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Biomedical subjects

K Hole

Publications and source records attributed to K Hole.

At least 37 records · Page 2Linked to original sources
PubMed1996

Differential expression of psoriasin messenger RNA between in situ and invasive human breast carcinoma.

The mRNA encoding the calcium-binding protein psoriasin was identified as being more highly expressed in the in situ versus the invasive component of the same breast tumor. Reverse transcription-PCR analysis of total RNA extracted from three independent cases of ductal carcinoma in situ of the comedo type and three cases of high-grade invasive ductal carcinoma revealed a detectable level of psoriasin mRNA expression in the in situ lesions only. Similar analysis performed on total RNA extracted from frozen sections of 32 independent breast samples, representing a continuum from normal to invasive tumor, confirmed high psoriasin expression in ductal carcinoma in situ of the comedo type only. The possible functional role of the psoriasin protein in breast tumor cells remains to be determined.

Breast Neoplasms↗
PubMed1996

Lumbar catheterization of the spinal subarachnoid space in the rat.

The method commonly used for catheterization of the lumbar subarachnoid space in the rat implies inserting the catheter through the atlanto-occipital (A-O) membrane and moving the catheter caudally along the spinal cord. The method is associated with a considerable morbidity. A method for direct catheterization of the lumbar subarachnoid space was therefore developed. Major surgery was avoided by using a catheter-through-needle technique. Of 32 rats, none died. There were no signs of neurological disturbances, and all animals gained weight as normal the first week after implantation. Data from rats catheterized by the A-O method were used for comparison. Of 40 animals, 2 died, 11 showed signs of neurological disturbances, and the mean weight was reduced during the first week after catheterization. The two groups of animals showed different behavioural responses to intrathecal injection of N-methyl-D-aspartate (NMDA, 0.1-1.6 mM, 15 microliters) which is thought to stimulate afferent pathways mediating nociception. Animals with a lumbar catheter showed licking, biting and scratching behaviour in a dose-related manner for concentrations up to 1.6 mM. The animals with A-O catheters showed a maximum level of this behaviour already at 0.4 mM, while 0.5 mM induced convulsions. A possible explanation of this difference in response to NMDA could be a long-lasting pain state in the A-O group, caused by catheter-induced changes in the spinal cord and by the extensive surgery. It is concluded that the direct lumbar catheterization has several advantages compared to the A-O method, decreasing the suffering of the animals, the neurological disturbances and the interference with nociceptive functions of the spinal cord.

Animals↗
PubMed1996

The medullary dorsal reticular nucleus facilitates acute nociception in the rat.

The influence on pain processing caused by destruction or stimulation of the dorsal reticular nucleus (DRt) was studied using the tail-flick and the increasing temperature hot-plate tests. Lesions of the DRt were obtained by injecting quinolinic acid (180 nmol/microliters) unilaterally or bilaterally, and nociceptive responses were evaluated by both tests. Following unilateral lesions, the tail-flick latencies and the hot-plate response temperatures were increased, values differing statistically from controls in the latter test. Bilateral lesions resulted in statistically significant increases of both tail-flick latency and hot-plate response temperature. Stimulation of the DRt was performed by injecting glutamate (100 nmol/microliters) unilaterally, which was followed 1 min later by a significant decrease in the tail-flick latency compared to saline injected controls. These results suggest that the DRt is involved in the facilitation of nociception after acute thermal noxious stimulation. This effect may be mediated through a spino-DRt-spinal loop causing a rebound of excitation in lamina I cells receiving noxious input from their own receptive field.

Animals↗
PubMed1994

The relationship between motor effects in rats following acute and chronic haloperidol treatment.

Tardive dyskinesia (TD) is a serious and sometimes irreversible side-effect to long-term neuroleptic treatment. In order to find predictors for development of TD, it would be of interest to known whether susceptibility to develop acute side-effects increases the risk of TD development. The study investigated in female Sprague-Dawley rats the relationship between haloperidol-induced acute motor effects, assessed by means of the grid test and the open field test, and the chronic motor effect assessed as vacuous chewing movements (VCM). The doses of haloperidol were 1.2, 2.4 and 4.8 mg/kg IP in the acute experiments and haloperidol decanoate 38 mg/kg per 4 weeks IM in the chronic experiment. The VCM obtained at different timepoints during the 24 weeks of chronic treatment were highly correlated. However, no correlation was found between the motor effects in the acute and the chronic experiments. The study does not indicate any connection between susceptibility to acute side-effects on neuroleptics and later development of TD.

Acute Disease↗
PubMed1993

Different functions of spinal 5-HT1A and 5-HT2 receptor subtypes in modulating behaviour induced by excitatory amino acid receptor agonists in mice.

