Biomedical subjects

K Hole

Publications and source records attributed to K Hole.

At least 91 records · Page 5Linked to original sources

PubMed1986

Learned and pharmacologically-induced tolerance to ethanol and cross-tolerance to morphine and clonidine.

The development of tolerance to the inhibitory effect of ethanol on the tail-flick reflex was studied in the spinal rat. This preparation was used in order to avoid uncontrolled learning effects. Tolerance due to intoxicated practice (learned tolerance) and tolerance due to mere ethanol exposure (pharmacologically-induced tolerance) were studied in separate experiments. It was found that that learned tolerance to ethanol also caused tolerance to morphine and clonidine, whereas pharmacologically-induced tolerance did not have the same effect. The results challenge the concept of "behaviorally augmented tolerance" and suggest that learned and pharmacologically-induced tolerance involve different basal mechanisms in the CNS.

Animals↗

PubMed1986

Lesions of the ascending serotonergic pathways and antinociceptive effects after systemic administration of p-chloroamphetamine in mice.

The present study reports a method for lesioning of the ascending serotonergic system. The neurotoxic substance p-chloroamphetamine (PCA) was given IP on 2 consecutive days (40 mg/kg/day). After each injection, the animals were kept at 4 degrees C for 4 hr since a lower dose of PCA (25 mg/kg) induced severe hyperthermia. The mortality rate was 12%, considerably lower than previously reported in similar studies. Evaluated 9 days after the last injection of PCA, the uptake of 14C-5-HT into cortical and hippocampal crude synaptosomal preparations was reduced by 50 and 60%, respectively, while the uptake into spinal synaptosomes was unaffected. The uptake of 3H-NA was not significantly altered in any of the structures. Measurements of PCA performed 30 min to 4 hr after IP injections of 5 to 40 mg/kg demonstrated higher concentrations in the cortex than in the lumbar spinal cord. Administration of PCA (5 mg/kg) had an acute antinociceptive effect in the hot-plate and formalin tests, but not in the tail-flick test. Prior treatment with neurotoxic doses of PCA prevented the antinociception but had in itself no effect on the responsiveness in any of the tests. Thus systemic administration of PCA produces highly selective and functional lesions of the ascending serotonergic pathways in mice.

Amphetamines↗

PubMed1986

A modified hot-plate test sensitive to mild analgesics.

The present study compares a modified hot-plate test in which the temperature is slowly increased from non-noxious levels with a standard constant temperature hot-plate test. In both tests, hindpaw lick was found to be a more reliable criterion response than forepaw lick, and was employed throughout the experiments. In the constant temperature hot-plate test, 1-min exposure to the test apparatus the day before testing significantly reduced the response latencies of both rats and mice. No effect of pre-exposure was found in the increasing temperature test. In both tests and in both species, sessions of repeated testing were conducted with only insignificant alterations in responsiveness between trials. In both rats and mice, dose-related increases in response temperature were obtained in the increasing temperature hot-plate test after administration of morphine, paracetamol and acetylsalicylic acid, whereas only morphine had consistent effects in the constant temperature test. Thus, the increasing temperature hot-plate is a useful analgesimetric test in both rats and mice, superior to the conventional hot-plate test with regard to consistency of results and sensitivity to non-narcotic analgesics.

Adaptation, Physiological↗

PubMed1986

Orphenadrine citrate increases and prolongs the antinociceptive effects of paracetamol in mice.

Orphenadrine, a muscle relaxant with antinociceptive effects, was shown to increase and prolong the antinociceptive effects of paracetamol in mice. Both in the increasing temperature hot plate test and in the formalin test, a combination of the two drugs showed a significantly improved effect compared to either of the drugs alone. The time course of the effects was tested in the increasing temperature hot plate test. The group treated with the drug combination showed a prolonged effect compared to both single drug treated groups, the effect lasting longer than 120 min. for the combination and about 80 min. for the single drugs. Orphenadrine and paracetamol increased antinociception even when orphenadrine was injected 90 min. after paracetamol, which by that time did not exert antinociceptive effects by itself. Thus the combination of orphenadrine and paracetamol enhances the antinociceptive effect of either drug in mice.

Acetaminophen↗

PubMed1985

Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin.

