Biomedical subjects

K Hole

Publications and source records attributed to K Hole.

At least 55 records · Page 3Linked to original sources

PubMed1991

Antinociceptive effect of paracetamol in rats is partly dependent on spinal serotonergic systems.

The possible involvement of bulbo-spinal monoaminergic pathways in the antinociceptive effect of paracetamol was investigated in rats. Serotonergic pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (5,6-DHT), and noradrenergic pathways with 6-hydroxydopamine (6-OHDA). Intact and lesioned rats were tested in the formalin test after i.p. paracetamol (400 mg/kg) or vehicle. Behaviour was scored for 1 h after the dorsal injection of 100 microliters of 5% formalin into one hind paw. Behavioural variables were evaluated with a multivariate statistical procedure, as well as an analysis of variance. Paracetamol itself reduced pain-related behaviour and increased normal motor activity. This antinociceptive effect was reduced in rats lesioned with 5,6-DHT. In lesioned rats paracetamol caused a change in nociceptive behaviour from active, focused behaviour towards passive, protective and non-focused behaviour in the early phase of the formalin test. No significant effect of lesioning with 6-OHDA upon the paracetamol effect was found. These results show that activation of spinal serotonergic systems is involved in the antinociceptive effect of paracetamol. The relative importance of this mechanism in the central effect of paracetamol and the mechanisms that cause the activation remain to be determined.

5,6-Dihydroxytryptamine↗

PubMed1991

Chronic administration of desipramine and zimelidine changes the behavioural response in the formalin test in rats.

In studies of the effect on nociception of chronic administration of antidepressants, the stress of the injections may influence the results. In this experiment, desipramine or zimelidine were administered in the drinking water of rats, in a concentration yielding a dose of approximately 8 mg/kg/24 hr. Desipramine, given both for a short time (24 hr) and chronically (14 days), induced antinociception in the increasing temperature hot-plate test; zimelidine did not significantly influence the results of this test. In the tail-flick test, neither short-term nor chronic administration of these antidepressants had any effect on nociception, when correction was made for the changes in the temperature of the tail skin. In the formalin test, nine behavioural categories were scored for 1 hr and the data were treated statistically, using a multivariate analysis. Chronic administration of desipramine increased nociceptive behaviour during the first 10 min of the test. Desipramine and, to a lesser extent, zimelidine, changed the response in the late phase (10-60 min), showing less focussed pain-related behaviour (jerks and shaking, licking and biting of the injected paw) and more non-focussed pain-related behaviour (activity states with elevation or protection of the injected paw). It was concluded that desipramine is antinociceptive in the increasing temperature hot-plate test. Desipramine and zimelidine, administered chronically, modify the late phase of the formalin test towards less focussed pain-related behaviour, suggesting an antinociceptive effect. Multivariate analysis of the data of the formalin test seemed to be of value for the interpretation of the data.

Animals↗

PubMed1991

Different role of 5-HT1A and 5-HT2 receptors in spinal cord in the control of nociceptive responsiveness.

The effects of the 5-hydroxytryptamine type-2 (5-HT2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)-8-OH-DPAT] on nociceptive responsiveness were compared in mice. Intrathecal administration of DOI (5-20 micrograms) produced a dose-dependent behavioural syndrome, consisting of biting or licking, directed towards the caudal part of the body and reciprocal hindlimb scratching. However, (+)-8-OH-DPAT (5-20 micrograms) did not produce the biting and scratching behaviour. The response to DOI (20 micrograms) was reversed by treatment with the substance P receptor antagonist, [D-Arg1, D-Trp7,9, Leu11]-SP (Spantide) (5 micrograms). The tail-flick reflex was markedly depressed 5-20 min after administration of (+)-8-OH-DPAT; DOI did not change the tail-flick reflex after 5 min but significantly inhibited the reflex response 10-20 min after injection. The data show that stimulation of 5-HT2 receptors, but not 5-HT1A receptors, induced a behavioural syndrome, which may reflect activation of nociceptive pathways. The tail-flick reflex was more markedly inhibited by stimulation of 5-HT1A than 5-HT2 receptors. Accordingly, 5-HT2 and 5-HT1A receptors seem to have a different function in the modulation of nociceptive responsiveness in the mouse.

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

PubMed1991

The increasing-temperature hot-plate test: an improved test of nociception in mice and rats.

The increasing-temperature hot-plate test has several advantages compared to the conventional hot-plate test, but available equipment has been impractical and restricted with regard to stimulus control. We now describe an apparatus consisting of an aluminum plate that is heated and cooled by Peltier elements in contact with its lower surface. Several plates can be used simultaneously, individually controlled by electronic proportional feedback circuits. The set temperature of the feedback circuit is controlled by a computer program run on an IBM XT-compatible PC, so that a linear increase in temperature is achieved. Experiments were performed using rats and mice, with hindpaw licking as an end-point criterion. Experiments with various heating rates showed that 3.0 degrees C/min is the lowest rate that can be applied without signs of stress in the animals. On the basis of the recorded data, nociceptive temperature thresholds were calculated to be approximately 44.5 degrees C for both rats and mice. Inspection of the paws after analgesic treatment and exposure to different end-point temperatures suggested that a cutoff temperature of 50 degrees C should be employed to minimize tissue damage. Testing at ambient temperatures of 18 degrees and 28 degrees C yielded similar results for rats, whereas mice responded at significantly higher plate temperatures in the colder environment. Dose-related antinociceptive effects were demonstrated for morphine and paracetamol in both species. The results confirm that the increasing-temperature hot-plate test is a valuable test of nociception, which is also suitable for demonstrating the antinociceptive effects of nonopioid analgesics. The test may also be used to estimate the nociceptive temperature threshold.