The modulating effects of 5-HT1A and 5-HT2 receptor agonists on behaviour spinal excitatory amino acid (EAA) agonists were examined. Intrathecal (i.th.) administration of both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) produce a behavioural syndrome of caudally directed biting and scratching. Serotonin (5-HT) agonists were coadministered with either NMDA or AMPA, and changes in EAA-induced behaviour were scored. All drugs were administered i.th. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) (15-60 nmol) reduced both NMDA (0.25 nmol) and AMPA (0.06 nmol) induced behaviour in a dose-dependent manner, and preadministration of the 5-HT1A receptor antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide (NAN-190) (20 nmol) reversed this effect. The administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.7-28 nmol) produced a dose-dependent behavioural syndrome similar to the EAA agonists. This was reversed by preadministration of ritanserin (10 nmol), a 5-HT2 antagonist. When DOI was coadministered with NMDA (0.25 nmol) or MAPA (0.06 nmol) there was an increase in the behaviour recorded and this effect was antagonised by ritanserin. The results of this study implicate that in the spinal cord subtypes of 5-HT receptors have different effects on modulation of behaviour induced by activation of the NMDA or the AMPA receptors; the activated 5-HT1A receptors have an inhibitory effect whereas activation of the 5-HT2 receptors enhance the induced behaviour.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

[Pain regulation and plasticity].

The pathophysiology of chronic pain is not well understood. To try to explain why pain may become long-lasting or chronic, it is necessary to understand the plasticity of the neuronal circuits involved in nociception. It seems that mechanisms of learning and memory are involved in this process. Interactions between peptide and nonpeptide neurotransmitters may be important. Other significant factors appear to be changes in gene induction and transcription, and cell injury and destruction as a result of excitation. Through these mechanisms, painful states may induce changes in the nervous system which lead to greater pain, making adequate prevention and treatment of nociceptive pain essential.

Acute Disease↗
PubMed1993

Solid-state stereochemistry and activity of 3-methylnefopam diastereomers: manipulation of eight-membered ring conformations in analogues of the non-narcotic analgesic drug.

The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1993

Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice.

The mechanisms of the antinociceptive effect of desipramine (DMI) are only partly known. It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N-methyl-D-aspartic acid (NMDA) receptor complex. In this study, the modulatory effect of DMI on the biting and scratching behaviour induced by intrathecal (i.th.) administration of NMDA (0.25 nmol) was investigated. Desipramine was administered acutely, either intrathecally (0.7-35 micrograms) or intraperitoneally (i.p., 10 mg/kg), or chronically in the drinking water (0.15 g/l) for 3 weeks. The NMDA-induced behaviour was significantly reduced both after acute and chronic administration of DMI. Several studies have shown a functional upregulation of the 5-HT1A receptor after chronic treatment with DMI. The activation of this receptor using the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), leads to a reduction in NMDA-induced behaviour. Using the 5-HT1A antagonist NAN-190 (10 micrograms, i.th.), the effect of chronic administration of DMI on the NMDA-induced behaviour was reversed. However, NAN-190 also increased NMDA-induced behaviour in the control group, suggesting that a tonic inhibition of this behaviour, mediated by the 5-HT1A receptor, may exist. These findings indicate that DMI may reduce glutaminergic transmission at the spinal NMDA receptor. As this receptor is central in spinal nociceptive transmission, this could be one mechanism for the antinociceptive effect of DMI.

Animals↗
PubMed1993

Antinociceptive effects of intrathecal administration of alpha-adrenoceptor antagonists and clonidine in the formalin test in the mouse.

The hypothesis that the descending noradrenergic system tonically inhibits nociception at the spinal level was investigated, using the formalin test in mice. The alpha-adrenoceptor agonist clonidine (0.46 and 0.92 microgram), injected intrathecally, significantly reduced licking activity in both the early and late phase of the test. The alpha 1-antagonist prazosin (3.75, 7.5 and 15 micrograms) and the alpha 2-antagonist yohimbine (7.5 micrograms) also significantly reduced licking activity in both phases. The smaller doses of yohimbine (1.87 and 3.75 micrograms) induced an insignificant reduction of licking in the early phase. Except for the largest doses of clonidine (0.92 microgram), the drugs used had no effect on the general level of activity and motor performance. These results support previous findings that increased noradrenergic activity in the spinal cord inhibits nociception, however, this inhibition seems not to be tonically active. The mechanisms of the antinociceptive actions of alpha-antagonists are not clear.

Adrenergic alpha-Antagonists↗
PubMed1993

The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity.

