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PubMed2005

Target-specific catecholamine elevation induced by anticonvulsant thalamic deep brain stimulation.

PURPOSE: Anterior thalamic nucleus (AN) deep brain stimulation (DBS) is effective in raising EEG and clonic seizure threshold in experimental models. Little is known about the specific properties of DBS that afford its anticonvulsant effect. We sought to test the hypothesis that experimental seizures and the anticonvulsant action of AN DBS alter the underlying regional neurochemistry of AN, specifically with facilitation of the serotonergic system to local electrical stimulation. METHODS: Halothane-anesthetized adult Sprague-Dawley male rats underwent stereotactically guided bilateral placement of bipolar stimulating steel electrodes and dialysis probes-guide cannulae in AN and posterior thalamus (PT), and placement of four epidural EEG screw electrodes 48 h before experiments. Both stimulated (AN DBS) and nonstimulated (NO DBS) animals (n=7 per group) were infused with i.v. pentylenetetrazol (PTZ, 5.5 mg/kg/min). Simultaneous thalamic and cortical EEG were recorded, and microdialysis samples were collected from AN and PT in 20-min epochs. AN stimulation was delivered (150 microA; 0.1-ms pulse duration) 40 min before and continued during PTZ infusion. RESULTS: Bilateral AN stimulation delayed the onset of EEG seizures compared with controls: 82+/-8 vs. 58+/-5 min (p=0.02). PTZ infusion alone, or together with stimulation, resulted in a steady increase in norepinephrine (NE), but not dopamine, at AN and PT sites (p<0.001). Although extracellular serotonin was measured at very low levels, the metabolite, 5-hydroxyindoleacetic acid (5-HIAA) increased selectively in AN after stimulation and during preconvulsant infusion of PTZ (p<0.001), returning to baseline after the first generalized seizure. CONCLUSIONS: These data suggest that PTZ and DBS together enhance the nonselective release of NE in thalamic nuclei while specifically stimulating AN-localized serotonin. Low serotonin levels at baseline and during STIM alone or PTZ infusion may indicate efficient reuptake systems for serotonin, with 5-HIAA serving as a surrogate marker for serotonergic activity. Modulation of the AN-specific serotonergic activity may be critical in altering PTZ seizure threshold and be an important neurotransmitter system underlying the efficacy of AN DBS.

Animals↗

PubMed2002

Influence of d orbital occupation on the binding of metal ions to adenine.

Threshold collision-induced dissociation of M(+)(adenine) with xenon is studied using guided ion beam mass spectrometry. M(+) includes all 10 first-row transition metal ions: Sc(+), Ti(+), V(+), Cr(+), Mn(+), Fe(+), Co(+), Ni(+), Cu(+), and Zn(+). For the systems involving the late metal ions, Cr(+) through Cu(+), the primary product corresponds to endothermic loss of the intact adenine molecule, whereas for Zn(+), this process occurs but to form Zn + adenine(+). For the complexes to the early metal ions, Sc(+), Ti(+), and V(+), intact ligand loss competes with endothermic elimination of purine and of HCN to form MNH(+) and M(+)(C(4)H(4)N(4)), respectively, as the primary ionic products. For Sc(+), loss of ammonia is also a prominent process at low energies. Several minor channels corresponding to formation of M(+)(C(x)H(x)N(x)), x = 1-3, are also observed for these three systems at elevated energies. The energy-dependent collision-induced dissociation cross sections for M(+)(adenine), where M(+) = V(+) through Zn(+), are modeled to yield thresholds that are directly related to 0 and 298 K bond dissociation energies for M(+)-adenine after accounting for the effects of multiple ion-molecule collisions, kinetic and internal energy distributions of the reactants, and dissociation lifetimes. The measured bond energies are compared to those previously studied for simple nitrogen donor ligands, NH(3) and pyrimidine, and to results for alkali metal cations bound to adenine. Trends in these results and theoretical calculations on Cu(+)(adenine) suggest distinct differences in the binding site propensities of adenine to the alkali vs transition metal ions, a consequence of s-dsigma hybridization on the latter.

Adenine↗

PubMed1994

A model to evaluate and maximize hearing aid performance by integrating the articulation index across listening conditions.

