nickel in serum and urine were within normal range with values of 0.6 +/- 0.2 microg/l and 3.1 +/- 1.2 microg/l, respectively. During the 6-week post closure period, the time needed for the formation of neointima on the surface of the graft, nickel levels in serum increased up to 5-fold (p < 0.01 versus baseline). Mean concentrations in serum and urine returned to baseline levels within 4-6 months post implantation. All patients showed satisfactory clinical improvements and there was no sonographic evidence of complications. CONCLUSIONS: The initial dissolution of nickel from the Amplatzer occluder is not a specific cardiovascular risk and is temporarily linked to the formation of the non-thrombogenic neointima on the surface of the graft. The antiplatelet drug regimen used (300 mg aspirin + 75 mg clopidogrel daily for 3 months in the initial phase and 100 mg aspirin daily for a further 3 months) appears to cover the period of neointima formation on the nickel device when nickel levels are significantly elevated. However, further studies in a larger number of patients and over a period greater than 12 months are needed to confirm the validity of these conclusions and to formulate definitive recommendations on the duration of the antiplatelet treatment.

Adult↗

PubMed2005

[Fundamental principles of clinical trials].

Medical conduct relies on the efficacy and tolerability of a given pharmacotherapy. On the basis of an experimental comparison of different treatment options, a clinical trial provides the foundation for an evidence-based medicine that complies with state-of-the-art scientific practice. The quality of the data assessment determines the clinical relevance of the study results. Clinical trials are classified into Phases I-IV to ensure the development of an effective and safe pharmaceutical. The investigator is responsible for being experienced in the relevant area of expertise, for conducting the study according to the investigational plan, and for complying with ethical guidelines and drug safety.

Adverse Drug Reaction Reporting Systems↗

PubMed2005

[Are polymorphisms in the mu-opioid receptor important for opioid therapy?].

Polymorphisms in the mu-opioid receptor gene may potentially alter the clinical effects of opioid analgesics. A common mu-opioid receptor polymorphism occurring at an allelic frequency of 12% decreases the potency of opioid analgesics in humans. Interestingly, in carriers of this mutation, it appears to be possible to reach analgesia by increasing the opioid dose but side effects appear to occur less often despite the higher opioid dose. This suggests a broadened therapeutic range of the opioids. Other mutations of the mu-opioid receptor, for example three mutations within the third intracellular loop of the receptor, impair receptor signaling, but they are too rare to greatly affect pain therapy or have not yet been investigated in the context of pain therapy.

Amino Acid Sequence↗

PubMed2005

Comparison of two screening methods for in-house genotyping in clinical pharmacology units.

Two genetic screening methods, the fluorescence resonance energy transfer (FRET) technique on the LightCycler and the real-time pyrophosphate detection technique on the Pyrosequencer have been compared with regard to their usefulness as screening methods for subject recruitment in clinical studies in pharmacology units. Two SNPs of possible clinical relevance were selected, namely the 118A>G SNP of the OPRM1 gene and the 3435C>T SNP of the ABCB1 gene. Genotypes diagnosed using conventional sequencing served as control. The allelic frequency of the mutated 118G allele of the OPRM1 gene was 12.7% and that of the mutated 3435T allele of the ABCB1 gene was 50.7%. All results obtained with the Pyrosequencer were in accord with those obtained using conventional sequencing. With the LightCycler, an incorrect genotype was assigned to 1 of the 130 DNA samples corresponding to an error rate of 0.8%. Although both methods were found suitable for rapid SNP detection, Pyrosequencing was the preferred method since it provides the nucleotide sequence directly thus facilitating interpretation.

ATP-Binding Cassette Transporters↗

PubMed2004

Cyclooxygenase 2 expression in the spared nerve injury model of neuropathic pain.