Intrathecally administered substance P (SP) or capsaicin in mice elicited a pain-related behavioral response consisting of vigorous biting, licking and scratching of the caudal part of the body. Pretreatment of the animals with intraperitoneally injected acetylsalicylic acid (300 and 400 mg/kg), paracetamol (300 and 400 mg/kg) and morphine (2.5 and 5 mg/kg) reduced the responses in a dose-dependent manner. The analgesia is probably mediated by inhibition of a postsynaptic SP sensitive mechanism. Thus these results demonstrate central antinociceptive effects of acetylsalicylic acid and paracetamol.

Acetaminophen↗

PubMed1985

Antinociceptive effects of orphenadrine citrate in mice.

The antinociceptive effect of orphenadrine citrate, a muscle relaxant, was investigated in mice. Four different pain tests were selected to involve different noxious stimuli. Clear antinociceptive effects were found in the formalin test. The increasing temperature hot-plate test showed a biphasic dose-response relationship with slight hyperalgesia after low doses and hypoalgesia after higher doses. No significant effects of orphenadrine (0-25 mg/kg) were found in the tail flick and constant temperature hot-plate tests. The data suggest that orphenadrine may reduce, enhance or leave unaffected different types of nociceptive transmission. Orphenadrine may also possess analgesic properties in conditions not involving muscle spasm.

Analgesics↗

PubMed1985

The putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin antagonizes the antinociceptive effect of morphine.

The effect of the selective 5-hydroxytryptamine (5-HT-1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on nociception and morphine analgesia was tested with the tail-flick method in mice. 8-OH-DPAT (0.06-1.0 mg/kg) had no apparent effect on the general behavior of the animals and did not change their reactivity to stimulation with noxious radiant heat. The compound did, however, dose-dependently attenuate the antinociception induced by administration of morphine hydrochloride (5.0 and 10.0 mg/kg). Thus, stimulation of a subpopulation of serotonin receptors may counteract the antinociceptive effect of morphine in the tail-flick test.

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

PubMed1985

Changes in nociception after lesions of descending serotonergic pathways induced with 5,6-dihydroxytryptamine. Different effects in the formalin and tail-flick tests.

Intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) in mice selectively lesioned descending serotonergic pathways. Nociception was evaluated 3 days after injection of 5,6-DHT using the tail-flick and formalin tests. In the tail-flick test shortened latencies were found in the lesioned animals. In contrast, the initial behavioural response (0-15 min) to formalin was reduced, while the late response (15-40 min) was not altered. Fourteen days after intrathecal administration of 5,6-DHT the changes in nociception, both in the tail-flick and in the formalin test, had returned to the control level. These findings support the contention that the raphe-spinal serotonergic system participates in the tonic regulation of nociception in the spinal cord. Apparently this system tonically inhibits spinal nociceptive reflexes, but tonically enhances the initial behavioural responses to noxious chemical stimulation, as measured with the formalin test.

5,6-Dihydroxytryptamine↗

PubMed1985

Learned tolerance to ethanol in a spinal reflex separated from supraspinal control.

We have recently reported that ethanol-induced inhibition of the tail flick reflex in intact and spinal rats is diminished during an eight day period if the animals are tested daily under the influence of ethanol. Ethanol only, or testing before ethanol administration, is not followed by tolerance. In the present study we used the tail flick testing of spinal rats to investigate the effect on tolerance development of repetitively triggering the tail flick reflex during intoxication, and of just placing the intoxicated animals in the test apparatus. We also investigated if damage to the tail tissue, due to repetitive prolonged test exposure, would facilitate the reflex and thereby reduce the inhibitory effect of ethanol. The results indicated that triggering of the reflex in the presence of ethanol was necessary for the tolerance to develop. Facilitation of the tail flick reflex, due to damage of the tail tissue, was not revealed. Thus the tolerance observed seems to be caused by an adaption to ethanol learned by structures involved in the tail flick reflex.

Animals↗

PubMed1985

Formalin test in mice, a useful technique for evaluating mild analgesics.

A modification of the formalin test appropriate for testing of mice is described. Formalin 1 or 5% was injected into the dorsal surface of a hindpaw, and the time the animal spent licking the paw was recorded. On the basis of the response pattern, two distinct periods of intensive licking activity were identified; an early (0-5 min after injection) and a late response (20-30 min after injection). The following analgesics were investigated (dose range): acetylsalicylic acid (100-400 mg/kg), paracetamol (100-400 mg/kg) and morphine (0.6-10 mg/kg). Acetylsalicylic acid (200-400 mg/kg early response, 300-400 mg/kg late response), paracetamol (200-400 mg/kg early response, 300-400 mg/kg late response) and morphine (2.5-10 mg/kg) inhibited the responses in a dose-dependent manner. The results indicate that the test is useful for evaluating mild analgesics. It may have advantages over some of the tests that are commonly used for testing analgesics.