This review shows that the role of 5-hydroxytryptamine (5-HT) in the regulation of nociception depends on the 5-HT receptor subtypes involved and on long-term functional changes in the 5-HT receptors. Stimulation of the 5-HT1 receptors, as well as of the 5-HT2 and 5-HT3 receptors, may reduce nociceptive sensitivity. In addition, activation of 5-HT2 and 5-HT3 receptors may also enhance nociceptive sensitivity. Up- or down-regulation of the 5-HT receptors may result in long-lasting changes, plasticity, in the 5-HT systems. Lesioning of 5-HT neurons induces denervation supersensitivity to 5-HT, and prolonged stimulation of 5-HT receptors may produce subsensitivity to 5-HT. In the spinal cord denervation supersensitivity to 5-HT may depend on reduced release of substance P (SP). An increase in the release of SP, on the other hand, may reduce the effects of 5-HT receptor activation. Long-term treatment with antidepressants which are used in clinical pain therapy appears to up-regulate the 5-HT1 receptors and to down-regulate the 5-HT2 receptors.

Animals↗
PubMed1992

Desipramine, administered chronically, influences 5-hydroxytryptamine1A-receptors, as measured by behavioral tests and receptor binding in rats.

The 5-hydroxytryptamine1A (5-HT1A) receptor subtype seems to be of importance in the pathogenesis of depression and in the mode of action of antidepressants. In this study, behavioural experiments were performed in rats after oral administration of desipramine for 18-20 days, followed by an acute injection of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), either systemically or intrathecally. Chronic administration of desipramine prolonged the behavioural 5-HT syndrome in the animals injected systemically with 8-OH-DPAT. Treatment with desipramine was also found to potentiate and prolong the antinociceptive effect of an acute injection, systemically or intrathecally, of 8-OH-DPAT in the increasing temperature hot plate test. After systemic administration of 8-OH-DPAT, the colonic temperature was lowered similarly in the desipramine-treated group and in controls, whereas an intrathecal injection of 8-OH-DPAT resulted in a fall in the colonic temperature in the desipramine-treated group only. In vitro receptor binding studies, using [3H]8-OH-DPAT as the ligand, showed a statistically significant reduction of Kd and Bmax in the frontal cortex and of Kd in the spinal cord, after treatment with desipramine. No changes of Kd and Bmax were found in the hippocampus after this treatment. Thus, desipramine, administered chronically, resulted in a functional up-regulation of the 5-HT1A-receptors, both spinally and supraspinally, whereas in the in vitro receptor binding, a slight down-regulation or no change was found. It seems therefore that the results of in vitro receptor binding studies do not necessarily reflect the functional state of the neuronal system.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

The effect of morphine on core and skin temperature in rats.

The temperature of the tail skin is an important factor determining tail-flick latency to noxious radiant heat in rats and mice. The temperature of the skin may also be important in determining the behavioural response in the formalin test. Morphine in low and moderate doses strongly affected the core and tail skin temperatures, preventing the increase in tail skin temperature normally observed during testing. For the correct interpretation of the results of several tests of nociception, it is important to know how treatment influences the temperature of the skin, to be able to correct for this confounding factor.

Analysis of Variance↗
PubMed1992

Acute and long term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in tests of nociception in mice.

Acute and long term changes in nociception after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 80 mg/kg (four injections of 20 mg/kg given at two hr intervals) were investigated in mice. MPTP caused shivering, lacrimation, salivation, teeth chattering and fur erection a few minutes after drug injection, but all these behavioural changes were normalized within 30 min., when the first behavioural testing was performed. No significant alteration in general behaviour, sensorimotor performance or body temperature could be detected at the time of nociceptive testing. The acute effects of MPTP on nociception were a reduced response latency in the tail flick test and a prolonged response latency compared to controls in the constant temperature hot plate test. No significant effects of MPTP were found in the increasing temperature hot plate test. The long term effects were a reduced response latency both in the tail flick test and the constant temperature hot plate test, indicating that the MPTP induced lesions of dopaminergic pathways result in hyperalgesia. In the increasing temperature hot plate test and the formalin test, no significant long term changes were demonstrated. Seven days after injection, the dopamine content was reduced to 62% of control values in striatum, to 51% in the rest of the forebrain, and to 41% in the spinal cord. Noradrenaline levels were only slightly and transiently reduced. Serotonin levels were not affected 7 days after injection, but 14 days after injection, a great increase was found in the forebrain and in the spinal cord. The results suggest that dopaminergic systems tonically inhibit nociception.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Interactions between substance P and norepinephrine in the regulation of nociception in mouse spinal cord.