Cyclooxygenase-2 (COX-2) after induction peripherally, and within the CNS, plays an important role in producing inflammatory pain. However, its role in neuropathic pain models is controversial. Recently a robust and persistent model of partial nerve injury pain, the spared nerve injury (SNI) model, has been developed. The aim of the present study was to examine the regulation of COX-2 in the rat SNI model and to evaluate the effectiveness of the selective COX-2 inhibitor rofecoxib in preventing neuropathic allodynia and hyperalgesia. RNase protection assays revealed only a very small and transient increase in COX-2 mRNA in the dorsal horn of the spinal cord in the SNI model with a maximum change at 24 h. Immunohistochemical analysis showed a small increase in COX-2 protein in the deep layers of the dorsal horn 10 h following SNI surgery. Rofecoxib (100 microM) did not affect spontaneous excitatory postsynaptic currents or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propanoic acid (AMPA) and N-methyl-d-aspartate (NMDA) responses in lamina II neurons from spinal cords of animals with SNI indicating no detectable action on transmitter release or postsynaptic activity. Furthermore, rofecoxib treatment (1 and 3.2 mg/kg for 5 and 3 days respectively starting on the day of surgery) failed to modify the development of allodynia and hyperalgesia in the SNI model. However, rofecoxib significantly reduced inflammatory hypersensitivity evoked by injection of complete Freund's adjuvant into one hindpaw, indicating that the doses used were pharmacologically active. The pain hypersensitivity produced by the SNI model is not COX-2-dependent.

Animals↗

PubMed2004

Programming of a flexible computer simulation to visualize pharmacokinetic-pharmacodynamic models.

Teaching pharmacokinetic-pharmacodynamic (PK/PD) models can be made more effective using computer simulations. We propose the programming of educational PK or PK/PD computer simulations as an alternative to the use of pre-built simulation software. This approach has the advantage of adaptability to non-standard or complicated PK or PK/PD models. Simplicity of the programming procedure was achieved by selecting the LabVIEW programming environment. An intuitive user interface to visualize the time courses of drug concentrations or effects can be obtained with pre-built elements. The environment uses a wiring analogy that resembles electrical circuit diagrams rather than abstract programming code. The goal of high interactivity of the simulation was attained by allowing the program to run in continuously repeating loops. This makes the program behave flexibly to the user input. The programming is described with the aid of a 2-compartment PK simulation. Examples of more sophisticated simulation programs are also given where the PK/PD simulation shows drug input, concentrations in plasma, and at effect site and the effects themselves as a function of time. A multi-compartmental model of morphine, including metabolite kinetics and effects is also included. The programs are available for download from the World Wide Web at http:// www. klinik.uni-frankfurt.de/zpharm/klin/ PKPDsimulation/content.html. For pharmacokineticists who only program occasionally, there is the possibility of building the computer simulation, together with the flexible interactive simulation algorithm for clinical pharmacological teaching in the field of PK/PD models.

Algorithms↗

PubMed2004

Single-step identification of all length polymorphisms in the UGT1A1 gene promoter.

AIM: To provide a sensitive genetic screening method for rapid identification of all known length polymorphisms in the promoter region of the uridine 5'-diphosphoglucose glucuronosyltransferase (UGT) 1A1 gene comprising (TA)5, (TA)7 and (TA)8 repeats as opposed to the non-mutated (TA)6 allele. METHODS: The UGT1A1 promoter genotype was assessed in 115 subjects by means of a newly developed pyrosequencing method. PCR-generated DNA templates of heterozygous (TA)5 and (TA)7 carriers were cloned into a TOPO TA vector and verified by sequencing. In addition, a (TA)8 segment was produced by cloning to demonstrate the ability of the method to detect this mutation. RESULTS: All length polymorphisms of the UGT1A1 promoter described in the literature were clearly identified. Fifteen subjects had Gilbert's syndrome with elevated serum bilirubin associated with a homozygous (TA)7TAA/(TA)7TAA genotype. Two subjects with the rare genotypes (TA)5TAA/(TA)6TAA and (TA)5TAA/(TA)7TAA were found, where only the latter one displayed elevated serum bilirubin levels. Allelic frequencies were 0.9%, 66.1% and 33% for the (TA)5TAA, (TA)6TAA and (TA)7TAA allele, respectively. CONCLUSION: Our method enables reliable genetic single-step screening for all known length polymorphisms in the UGT1A1 gene promoter that cause Gilbert's syndrome. This facilitates pharmacogenetic-guided dosing of drugs with known toxicity metabolized by UGT1A1.

Genetic Testing↗

PubMed2003

Review article: The pharmacological properties and clinical use of valdecoxib, a new cyclo-oxygenase-2-selective inhibitor.