Acetaminophen↗

PubMed1985

Selective neurotoxic lesions of descending serotonergic and noradrenergic pathways in the rat.

The ability of neurotoxic substances to induce selective lesions of the descending monoaminergic pathways in rats was investigated. Saline, 6-hydroxydopamine, 5,6-dihydroxytryptamine, or 5,7-dihydroxytryptamine were administered into the lumbar subarachnoid space through a chronically indwelling catheter. The lesions were evaluated 2-3 weeks later by in vitro uptake of [3H]noradrenaline and [14C]5-hydroxytryptamine into synaptosomal preparations from the frontal cortex, brainstem, cervical spinal cord, and lumbar spinal cord of each animal. There was no difference in uptake between saline-injected and noncatheterized controls and no significant changes in cortical uptake after any of the treatments (dose range of neurotoxins: 0.6-80 micrograms). In the lumbar spinal cord, 6-hydroxydopamine (5-80 micrograms) reduced the [3H]noradrenaline uptake by approximately 90% with no effects on [14C]5-hydroxytryptamine uptake, whereas 5,6-dihydroxytryptamine reduced the uptake of [14C]5-hydroxytryptamine by 90% (20-80 micrograms). [3H]Noradrenaline uptake was unaffected by lower doses of 5,6-dihydroxytryptamine but fell by 45-55% after 40-80 micrograms. 5,7-Dihydroxytryptamine (10-80 micrograms) reduced [3H]noradrenaline uptake by 90-95% and [14C]5-hydroxytryptamine uptake by approximately 80% (5-80 micrograms) in the lumbar cord. It is concluded that intrathecal administration of suitable doses of neurotoxins may produce extensive selective lesions of descending noradrenergic and serotonergic pathways.

5,6-Dihydroxytryptamine↗

PubMed1985

Test-dependent antinociceptive effect of spinal serotonin release induced by intrathecal p-chloroamphetamine in mice.

The effect of direct intrathecal injection of p-chloroamphetamine (PCA) into the lumbar subarachnoid space was investigated in mice. PCA (0.6 - 20 micrograms) induced a dose-related prolongation of response latencies in the tail-flick test, but failed to affect the hind-paw lick response in a hot-plate test employing slowly rising temperature. PCA (5 micrograms) given intracerebroventricularly did, however, significantly elevate the response temperature in the hot-plate test. The antinociceptive effect of PCA in the tail-flick test was prevented by spinalization, by pretreatment with the selective serotonergic re-uptake blocker zimelidine (20 mg X kg-1 i.p.) and by the serotonin synthesis inhibitor p-chlorophenylalanine (300 + 300 + 150 mg X kg-1 i.p. 72, 48 and 24 h before test). It is concluded that PCA given intrathecally releases serotonin from spinal terminals, which may under certain conditions induce antinociception.

Amphetamines↗

PubMed1984

Metergoline elevates or reduces nociceptive thresholds in mice depending on test method and route of administration.

Intrathecal injection of metergoline reduced the response latencies in the tail-flick and hot-plate tests, supporting the contention that descending 5-hydroxytryptamine (5-HT) pathways tonically inhibit pain sensitivity. Elevated latencies were, however, observed after both intraperitoneal (IP) and intracerebroventricular (ICV) injections in the hot-plate test, when hindpaw lick was used as the response criterion. These findings may indicate that supraspinal 5-HT pathways tonically increase pain responsiveness in certain test situations . Alternative hypotheses are that metergoline in supraspinal structures acts as an agonist at post-synaptic 5-HT receptors mediating antinociception, or as an antagonist at pre-synaptic 5-HT receptors. Recording of first reaction latencies on the hot-plate showed increased thresholds after IP, but not after ICV injections. This may indicate an action on 5-HT receptors in the brain not accessible after ICV injections, or that the effect is mediated by blockade of peripheral 5-HT receptors.

Animals↗

PubMed1984

Transport and distribution of homocarnosine after intracerebroventricular and intravenous injection in the rat.