This study examined interactions between effects of the undecapeptide substance P and norepinephrine and the alpha-adrenoceptor agonist clonidine in the mouse spinal cord. All compounds were injected into the lumbar subarachnoid space, and effects on the tail-flick reflex and the behavioural response to intrathecal substance P were evaluated. The tail-flick response latencies were markedly increased 5-20 min. after intrathecal application of norepinephrine (0.0125-0.1 microgram) or clonidine (0.0125-0.1 microgram). The actions of both intrathecal norepinephrine (0.025 microgram) and intrathecal clonidine (0.025 microgram) were significantly attenuated when substance P (5 micrograms) was given intrathecally 55 and 45 min. before the agonists. There was a significant relationship between the tail-flick response latencies and the tail skin temperature. However, the tail-flick results were not due to changes in the skin temperature. Intrathecally applied substance P (10 ng) produced a response consisting of biting of the caudal part of the body and a few hindlimb scratches. The number of bites was significantly reduced 5 min. after injection of norepinephrine (0.1 micrograms) or clonidine (0.05-0.1 microgram), but the number of scratches was unchanged. The data show that increased stimulation of spinal alpha-adrenoceptors inhibits a spinal nociceptive reflex as well as the action of substance P in the spinal cord. Substance P modulates the action of alpha-adrenoceptor agonists on the tail-flick reflex, which may tentatively be explained by downregulation of alpha-adrenoceptors by substance P.

Adrenergic alpha-Agonists↗
PubMed1992

Supersensitivity to the antinociceptive effect of a 5-HT1 receptor agonist after lesion of raphe-spinal serotonergic neurones.

The actions of the 5-hydroxytryptamine type-1B (5-HT1) receptor agonist 1(m-chlorophenyl)piperazine (mCPP) on response latencies in the tail-flick test and tail skin temperature were examined in mice after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT). All the compounds were given intrathecally. The level of 5-HT in spinal cord was reduced by 79% 4 days after intrathecal injection of 5,6-DHT (10 micrograms). There was a significant relationship between the tail-flick latency and tail skin temperature, and the reduced baseline tail-flick latencies induced by 5,6-DHT were non-significant after the change in skin temperature was taken into account. Intrathecal mCPP (5 micrograms) significantly increased the tail-flick latency and significantly reduced the tail skin temperature in 5,6-DHT pretreated animals when compared to control animals. These differences in tail-flick latencies could not be explained by alterations in skin temperature. The results provide evidence that neurotoxic lesion of descending 5-HT pathways induces supersensitivity to the antinociceptive effect of 5-HT1 receptor stimulation.

5,6-Dihydroxytryptamine↗
PubMed1991

Potentiation of a behavioural response in mice by spinal coadministration of substance P and excitatory amino acid agonists.

The functional interaction in the spinal cord between substance P and excitatory amino acid agonists was investigated. Behavioural responses were scored in mice after intrathecal administration of excitatory amino acid agonists and substance P, given separately or in combination. A strong potentiation of the effect was seen when substance P was coadministered with N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) or kainic acid (KA). The potentiation was blocked by the corresponding antagonists: the selective NMDA-receptor antagonist (+/-)-3- (2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the substance P analog, [D-Arg1,D-Trp7,9,Leu11]-substance P (Spantide). These findings indicate a functional interaction between substance P and glutamate in the dorsal horn of the spinal cord, compatible with the hypothesis that corelease of substance P and glutamate from primary afferent neurons may enhance nociception.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1991

Interactions between serotonin and substance P in the spinal regulation of nociception.

Interactions between 5-hydroxytryptamine (5-HT) and substance P (SP) in the mouse spinal cord were investigated using the tail-flick test and the behavioral response evoked by intrathecal (i.th.) SP or i.th. 5-HT. I.th. injection of 5-HT (20 micrograms) or the 5-HT1 receptor agonists (+)-8-hydroxy-2-(di-n-propylamino)tetralin ((+)-8-OH-DPAT) (20 micrograms) or 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969) (20 micrograms) markedly inhibited the tail-flick reflex. The effect of these compounds was reduced when SP (5 micrograms) was given i.th. 55 min, or 55 and 45 min before the agonists. The tail-flick latencies recorded 5 min before injection of a 5-HT receptor agonist were similar in animals treated with SP or vehicle. The changes in the tail-flick test were not due to changes in tail skin temperature since only minimal differences in the skin temperature were recorded between the groups injected with SP or vehicle. I.th. injection of SP (10 ng) or 5-HT (2 micrograms) produced a similar behavioral response consisting of biting, licking and scratching of the caudal part of the body, indicative of nociceptive stimulation. The responses both to i.th. SP and 5-HT were reduced after i.th. application of the SP receptor antagonist [D-Arg1,D-Trp7.9,Leu11]-SP (Spantide) (5 micrograms), as well as 5 min after i.th. injection of the 5-HT receptor antagonist metergoline (4 micrograms). The data may indicate functional interactions between SP and 5-HT in the mouse spinal cord, which may take place in neurons involved in the processing of nociception.

8-Hydroxy-2-(di-n-propylamino)tetralin↗