A method for integrating the articulation index (AI) across listening conditions was developed and applied to a preliminary model for evaluating and optimizing prescriptions of hearing aid characteristics. The model takes hearing threshold, masking of noise, self-masking of speech, high level cochlear distortion, and the peak-clipping effects of a hearing aid into account. The integrated AI (IAI) across a range of listening conditions is used as a criterion for evaluating a specific hearing aid response characteristic and calculating an optimal frequency-gain characteristic that maximizes the IAI. For a high-frequency hearing loss, the frequency-gain characteristics and IAI's derived from an optimal IAI (OIAI), POGO, and NAL prescriptions are compared for two of listening situations: a quiet setting and a setting with a signal-to-noise ratio of -3 dB. The results predict that, in quiet, the OIAI prescription is not significantly different from the well-established prescriptive procedures such as the POGO and the NAL. For the noise condition, however, the optimal IAI model is predicted to be better in terms of speech intelligibility.

Acoustic Stimulation↗

PubMed1991

Simulation model for thrombin generation in plasma.

A simulation model for the production of thrombin in plasma is presented. Values of the reaction rate constants as determined in purified systems are used and the model is tested by comparison of simulations of factor Xa, factor Va and thrombin generation curves with experimental data obtained in thromboplastin-activated plasma. Simulations of the effect of hirudin indicate that factor V is predominantly activated by thrombin and not by factor Xa. The model predicts a threshold value for the factor Xa production which, if exceeded, results in explosive and complete activation of prothrombinase. The dependence of this threshold value on different negative feedback reactions, e.g. the inactivation of thrombin and factor Xa by antithrombin III (+ heparin), is investigated. The threshold value, for control plasma in the range of 1-10 pM total factor Xa production, can be raised two orders of magnitude by accelerated inactivation of factor Xa and prothrombinase but is hardly affected by a tenfold increase in the rate of thrombin inactivation or by increased production of activated protein C. This latter effect, however, results in a more gradual input-response relation between factor Xa input and the extent of prothrombinase activation.

Computer Simulation↗

PubMed2004

Antioxidant protection in a new animal model of cisplatin-induced ototoxicity.

Mortality is a major complication in animal models of cisplatin-induced hearing loss due to the systemic toxicity of the drug. Here we report on a novel two-cycle treatment in rats, each cycle consisting of four days of cisplatin injections (1 mg/kg, i.p., twice daily) separated by 10 days of rest. This regimen, similar to clinical courses of cancer chemotherapy, produced significant hearing loss without mortality. Auditory brain stem evoked responses were unchanged after the first cycle but were elevated by 40-50 dB at 16 and 20 kHz after the second. Loss of outer hair cells occurred after the second cycle, predominantly in the base of the cochlea. Total cochlear antioxidants declined progressively during drug treatment and were reduced to 60% of control values after the second cisplatin cycle. Co-administration of salicylate (100 mg/kg, s.c., twice daily) during both cycles or during the second cycle restored antioxidant levels and reduced cisplatin-induced threshold shifts. This model of cisplatin ototoxicity without mortality eliminates potentially confounding factors that may determine the survival of a special cohort of animals. The results also support the notion that reactive oxygen species are involved in cisplatin ototoxicity and show the potential usefulness of antioxidant treatment.

Animals↗

PubMed2000

Assessment of prognosis in patients with community-acquired pneumonia who require mechanical ventilation.

STUDY OBJECTIVES: Knowing that mortality is high in patients who require mechanical ventilation patients with community-acquired pneumonia (CAP), we hypothesized that the severity of acute lung injury could be used along with nonpulmonary factors to identify patients with the highest risk of death. We formulated a prediction model to quantitate the risk of hospital mortality in this population of patients. DESIGN: Historical prospective study using data collected over the first 24 h of mechanical ventilation. We utilized a hypoxemia index-(1 - lowest [PaO(2)/PAO(2)]) x (minimum fraction of inspired oxygen to maintain PaO(2) at > 60 mm Hg) x 100], where PAO(2) is the alveolar partial pressure of oxygen-to grade the severity of acute lung injury on a scale from 0 to 100. SETTING: Tertiary care university hospital ICU. PATIENTS: One hundred forty-four adult patients mechanically ventilated for respiratory failure caused by CAP. MEASUREMENTS AND RESULTS: Hospital mortality was 46% (n = 66). Multivariate logistic regression analysis revealed five independent predictors of hospital mortality: (1) the extent of lung injury assessed by the hypoxemia index; (2) the number of nonpulmonary organs that failed; (3) immunosuppression; (4) age > 80 years; and (5) medical comorbidity with a prognosis for survival < 5 years. At a 50% mortality threshold, the prediction model correctly classified outcome in 88% of cases. All patients with > 95% predicted probability of death died in hospital. CONCLUSIONS: Based on clinical parameters measured over the first 24 h of mechanical ventilation, this model accurately identified critically ill, mechanically ventilated patients with CAP for whom prolonged intensive care may not be of benefit.