Cyclo-oxygenase-2-selective inhibitors produce less gastric damage than conventional non-steroidal anti-inflammatory drugs. Valdecoxib is a new orally administered cyclo-oxygenase-2-selective inhibitor, recently approved for use in osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea in the USA. The drug has been evaluated in more than 60 clinical studies involving more than 14 000 patients and healthy volunteers. The analgesic efficacy of valdecoxib at a dose of 10 mg once daily in both osteoarthritis and rheumatoid arthritis is superior to that of placebo and similar to that of traditional non-steroidal anti-inflammatory drugs. Valdecoxib is effective in single doses of up to 40 mg for the alleviation of acute menstrual pain and has a rapid onset of action (within 30 min) and a long duration of analgesia (up to 24 h). Valdecoxib is well tolerated and has safety advantages compared with traditional non-steroidal anti-inflammatory drugs in terms of less gastrointestinal toxicity and a lack of an effect on platelet function. The incidence of adverse effects involving the kidney (fluid retention, oedema and hypertension) is similar to that of non-selective, non-steroidal anti-inflammatory drugs.

Adult↗

PubMed2003

[Clinical pharmacology of the selective COX-2 inhibitors].

The discovery of two isoforms of cyclooxygenases (COX-1 and COX-2) has provided a new insight into the involvement of prostaglandins in the clinical effectiveness and gastrointestinal toxicity of NSAIDs. Currently, there are four selective COX-2 inhibitors available in Germany: celecoxib, rofecoxib, valdecoxib and parecoxib. Orally administered rofecoxib, celecoxib and valdecoxib have been approved for the relief of symptoms of osteoarthritis and rheumatoid arthritis. Parecoxib, the first selective COX-2 inhibitor for parenteral administration, has been approved for the short-term treatment of post-operative pain. The clinical efficacy of the marketed COX-2 inhibitors has been proved in large phase III clinical trials in comparison to both placebo and classical NSAIDs (e.g. diclofenac, naproxen). The incidence of gastrointestinal complications was significantly lower than that with the non-selective NSAIDs. However, the clinical relevance of these effects was, at least in some populations of patients (e.g. patients on low dose aspirin), not as high as initially expected. While not replacing less expensive classical NSAIDs, selective COX-2 inhibitors provide a marked enrichment of the spectrum of anti-inflammatory and analgesic therapeutics.

Acute Disease↗

PubMed2003

Modulation of spinal nociceptive processing through the glutamate transporter GLT-1.

GLT-1 is the predominant glutamate transporter in most brain regions and therefore plays a major role in terminating synaptic transmission and protecting neurons from glutamate neurotoxicity. In the present study we assessed (i) the regulation of GLT-1 expression in the spinal cord after peripheral nociceptive stimulation and (ii) the nociceptive behavior of rats following inhibition or transient knockdown of spinal GLT-1. Formalin injection into one hindpaw caused a rapid transient upregulation of GLT-1 protein expression in the spinal cord which did not occur when rats were pretreated with morphine (10 mg/kg, i.p.) suggesting that the nociceptive input specifically caused the increase of GLT-1 transcription. Inhibition of GLT-1 by the transportable inhibitor trans-pyrrolidine-2,4-dicarboxylic acid resulted in a significant reduction of nociceptive behavior in the rat formalin assay. Similar results were obtained with a transient reduction of GLT-1 protein expression by antisense oligonucleotides. These data suggest that inhibition of GLT-1 activity or expression reduces excitatory synaptic efficacy and thereby nociception. Mechanisms that might explain this phenomenon may include activation of inhibitory metabotropic glutamate receptors, postsynaptic desensitization or disturbance of glutamate recycling.

Analgesics, Opioid↗

PubMed2002

Release of algesic substances in human experimental muscle pain.

OBJECTIVE: We employed the 'delayed onset of muscle soreness' (DOMS) and the 'hypertonic saline' muscle pain models in combination with muscle microdialysis to evaluate the role of potentially algesic substances (lactate, glutamate, prostaglandin E2 (PGE2), nitric oxide (NO) and substance P (SP)) in the development of human muscle pain. METHODS: DOMS was induced by 2 sets of 50 concentric/eccentric contractions of the calf muscles 24 h before the start of microdialysis. During microdialysis pain was stimulated through calf muscle contractions (dorsal and plantar flexions of the foot). Hypertonic saline was injected into the biceps muscle (5 x 200 microl 5.8% NaCl, 2 min interval) during dialysis. The calf (no treatment) and biceps (normal saline) of the other side was used as control. RESULTS: Both models reliably induced muscle pain with similar intensities as assessed by visual analog scale. The DOMS exercise caused an increase of lactate in serum and the calf muscles of the DOMS leg. In addition, glutamate, PGE2 and substance P dialysate concentrations increased following contraction-induced pain stimulation (peak concentrations 125 +/- 20 microM, 239 +/- 45 pg/ml and 60 +/- 11 pg/ml for glutamate, PGE2 and SP, respectively). This increase did not occur in the control leg (peak concentrations 97 +/- 12 microM, 114 +/- 26 pg/ml and 46 +/- 9 pg/ml for glutamate, PGE2 and SP, respectively). Concentrations of nitric oxide were lower in the DOMS than control leg, particularly during the first 4h of microdialysis. Injection of hypertonic saline into the biceps muscle caused a significant increase of dialysate glutamate concentrations (peak 50 +/- 3 microM) whereas glutamate remained constant after injection of normal saline (mean 26 +/- 1 microM). Injection of hypertonic saline had no effect on lactate, PGE2 or NO levels. CONCLUSION: Our data support the notion that an inflammatory reaction may be involved in muscle soreness following eccentric exercise, whereas the injection of hypertonic saline into the muscle probably directly stimulates muscle nociceptors and causes glutamate release.

