Nucleotide-induced mucin release from primary hamster tracheal surface epithelial cells involves the P2u purinoceptor.
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Animals↗
Biomedical subjects
K H Ko
Publications and source records attributed to K H Ko.
Mechanical allodynia is more strongly manifested in older rats in an experimental model of peripheral neuropathy.
Partial peripheral nerve injury often leads to chronic neuropathic pain characterized by symptoms such as allodynia. In the present study, employing a rat model of experimental neuropathy produced by partial denervation of the tail, we examined whether peripheral nerve injury-induced mechanical and thermal allodynia were affected by the animal's age at the time of the injury. The motive of this study was the demonstration in other neuropathy models of the age effects on the manifestation of neuropathic pain symptoms following partial peripheral nerve injury. We compared two groups of young (n = 23, 7-8 weeks old, 150-200 g) and old rats (n = 14, 16-18 months old, 550-800 g). We found that the older rats exhibited more vigorously the behavioral signs of mechanical allodynia during the first week after the nerve injury. With respect to thermal (cold or warm) allodynia, however, we detected no significant difference between young and old rat groups. The results of the present study, as those of previous studies, support the idea that the age at the time of partial peripheral nerve injury affects the severity of certain neuropathic pain symptoms appearing after the injury. However, the present results argue against the suggestion from previous studies that younger subjects are more vulnerable to partial peripheral nerve injury-induced neuropathic pain symptoms.
Aging↗
Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response.
D-20443 is an experimental antiepileptic drug. Its mechanism of antiepileptic action is unknown. We evaluated the anticonvulsant effectiveness of D-20443 against sound-induced seizures in genetically epilepsy-prone rats (GEPRs). This compound produced anticonvulsant effects against sound-induced seizures in moderate seizure GEPRs (GEPR-3s) at significantly lower doses than in severe seizure GEPRs (GEPR-9s). Based on these data and on the responses of GEPRs to other antiepileptic drugs, we predict that D-20443 will be a broad spectrum antiepileptic agent in humans. That is, we predict that D-20443 will suppress both tonic/clonic and absence seizures in humans.
Animals↗
The anticonvulsant effect of the broad spectrum anticonvulsant loreclezole may be mediated in part by serotonin in rats: a microdialysis study.
Loreclezole is an experimental anticonvulsant drug. We found previously that several established anticonvulsants increase extracellular serotonin as measured by microdialysis. We have concluded that the increase in extracellular serotonin and the anticonvulsant effect produced by these anticonvulsant drugs are related in a cause and effect manner. To determine if anticonvulsant doses of loreclezole increase extracellular serotonin, we determined anticonvulsant dose-response relationships in genetically epilepsy-prone rats (GEPRs). Then, we administered ED99 doses of loreclezole to GEPRs and determined the effect on extracellular serotonin as measured by microdialysis in the striatum. We conclude that loreclezole produces a dose-related anticonvulsant effect in GEPRs and that anticonvulsant doses of loreclezole increase extracellular serotonin in these animals.
Acoustic Stimulation↗
A behavioral model for peripheral neuropathy produced in rat's tail by inferior caudal trunk injury.
We attempted to develop an experimental animal model using rat's tail for understanding the mechanisms involving peripheral neuropathic pain. Under sodium pentobarbital anesthesia, the left inferior caudal trunk of the rat was resected between the S3 and S4 spinal nerves. Latencies of tail-flick induced by the stimulus such as warm (40 degrees C) and cold (4 degrees C) water to the tail were measured for the following 30 weeks. In addition, sensitivity of the tail to mechanical stimulation was tested with von Frey hairs on these rats. Operated rats showed abnormal sensitivity of the tail to normally innocuous mechanical and thermal (warm and cold) stimuli. We interpreted these results as signs of neuropathic pain following nerve injury. The present model offers several advantages in performing behavioral tests; (1) it is easy to apply thermal stimulation to the rat's tail using a water bottle; (2) it is easy to apply the mechanical stimulation with von Frey hairs and to localize sensitive areas in the tail; and (3) blind behavioral studies are possible due to the lack of deformity in the tail after surgery.
Animals↗
Role of serotonin in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats.