APACHE↗

PubMed2006

Dimensional accuracy of a binder jet model produced from computerized tomography data for dental implants.

A full-scale model produced by multislice helical computerized tomography (CT) was made by using the binder jet method and applied for presurgical diagnosis, surgical simulation, and the production of surgical templates for dental implant treatment. In this study, accuracy of the full-scale model with plaster powder was assessed by shifting the binary threshold values. A step phantom was made from bone-equivalent material. When it was placed in water, the CT imaging was performed with a multislice helical CT unit. Three-dimensional (3-D) images were reconstructed by 3-D visualization software. Using 4 different threshold values, full-scale models were produced by a binder jet method with plaster powder. All sides of the full-scale models were directly measured, and their values were compared with that of the step phantom. The mean difference was approximately 0.1 mm in the axial plane when the setting was 0.75 for the threshold. In total, the mean difference was approximately 0.2 mm when the setting was 0.50 for the threshold. It is suggested this full-scale model could be applied for presurgical diagnosis, surgical simulation, and the production of surgical templates in dental implant treatment.

Computer-Aided Design↗

PubMed1999

Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic compounds.

A model was developed for describing the triggering of nasal pungency in humans, based on the partition of volatile organic compounds (VOCs) between the air phase and the biophase. Two partition parameters are used in the model: the water-air partition coefficient and the octanol-water partition coefficient. The model was validated using data from the literature, principally on alcohols, acetates and ketones. The model suggests that all test compounds, regardless of their chemical functional groups, bind to a common receptor site within the hydrophobic interior of the bilayer membrane of the trigeminal nerve endings. There is probably only a slight, non-specific interaction between the VOC molecule and the receptor molecule, whereas this type of non-specific interaction for the detection of odor is much stronger. In practical terms, the suggestion that all VOCs share a common irritation receptor site implies that nasal-pungency thresholds of individual VOCs may be additive. Quantitative structure-activity relationships (QSARs) for nasal-pungency thresholds were also developed from the model, which can be used to predict nasal-pungency thresholds of common VOCs. Although the present model does not offer additional precision over that of M.H. Abraham et al., 1996, Fundam. Appl. Toxicol. 31, 71-76, it requires fewer descriptors and offers a physiological basis to the QSAR. Another advantage of the present model is that it also provides a basis for comparison between the olfactory process and nasal pungency.

Air Pollutants↗

PubMedDate not supplied

[The general behavioral characteristics of rats selected for the duration of the passive defense reaction and for the threshold of neuromuscular excitability].

Two strains of rats, (GC) ("genetic catalepsy"), and (Lt), ("low-threshold") proposed as models of human psychopathological symptoms, were compared. Characteristics of "activity" and "emotionality" in the open field were practically the same in the strains studied. Disturbance of motor plasticity seemed to be for the lack of circular movements in free behaviour. Injections of apomorphine induced oppositely directed effects on the number of yawns in GC and Lt rats. Galoperidol effect was cataleptogenic in both the strains. The similarity in open field behaviour parameters and the effects of apomorphine and galoperidol appeared to be underlain by a large number of common features in nervous system organization.

Animals↗

PubMed2003

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents.

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.

Allylisopropylacetamide↗

PubMed1992

Coexistence and competition in HIV infections.

In this paper we extend our explanation of a model for the dynamics of the interaction between HIV and the cells of the immune system (Nowak et al., 1990). We show that the Simpson index of viral diversity is a Lyapunov function for a simplified version of this model. We also present a more general mathematical characterization of the nature of the diversity threshold exhibited by the model, including for the first time heterogeneity in parameters like virus replication rate, cytopathicity and antigenicity. The more general diversity threshold condition includes the different contributions of strains with higher replication rates and cytopathicities or strains that are only weakly recognized by the immune system. This leads to some new insights and a more detailed understanding of why the viral diversity falls once the diversity threshold is exceeded.