Adult↗

PubMed2001

COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib.

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX-independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors.

Animals↗

PubMed2001

Effects of the opioid remifentanil on olfactory function in healthy volunteers.

The effects of opioids on human subjective olfactory function have rarely been investigated. This is despite the fact that opioid receptors are widely distributed throughout the olfactory systems. Using an established validated test of subjective olfactory function, olfactory threshold, odor discrimination and odor identification performance were tested in 16 healthy volunteers before opioid administration and at steady state after 3 hours remifentanil infusion. Each one man and one women were assigned randomly to one out of eight predefined remifentanil target plasma concentrations: 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml. In the thirteen subjects that had completed the tests, olfactory thresholds were elevated with increasing remifentanil dose, and this correlated statistically significant with the remifentanil dose. Remifentanil plasma concentrations were linearly related to changes in olfactory thresholds. In contrast, effects of remifentanil on odor discrimination and identification were not statistically significant. However, remifentanil target plasma concentrations were also significantly correlated with the subjects' ratings of tiredness and drowsiness, although only drowsiness was significantly correlated with the differences in odor thresholds. We conclude that opioid administration leads to impaired olfactory function expressed in raised olfactory thresholds. This is compatible with previously reported opioidergic effects at the level of the olfactory bulb.

Adult↗

PubMed2001

Determination of celecoxib in human plasma and rat microdialysis samples by liquid chromatography tandem mass spectrometry.

Methods for the determination of celecoxib in human plasma and rat microdialysis samples using liquid chromatography tandem mass spectrometry are described. Celecoxib and an internal standard were extracted from plasma by solid-phase extraction with C18 cartridges. Thereafter compounds were separated on a short narrow bore RP C18 column (30 x 2 mm). Microdialysis samples did not require extraction and were injected directly using a narrow bore RP C18 column (70 x 2 mm). The detection was by a PE Sciex API 3000 mass spectrometer equipped with a turbo ion spray interface. The compounds were detected in the negative ion mode using the mass transitions m/z 380-->316 and m/z 366-->302 for celecoxib and internal standard, respectively. The assay was validated for human plasma over a concentration range of 0.25-250 ng/ml using 0.2 ml of sample. The assay for microdialysis samples (50 microl) was validated over a concentration range of 0.5-20 ng/ml. The method was utilised to determine pharmacokinetics of celecoxib in human plasma and in rat spinal cord perfusate.

Animals↗

PubMed2001

Interleukin-1beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells.