This study was designed to demonstrate a role of serotonin in the anticonvulsant effect of fluoxetine, a serotonin reuptake inhibitor, in genetically epilepsy-prone rats. When varied doses of 5-hydroxytryptophan (12.5, 25, 50 mg/kg) were administered i.p. along with a fixed dose of fluoxetine (15 mg/kg) to severe seizure genetically epilepsy-prone rats, the severity of audiogenic seizures was decreased dose-dependently, and the combination treatment also produced a marked potentiation of the anticonvulsant effect when compared with administration of either drug alone. Pretreatment of severe seizure genetically epilepsy-prone rats with p-chlorophenylalanine depleted brain serotonin and reduced the anticonvulsant effectiveness of fluoxetine. By using intracerebral microdialysis, the depletion of serotonin after p-chlorophenylalanine treatment was confirmed by measuring thalamic extracellular serotonin and 5-hydroxyindoleacetic acid concentrations during basal release and in response to a challenge dose of fluoxetine. We concluded that serotonergic transmission may be involved in the anticonvulsant effect of fluoxetine in severe seizure genetically epilepsy-prone rats.
5-Hydroxytryptophan↗
Effects of naltrexone pellet implantation on morphine tolerance and physical dependence in the rat.
1. The effect of naltrexone pellets containing either 10 or 30 mg of naltrexone base on the development of tolerance and physical dependence on morphine was assessed in male Sprague-Dawley rats. Tolerance-dependence on morphine was induced by s.c. implantation of six morphine pellets, each containing 75 mg morphine base for 7 days. 2. Naltrexone pellet implantation blocked the development of tolerance to the analgesic and hyperthermic effects of morphine. Similarly, naltrexone pellet implantation reversed morphine withdrawal-induced body weight loss. The effect of pellets containing 10 and 30 mg naltrexone did not differ. 3. The effect of naltrexone (10 mg) pellet implantation on various signs of naltrexone-precipitated withdrawal such as body weight loss, hypothermia and increases in urinary and fecal output was investigated. Naltrexone pellet implantation did not alter the naltrexone-precipitated withdrawal-induced body weight loss. Concurrent naltrexone pellet implantation blocked the naltrexone-precipitated withdrawal-induced hypothermia, increased fecal and urinary output in morphine-dependent rats. 4. These results indicate that a single pellet of 10 mg of naltrexone can effectively block morphine tolerance and physical dependence in the rat. Such a procedure may be useful in studying biochemical, endocrinological and immunological mechanisms involved in opioid addiction processes.
Analgesia↗
Noradrenergic abnormalities in the genetically epilepsy-prone rat.
The genetically epilepsy-prone rat (GEPR) has central nervous system noradrenergic deficits as compared to normal rats. It is possible that these deficits contribute to seizure predisposition because they are exhibited by seizure-naive as well as by seizure-experienced GEPRs. On the basis of pharmacological studies, it is hypothesized that there is an inverse relation between seizure predisposition and levels of noradrenergic activity in brain. Neurochemical studies indicate that deficits exist in areas innervated by both the locus ceruleus and the lateral tegmental noradrenergic systems. These deficits exist in GEPRs without seizure experience and are more pronounced in the severe seizure strain as compared to the moderate seizure strain. We review eight experimental steps undertaken to identify more precisely the anatomical location of noradrenergic determinants of seizure predisposition. These steps illustrate the theoretical bases for the studies and describe the specific experiments completed. Evidence supports the hypothesis that noradrenergic deficits in the superior colliculus and/or ventrally adjacent regions are determinants of seizure predisposition.
Animals↗
Effect of ouabain on relaxation induced by cromakalim in human and canine mesenteric arteries.
We investigated the effect of cromakalim, a K+ channel opener, that activates indirectly the Na(+)-K+ pump, in association with increased K+ conductance in the mesenteric arteries. In 65% of human mesenteric arteries tested, the concentration-dependent relaxation curves for cromakalim were biphasic: the low concentration (< 10(-7) M) effect was preferentially inhibited by ouabain, whereas the higher concentration effect was significantly inhibited by glibenclamide. In branches of canine mesenteric artery, the cromakalim-induced relaxation was inhibited by pretreatment with ouabain (1 microM) as well as by glibenclamide (1 microM). The reduction in contraction of human and canine mesenteric arterial strips caused by cromakalim was totally reversed by pretreatment with ouabain (1 microM) or glibenclamide (1 microM). On the other hand, in canine mesenteric artery, cromakalim caused a significant stimulation of 22Na+ influx and ouabain-sensitive 86Rb+ uptake in association with increased 86Rb+ efflux, all of which were inhibited by glibenclamide (1 microM). Thus, it is suggested that cromakalim possesses the additional property to stimulate the Na(+)-K+ pump through an elevation in intracellular Na+, resulting in strong relaxation of blood vessels.