HIV↗

PubMed1991

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models.

Although seizure models using systemic administration of the chemoconvulsant pentylenetetrazol (PTZ) for induction of generalized clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of diverse technical, biological and pharmacological factors in interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate, and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following PTZ models: (1) the threshold for different types of PTZ seizures, i.e., initial myoclonic twitch, generalized clonus with loss of righting reflexes, and tonic backward extension of forelimbs (forelimb tonus), in mice; (2) the traditional PTZ seizure test with s.c. injection of the CD97 for generalized clonic seizures in mice; and (3) the s.c. PTZ seizure test in rats. In rats, in addition to evaluating drug effects on generalized clonic seizures, a ranking system was used to determine drug effects on other seizure types. When drugs were dissolved in vehicles which themselves did not exert effects on seizure susceptibility, the most important factors which influenced drug potencies were: (1) bishaped dose-response curves, i.e., a decline in anticonvulsant dose-response at high doses of some drugs, leading to misinterpretations of drug efficacy if only a single high drug dosage is tested; (2) effects of route of PTZ administration (i.v. infusion vs. s.c. injection) on estimation of anticonvulsant potency; (3) species differences in drug metabolism; (4) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on 'active' drug concentrations in plasma; (5) qualitative and quantitative species differences in drug actions; (6) endpoints used for PTZ tests; (7) misleading predictions from PTZ seizure models. Analysis of anticonvulsant drug actions indicated that myoclonic or clonic seizures induced by i.v. or s.c. PTZ might be suitable for predicting efficacy against myoclonic petit mal seizures in humans, but certainly not to predict efficacy against absence seizures. Tonic seizures induced by PTZ were blocked by drugs, such as ethosuximide, which exert no effect on tonic seizures in humans. In order to reduce the variability among estimates of anticonvulsant activity in PTZ seizure models, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.

Animals↗

PubMed2005

Functional MRI BOLD response to Tower of London performance of first-episode schizophrenia patients using cortical pattern matching.

Due to its three-dimensional folding pattern, the human neocortex poses a challenge for accurate co-registration of grouped functional brain imaging data. The present study addressed this problem by employing three-dimensional continuum-mechanical image-warping techniques to derive average anatomical representations for co-registration of functional magnetic resonance brain imaging data obtained from 10 male first-episode schizophrenia patients and 10 age-matched male healthy volunteers while they performed a version of the Tower of London task. This novel technique produced an equivalent representation of blood oxygenation level dependent (BOLD) response across hemispheres, cortical regions, and groups, respectively, when compared to intensity average co-registration, using a deformable Brodmann area atlas as anatomical reference. Somewhat closer association of Brodmann area boundaries with primary visual and auditory areas was evident using the gyral pattern average model. Statistically-thresholded BOLD cluster data confirmed predominantly bilateral prefrontal and parietal, right frontal and dorsolateral prefrontal, and left occipital activation in healthy subjects, while patients' hemispheric dominance pattern was diminished or reversed, particularly decreasing cortical BOLD response with increasing task difficulty in the right superior temporal gyrus. Reduced regional gray matter thickness correlated with reduced left-hemispheric prefrontal/frontal and bilateral parietal BOLD activation in patients. This is the first study demonstrating that reduction of regional gray matter in first-episode schizophrenia patients is associated with impaired brain function when performing the Tower of London task, and supports previous findings of impaired executive attention and working memory in schizophrenia.

Adolescent↗

PubMed2003

Effects of elevated extracellular potassium ion concentration on anodal excitation of cardiac tissue.