The lipid signaling molecule ceramide is formed by the action of acid and neutral sphingomyelinases and degraded by acid and neutral ceramidases. Short-term stimulation of mesangial cells with the pro-inflammatory cytokine interleukin-1beta (IL-1beta) leads to a rapid and transient increase in neutral sphingomyelinase activity (Kaszkin, M., Huwiler, A., Scholz, K., van den Bosch, H., and Pfeilschifter, J. (1998) FEBS Lett. 440, 163-166). In this study, we report on a second delayed peak of activation occurring after hours of IL-1beta treatment. This second phase of activation was first detectable after 2 h of treatment and steadily increased over the next 2 h, reaching maximal values after 4 h. In parallel, a pronounced increase in neutral ceramidase activity was observed, accounting for a constant or even decreased level of ceramide after long-term IL-1beta treatment, despite continuous sphingomyelinase activation. The increase in neutral ceramidase activity was due to expressional up-regulation, as detected by an increase in mRNA levels and enhanced de novo protein synthesis. The increase in neutral ceramidase protein levels and activity could be blocked dose- dependently by the p38 MAPK inhibitor SB 202190, whereas the classical MAPK pathway inhibitor U0126 and the protein kinase C inhibitor Ro 318220 were ineffective. Moreover, cotreatment of cells for 24 h with IL-1beta and SB 202190 led to an increase in ceramide formation. Interestingly, IL-1beta-stimulated neutral ceramidase activation was not reduced in mesangial cells isolated from mice deficient in MAPK-activated protein kinase-2, which is a downstream substrate of p38 MAPK, thus suggesting that the p38 MAPK-mediated induction of neutral ceramidase occurs independently of the MAPK-activated protein kinase-2 pathway. In summary, our results suggest a biphasic regulation of sphingomyelin hydrolysis in cytokine-treated mesangial cells with delayed de novo synthesis of neutral ceramidase counteracting sphingomyelinase activity and apoptosis. Neutral ceramidase may thus represent a novel cytoprotective enzyme for mesangial cells exposed to inflammatory stress conditions.

Amidohydrolases↗

PubMed2001

Expression of rat liver long-chain acyl-CoA synthetase and characterization of its role in the metabolism of R-ibuprofen and other fatty acid-like xenobiotics.

Our investigations of fatty acid metabolism and epimerization of the 2-arylpropionic acid derivative, R-ibuprofen, resulted in the successful purification of an acyl-CoA synthetase from rat liver microsomes that catalyzes the formation of both palmitoyl-CoA and R-ibuprofenoyl-CoA. To investigate whether R-ibuprofenoyl-CoA synthetase and long-chain acyl-CoA synthetase (LACS) are identical enzymes, we cloned the cDNA from LACS into the pQE30 expression vector and transformed the construct into Escherichia coli M15[pREP4]. Induction of the bacterial protein synthesis with 0.2 mM isopropyl-beta-D-galactoside resulted in a strong, time-dependent increase in LACS protein as determined by Western blot analysis using a polyclonal rabbit anti-LACS antibody. Incubations of the recombinantly expressed protein with palmitic acid as physiological LACS substrate or R-ibuprofen in the presence of Mg2+, ATP, and CoA resulted in a 5-fold increase in the thioesterification of both substrates. Western blot analysis using tissue homogenates of rat liver, heart, kidney, lung, brain, and ileum showed that LACS was found in every tissue investigated, with the greatest expression in the liver. Similar results were obtained with activity measurements using R-ibuprofen and palmitic acid as substrates. Northern blot analysis revealed a hybridization with a 3.8-kb mRNA transcript in rat liver, heart, and kidney, but no signal was observed in lung, brain and ileum, suggesting the expression of different LACS isoform(s) in these organs. In summary, our results further show that R-ibuprofenoyl-CoA synthetase and long-chain acyl-CoA synthetase are identical enzymes that are involved in the metabolism of various xenobiotics.

Acyl Coenzyme A↗

PubMed2001

Role of nitric oxide in zymosan induced paw inflammation and thermal hyperalgesia.

OBJECTIVE: To assess the involvement of spinal inducible nitric oxide synthase (iNOS) in inflammation and nociception. MATERIALS AND METHODS: The time course of iNOS mRNA expression in rat spinal cord and inflamed paw was assessed by means of quantitative real time RT-PCR. In addition, the effects of the iNOS inhibitor L-NIL on inflammatory paw edema and thermal hyperalgesia were studied in comparison to those of the NO-donor RE-2047. L-NIL (3, 9, 27 and 81 mg/kg) and RE-2047 (3, 9 and 27 mg/kg) or vehicle were administered orally 15 min prior to the intraplantar injection of 0.625 mg zymosan. RESULTS: Following zymosan injection, mRNA expression of iNOS increased in the inflamed paw and spinal cord with a maximum at 2.5 and 4 h, respectively. In the spinal cord iNOS mRNA started to decline at 10 h whereas it remained at maximum in the inflamed paw up to the end of the observation period of 24 h. As expected, RE-2047 had significant pronociceptive and proinflammatory effects. L-NIL significantly reduced paw inflammation at 27 and 81 mg/kg but failed to reduce hyperalgesia at the doses tested. CONCLUSIONS: The results show that iNOS is upregulated in the inflamed tissue and spinal cord with a similar time course. The effects obtained with L-NIL suggest that iNOS differently contributes to the inflammatory and nociceptive response induced by zymosan.

Animals↗