Adult↗
Selective effect of chronic lead ingestion. II: Effect on phenylethanolamine N-methyltransferase activity in brain regions of rats.
Selectivity of lead effect to phenylethanolamine N-methyltransferase (PNMT) activity in regions of brain from rats postnatally exposed to lead was tested. Three groups of animals were prepared; (1) Rats exposed to lead at a low dose (0.05% PbAcetate: PbAc); (2) Rats exposed to lead at a high dose (0.2% PbAc); (3) Age-matched normal control rats. At 2, 4, 6 and 8 weeks of age weight of whole brain and body in each group were measured. At the same ages activities of PNMT and Na+/K(+)-ATPase were examined on 4 brain regions of each animal. Exposure of rats to lead generally decreased activity of Na+/K(+)-ATPase and showed alternative change of those of PNMT. Brain regions where changes of PNMT activity were detected without concomitant changes of Na+/K(+)-ATPase activity, were telencephalon and pons/medulla at 2 weeks of age and telencephalon at 4 weeks of age in rats exposed to lead at a low dose, and those in rats exposed to lead at a high dose were pons/medulla at 8 weeks of age. These data imply that adrenergic nervous system in the brain regions described above could selectively be affected by lead.
Age Factors↗
Selective effect of chronic lead ingestion. III: Effect on dopamine beta-hydroxylase activity in brain regions of rats.
Selectivity of lead effect on dopamine beta-hydroxylase activity in regions of brai nfrom rats postnatally exposed to lead was tested. Three groups of animals were prepared; (1) Rats exposed to lead at a low dose (0.05% PbAcetate: PbAc); (2) Rats exposed to lead at a high dose (0.2% PbAc); (3) Age-matched normal control rats. At 2, 4, 6 and 8 weeks of age weight of whole brain and body in each group were measured. At the same ages activities of dopamine beta-hydroxylase and Na+K(+)-ATPase were measured in 5 brain regions of each animal. Exposure of rats to lead generally decreased Na+/K(+)-ATPase activity and showed alternative changes of dopamine beta-hydroxylase activity were detected without concomitant changes of Na+/K(+)-ATPase activity were telencephalon and pons/medulla at 2 weeks of age and telencephalon, diencephalon and pons/medulla at 4 weeks of age and midbrain and pons/medulla at 6 weeks of age and cerebellum at 8 weeks of age in rats exposed to lead at a low dose, and those in rats exposed to lead at a high dose were midbrain at 6 weeks of age and cerebellum at 8 weeks of age. These data imply that noradrenergic nervous system in the brain regions described above could selectively be affected by lead.
Age Factors↗
Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats.
Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.
Animals↗
Selective effect of chronic lead ingestion on tyrosine hydroxylase activity in brain regions of rats.
Alterations of tyrosine hydroxylase activity in various regions of brain from rats postnatally exposed to lead were tested. Three groups of animals were prepared; (1) Rats exposed to lead at a low dose (0.05% lead acetate, PbAc); (2) Rats exposed to lead at a high dose (0.2% PbAc); (3) Age-matched normal control rats. At 2, 4, 6, and 8 weeks of age, weight of brain and body, and concentrations of lead in whole brain of animals in each group were measured. Activities of tyrosine hydroxylase and Na(+)-K+ ATPase were also measured at the same ages in 4 brain regions of each animal. Body weight gain was decreased after 6 weeks of age in rats exposed to lead at a high dose. Concentrations of lead in whole brain were increased from 0.37 to 0.83 (ng/mg wet tissue) in these animals. Exposure of rats to lead generally increased tyrosine hydroxylase activity and decreased Na(+)-K+ ATPase activity. However, changes of tyrosine hydroxylase activity were detected without concomitant changes of Na(+)-K+ ATPase activity in pons-medulla at 2 weeks of age and telencephalon at 6 weeks of age in rats exposed to lead at a low dose, and in midbrain at 4 and 6 weeks of age in rats exposed to lead at a high dose. These data imply that catecholaminergic nervous system in the brain regions described above could be selectively affected by lead.
Animals↗
A tube latex test based on colour separation for the detection of IgM antibodies to either one of two different microorganisms.