INTRODUCTION: Anodal excitation of cardiac tissue occurs by two mechanisms: "make" and "break." Anodal strength-interval curves are divided into two sections, with break excitation occurring at short intervals and make at long intervals. Our goal is to determine how an elevated extracellular potassium ion concentration, [K]o, affects the mechanism of anodal excitation and influences the anodal strength-interval curve. METHODS AND RESULTS: Computer simulations of unipolar stimulation were performed using the bidomain model, with membrane kinetics governed by the Luo-Rudy model. The diastolic threshold for anodal stimulation first decreased and then increased with increasing [K]o, reaching a minimum value at [K]o = 12 mM. The mechanism for diastolic anodal excitation was make for all [K]o values except 13.3 mM, in which case it was break. For low [K]o (4 and 8 mM) the break section of the anodal strength-interval contained a "dip," but for high [K]o (12 and 13 mM), the dip disappeared. CONCLUSION: High [K]o predisposes cardiac tissue to break excitation, which is thought to play an important role in reentry induction and defibrillation. Because fibrillation raises extracellular [K]o levels, break excitation may play a more important role in defibrillation than is suggested by simulations and experiments using normal [K]o values.

Computer Simulation↗

PubMed1999

Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results.

We describe a variance-components method for multipoint linkage analysis that allows joint consideration of a discrete trait and a correlated continuous biological marker (e.g., a disease precursor or associated risk factor) in pedigrees of arbitrary size and complexity. The continuous trait is assumed to be multivariate normally distributed within pedigrees, and the discrete trait is modeled by a threshold process acting on an underlying multivariate normal liability distribution. The liability is allowed to be correlated with the quantitative trait, and the liability and quantitative phenotype may each include covariate effects. Bivariate discrete-continuous observations will be common, but the method easily accommodates qualitative and quantitative phenotypes that are themselves multivariate. Formal likelihood-based tests are described for coincident linkage (i.e., linkage of the traits to distinct quantitative-trait loci [QTLs] that happen to be linked) and pleiotropy (i.e., the same QTL influences both discrete-trait status and the correlated continuous phenotype). The properties of the method are demonstrated by use of simulated data from Genetic Analysis Workshop 10. In a companion paper, the method is applied to data from the Collaborative Study on the Genetics of Alcoholism, in a bivariate linkage analysis of alcoholism diagnoses and P300 amplitude of event-related brain potentials.

Chromosome Mapping↗

PubMed2003

Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats.

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral + mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirror-image SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.

Aconitate Hydratase↗

PubMed1993

Interpreting multifocal intraocular lens modulation transfer functions.

The optical performance of new multifocal intraocular lens designs is frequently assessed using the modulation transfer function (MTF). We discuss the relationship between the MTF and clinical measures of human visual function, such as threshold visual acuity and contrast sensitivity. Using in vitro MTF measurements of a human eye model containing a multifocal or monofocal intraocular lens, we predict relative changes in acuity and contrast sensitivity and outline the techniques using a simple model of human retinal threshold detection. Specific concepts introduced include the visual acuity graph, predicted visual acuity graph, and predicted contrast sensitivity function.

Contrast Sensitivity↗

PubMed2001

A novel analgesic compound OT-7100 attenuates nociceptive responses in animal models of inflammatory and neuropathic hyperalgesia: a possible involvement of adenosinergic anti-nociception.

We studied the effects of OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo [1,5-a]pyrimidine), a novel analgesic compound, on the inhibitory action of adenosine on the contraction of guinea pig ileum and investigated the effects of OT-7100 on the nociceptive responses in animal models of inflammatory and peripheral neuropathic hyperalgesia and decreases spinal c-Fos expression. OT-7100 at 0.3 - 3 microM significantly enhanced the inhibitory effect of adenosine on the contraction of guinea pig ileum. The efficacy of OT-7100 (1, 3 or 10 mg/kg, p.o.) on hyperalgesia induced by yeast or substance P and in the Bennett model was significantly suppressed by coadministration of the adenosine A1 antagonist DPCPX (0.01 or 0.1 pmol/animal, i.t.), while OT-7100 without DPCPX significantly increased the nociceptive threshold in each rat model. OT-7100 (3, 10 and 30 mg/kg per day, p.o.) significantly inhibited the mechanical nociceptive threshold in the injured paw in the Chung model. OT-7100 (30 mg/kg, p.o.) significantly decreased the number of Fos-LI neurons in the spinal dorsal horn in the Bennett model. These finding suggest that OT-7100 inhibits hyperalgesia in these animal models possibly by enhancing adenosinergic neurotransmission in the dorsal horn, although we still lack direct evidence for it.

Adenosine↗