Acetaminophen↗

PubMed1991

Lesions of bulbo-spinal serotonergic or noradrenergic pathways reduce nociception as measured by the formalin test.

Intrathecal administration of the neurotoxins 5,6-dihydroxytryptamine (5,6-DHT) and 6-hydroxydopamine (6-OHDA) in rats selectively lesioned the descending spinal serotonergic and noradrenergic pathways, respectively. Four days after neurotoxin administration the behaviour was evaluated in the formalin test. Several behavioural variables were recorded. The statistical analysis of the results was supplemented using a multivariate statistical method (partial least squares projection to latent variables, PLS) in addition to traditional analysis of variance. The described methods for recording and statistical analysis of behaviour appear to be useful in describing drug-induced differences in behavioural patterns in the formalin test. Both types of lesion reduced the pain-related behaviour in the formalin test (protection of the paw, biting and licking). The results indicate that the descending monoaminergic pathways are parts of a network which maintains adequate nociceptive responses to a chemical stimulus, or to stimuli lasting several minutes, as in the formalin test.

Animals↗

PubMed1990

The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex.

The role of the 5-hydroxytryptamine (5-HT) receptor subtypes in the spinal cord in the regulation of nociception is unknown. This study examined whether administration of different 5-HT1 receptor agonists into the spinal subarachnoid space of mice modulates the nociceptive tail-flick reflex, and whether effects on the tail-flick reflex involve changes in tail skin temperature. The tail-flick latencies (the time needed to evoke the tail-flick reflex by noxious radiant heat) were significantly increased after intrathecal (i. th.) injection of 5-HT (10-20 micrograms), the 5-HT1A/5-HT1B receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 10-20 micrograms), the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 20 micrograms) and after i.th. injection of 1(m-chlorophenyl)piperazine (mCPP, 5-20 micrograms) and 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 5-20 micrograms) which have high affinity for the 5-HT1B receptors. None of the 5-HT1 receptor agonists had the ability to change the tail skin temperature. The results show that in the mouse i.th. injection of both 5-HT1A and 5-HT1B receptor agonists has the ability to inhibit the tail-flick reflex without interfering with the tail skin temperature.

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

PubMed1990

Antinociceptive effect of intrathecally-administered desipramine and zimelidine in rats.

The effect of intrathecally (i.th.) administered desipramine and zimelidine, in doses of 5, 10 and 50 micrograms, were investigated in the tail-flick test with simultaneous measurement of the temperature of the tail skin and in the increasing temperature hot-plate test. A constant negative correlation between the temperature of the tail skin and tail-flick latency, as described previously, was found. For all doses tested, desipramine induced longer tail-flick latencies, 10 min after injection than vehicle and the temperature of the tail skin tended to increase less in this group than in controls. After adjustment of the tail-flick latencies for the changes in the temperature of the tail skin, an antinociceptive effect of desipramine was still found. For zimelidine, only the largest dose (50 micrograms) was found to be antinociceptive, after adjustment for the tail skin temperature. In the increasing temperature hot-plate test, no antinociceptive effect of these antidepressants was found. For desipramine and zimelidine, the effect in the tail-flick test, 10 min after injection, indicates that the antinociceptive effect of these drugs may have, at least partly, a spinal site of action. In the increasing temperature hot-plate test, the response is integrated supraspinally. This may partly explain the lack of effect in this test when desipramine and zimelidine were administered intrathecally.

Analgesics↗

PubMed1990

Benzodiazepine-induced antagonism of opioid antinociception may be abolished by spinalization or blockade of the benzodiazepine receptor.

The mechanisms underlying benzodiazepine antagonism of opioid antinociception were studied using the tail flick test and the hot plate test in mice. Both single-dose and repeated diazepam treatment antagonized the antinociceptive effect of morphine. The specific benzodiazepine antagonist flumazenil completely reversed the antagonism between diazepam and morphine. Mid-thoracic spinalization also abolished the antagonism, indicating that the antagonism takes place at higher levels in the CNS. Neither diazepam nor midazolam showed any affinity for opioid mu or kappa receptors in membranes prepared from mouse forebrain. Taken together with the results of other studies of interactions between GABAergic drugs and opioids, the results indicate that a benzodiazepine receptor-mediated mechanism at higher levels in the CNS, possibly in the brainstem, blocks the effect of opioids on nociceptive transmission.

Analgesics↗

PubMed1990

Morphine induces aggression but not analgesia in the naked mole-rat (Heterocephalus glaber).