A simple two stage assay was developed for the detection of IgM antibodies to either one of two microorganisms chosen arbitrarily for this study. Salmonella enteritidis and Trichinella spiralis. In the first stage, magnetic polystyrene beads (Dynabeads) coated with anti-mu (mouse) antibodies were incubated with the test material for 45 min to capture the IgM antibodies. In the second stage, indicator latex particles were incubated with the Dynabeads for 30 min and the results read following settlement of the Dynabeads under the influence of a magnet. Two types of indicator particles were used: blue-coloured (sensitized with Trichinella antigen) and red-coloured (sensitized with Salmonella antigen). These were mixed in suitable proportions to form a purple suspension. Reaction of either type of latex particles due to binding to the adsorbed IgM antibodies resulted in the settlement of that particle and hence a change of colour in the suspension to either red (if Trichinella-specific antibodies alone were present) or blue (if Salmonella-specific antibodies alone were present). When applied to the sera (used at 1/10 dilution) of both normal and immunized mice, the assay was positive for all but one (18) immune sera, and negative for all but one (9) normal sera.
Animals↗
A two-particle turbidometric latex immunoassay for the detection of specific IgM antibodies.
A simple two stage assay using latex particles as a reaction indicator has been developed for the detection of IgM antibodies to Trichinella spiralis. In the first stage, magnetic polystyrene beads (Dynabeads) coated with T. spiralis antigen were incubated for 30 min with the test serum. After washing, in the second stage, the assay was developed for 1 h using anti-mu-coated latex particles. After sedimentation of the Dynabeads the turbidity of the resultant latex suspension was measured spectrophotometrically at a wavelength of 400 nm. A decrease in turbidity of more than 20% from that of the control, unreacted, suspension was considered positive. Using an IgM phosphorylcholine-binding monoclonal antibody which was reactive with T. spiralis, the sensitivity of the assay was determined to be 110 ng/ml of antibody. This was 20-fold less than the sensitivity achieved in an indirect enzyme-linked immunosorbent assay (ELISA). When the assay was applied to sera obtained from CBA/N or BALB/c mice, which were either normal or immunized against T. spiralis, the expected results were obtained with titers up to 1/640 observed, and confirmed (r = 0.93, P less than 0.001) in the ELISA.
Animals↗
Evaluation of monoaminergic receptors in the genetically epilepsy prone rat.
The intensity of sound-induced convulsions in the genetically epilepsy-prone rat (GEPR) was reduced in a dose related fashion by intracerebroventricular administration of dobutamine, (beta 1 agonist), terbutaline (beta 2 agonist) or phenylephrine (alpha 1 agonist). BHT-920 (alpha 2 agonist) did not cause a dose-related decrease in sound-induced convulsion intensity. Binding studies showed that whole brain alpha and beta receptor densities (Bmax) were normal while the Kd was increased for the beta ligand in GEPR brain.
Acoustic Stimulation↗
Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat.
Norepinephrine turnover rates were estimated in the hypothalamus-thalamus, midbrain, pons-medulla and telencephalon of genetically epilepsy-prone rats (GEPR). In each of these 4 brain areas the endogenous norepinephrine levels were significantly lower in the GEPR than in control animals. In the hypothalamus-thalamus, midbrain and telencephalon the calculated norepinephrine turnover rates were also significantly lower in GEPRs than in control. These studies confirm and extend earlier observations relating seizures in the GEPR to decrements in central nervous system noradrenergic function.
Animals↗
Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy-prone rat.
Norepinephrine, dopamine, and 5-hydroxytryptamine concentrations were determined in the central nervous systems of genetically epilepsy-prone rats (GEPR) and in control rats. Norepinephrine concentrations were abnormal in all major areas of the central nervous system of the GEPR, with decrements existing in the telencephalon, hypothalamus-thalamus, midbrain, pons-medulla and spinal cord. An increment in the concentration of this neurotransmitter existed in the cerebellum. Dopamine concentrations were normal in all areas of the GEPR brain. Abnormalities in 5-hydroxytryptamine concentrations were also present in the GEPR. They were exclusively decrements and occurred in the telencephalon, hypothalamus-thalamus, midbrain, and pons medulla. Concentrations of this neurotransmitter were normal in the cerebellum and spinal cord. Coupled with our earlier pharmacologic data, these observations support our concept that noradrenergic and/or 5-hydroxytryptaminergic decrements are etiologically important in seizure susceptibility in the GEPR. The lack of abnormalities in brain dopamine concentrations strengthens our hypothesis that dopaminergic transmission does not regulate seizure susceptibility in this model.
Animals↗