Rats were injected intracerebroventricularly (i.c.v.) or i.v. with [14C]homocarnosine (250 nmol). Distribution of the dipeptide in brain structures, transport from the brain to the blood, distribution in peripheral organs, and excretion in the urine were studied by measuring radioactivity in tissue, plasma, and urine samples by liquid scintillation counting 15-120 min after injection. After i.c.v. injection, [14C]homocarnosine was taken up into all parts of the brain investigated (highest uptake in structures close to the site of injection), it was transported to the blood, and radioactive substances were found in low concentration in muscle, spleen, and liver, in high concentration in the kidneys, and very high concentration in the urine. Investigations using high pressure liquid chromatography (HPLC) showed that no degradation took place in the brain, all radioactivity was found in the homocarnosine fraction. In the plasma 86% of the radioactivity was found in the GABA fraction presumed to be formed by cleavage of the peptide.

Animals↗

PubMed1984

Learned tolerance to ethanol in the spinal cord.

Learning has been claimed to be of major importance in the development of tolerance to ethanol. In the present study we investigated the influence of learning on tolerance to ethanol-induced inhibition of a spinal reflex (tail-flick response) in intact and spinal rats. On day 1 and 9, groups of rats were injected with either ethanol 2.5 g/kg IP or saline 30 min prior to tail-flick testing. On days 2-8 the groups were treated differently in order to reveal the importance of the drug alone, the test alone and the combination of the two on development of tolerance. On day 10, the rats rendered tolerant in the home room were transferred to a new test room to be tested. Both in intact and spinal rats development of tolerance was observed only if the animals were repetitively tested while intoxicated. Tolerance acquired in the home room was not attenuated by transfer to a new environment. Results in the spinal rats suggested that adaptive mechanisms leading to tolerance may also be located in the spinal cord. The tolerance observed may be regarded as learned from practice while intoxicated.

Animals↗

PubMed1984

Immobilization-induced analgesia: possible involvement of a non-opioid circulating substance.

Stress induced analgesia (SIA) and stress-induced changes in body temperature were studied in mice and rats. Immobilization was used as the stressor. Nociception was measured with the tail-flick method and body temperature was recorded in the colon. Within 5 min of immobilization a similar increase in tail-flick latencies was observed in the two species. Concomitantly, the body temperature increased in the rats and decreased in the mice. Transection of the spinal cord 7 days before the experiments tended to increase the effect of stress on the tail-flick latencies in both species. Pretreatment with naloxone HCL (2 mg/kg SC, 5 min before immobilization) did not influence SIA in either intact or spinal rats. Thus, analgesia induced by immobilization may be due to a non-opioid substance acting peripherally or reaching the spinal cord via the systemic circulation.

Analgesia↗

PubMed1983

Attenuation of morphine-induced analgesia by p-chlorophenylalanine and p-chloroamphetamine: test-dependent effects and evidence for brainstem 5-hydroxytryptamine involvement.

A number of studies on the role of 5-HT in morphine analgesia and regulation of nociception are reviewed. Highly divergent conclusions are found in the literature with regard to the importance of serotonergic structures. Several methodological differences, particularly with regard to lesion and depletion techniques and testing procedures, may account for the controversies in the literature. The experimental findings presented demonstrate attenuation of morphine-induced analgesia in the hot-plate and tail-flick tests, and increased responsiveness to noxious electrical shock following depletion of 5-HT in ascending and descending 5-HT pathways by PCPA (200 + 100 + 100 mg/kg on 3 consecutive days prior to testing) as well as following destruction of cerebral 5-HT terminals by PCA (2 X 10 mg/kg, 7 and 8 days before testing). This was also the case when the neurotoxic effect of PCA was largely restricted to the brainstem by pretreatment with the 5-HT reuptake inhibitor zimelidine (20 mg/kg prior to each PCA injection). Attenuation of morphine analgesia was not found in the flinch-jump test or in the hot-plate test when conducted immediately after flinch-jump testing. It is concluded that brainstem 5-HT connections may contribute to the analgetic effect of morphine, but only under certain test conditions.

Amphetamines↗

PubMed1983

Inhibitory effect of 5-methoxy-N,N-dimethyltryptamine on the synaptosomal uptake of 5-hydroxytryptamine.

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) in concentrations of 0.5-500 microM produced a significant inhibition of [14C]5-hydroxytryptamine [14C]5-HT) uptake in striatal, hippocampal and hypothalamic crude synaptosomes from rat brain. Higher concentrations of 5-MeODMT (10 microM) also inhibited the uptake of [3H]dopamine [3H]DA) and induced the release of [14C]5-HT and [3H]DA from preloaded synaptosomes. It appears that the 5-HT agonist properties of 5-MeODMT may involve reuptake inhibition in addition to the previously documented direct receptor stimulation.

Animals↗