1. The antinociceptive effect in the mole-rat of morphine (1, 10, 20 or 30 mg/kg) and nefopam (10 or 20 mg/kg) was studied. 2. In the hotplate test, morphine had no analgesic effect. A reduced response latency after morphine (10 and 20 mg/kg) could possibly be explained by hyperactivity and excited behaviour. 3. After morphine (10, 20 and 30 mg/kg) most of the animals died after fighting when kept in colony cages. Aggressive behaviour and death was prevented by naloxone, or by keeping the animals in single cages. 4. Nefopam (20 mg/kg) significantly increased the latency for the nociceptive response. 5. It was concluded that in the mole-rat, opioid systems in the CNS may not be involved in the regulation of nociception, but in the regulation of agonistic and motor behaviour.

Aggression↗

PubMed1990

Diazepam attenuates morphine antinociception test-dependently in mice.

The influence of diazepam on the antinociceptive effect of morphine was studied using four different nociceptive tests in mice. In the tail flick test, diazepam induced a dose-dependent reduction of the morphine effect, with an almost total reversed morphine effect following diazepam 2 mg/kg. The effect could not be explained by altered tail skin temperature or pharmacokinetic changes. Diazepam 1 mg/kg and higher induced sedation and significantly impaired the performance in a rotarod test, a dose of 0.5 mg/kg diazepam was therefore used in the other nociceptive tests. This dose of diazepam significantly attenuated the antinociceptive effect of morphine in the constant temperature hot plate test and the tail flick test. In the increasing temperature hot plate test and in the formalin test, no effect of diazepam on the nociceptive effect of morphine was observed. The results indicate that diazepam antagonizes the effect of morphine dependent upon the test employed. No antagonism could be observed in tests with a long-lasting stimulus, and a response integration probably at a rather high level in the CNS. In the two tests showing antagonism, the stimulus is more short-lasting, and at least for the tail flick test, the integration takes place at a lower level in the CNS.

Analgesics↗

PubMed1990

The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations.

The effect of (+/-), (+) and (-)-nefopam on the uptake of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in synaptosomal preparations from rat forebrain, hippocampus and striatum has been investigated. All three forms of nefopam inhibited the amine uptake in the investigated structures, the order of potency being (+) greater than (+/-) greater than (-). (+)-Nefopam was 7-30 times more potent than (-)-nefopam. The same order of potency has also been found for the antinociceptive effect of these three forms, however, the differences were smaller. Inhibition of 5-HT and noradrenaline uptake may not be the sole mechanism underlying the analgesic effect of nefopam.

Animals↗

PubMed1990

1,4-Benzodiazepines antagonize opiate-induced antinociception in mice.

The influence of diazepam, midazolam, and flunitrazepam on the antinociceptive effect of morphine, fentanyl, and buprenorphine was studied using the hot-plate test and the tail-flick test in mice. Diazepam and midazolam induced a dose-dependent attenuation of the effect of all three opiates in both tests of nociception. Flunitrazepam antagonized the antinociceptive effect only in the tail-flick test. The benzodiazepine effect could not be explained by altered tail-skin temperature. The antagonism did not correlate well with the sedative or muscle-relaxing properties of the benzodiazepines, and a different mechanism may therefore be involved. It is proposed that the antagonism represents an interaction between benzodiazepines and opioid systems in the brain participating in modulation of nociceptive inputs.

Analgesia↗

PubMed1989

Mechanisms of orphenadrine-induced antinociception in mice: a role for serotonergic pathways.

The possible involvement of central serotonergic pathways in the mechanism of action of orphenadrine citrate was investigated in male albino mice. Orphenadrine (20 mg/kg) did not alter the concentration of 5-hydroxytryptamine (5-HT) or its metabolite 5-hydroxyindole acetic acid in the frontal cortex or spinal cord, nor did it, in moderate concentrations, inhibit the uptake of [14C]5-HT, [3H]noradrenaline ([3H]NA) or [3H]dopamine ([3H]DA) into crude synaptosomal preparations from the cortex. The antinociceptive effect of orphenadrine was studied in the formalin test and in the increasing temperature hot plate test. No sensorimotor impairment was observed for doses of 30 mg/kg or lower. A general depletion of serotonin by means of p-chlorophenylalanine significantly reduced the effect of orphenadrine in both tests, while lesion of the ascending serotonergic systems by means of p-chloroamphetamine did not affect the analgesia. It is concluded that the antinociceptive effect of orphenadrine may be mediated in part via the raphe-spinal serotonergic systems.

Analgesics↗

PubMed1989

Subsensitivity of serotonin and substance P receptors involved in nociception after repeated administration of a serotonin receptor agonist.

The antinociceptive effects of subcutaneous 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the responses to intrathecal (i.th.) serotonin (5-HT) and substance P (SP) were examined in mice after repeated administration of 5-MeODMT (3 mg/kg every 30 min for 4 hours). Ninety min after the last injection of 5-MeODMT the basal tail-flick and hot-plate response latencies were unaltered, but the antinociceptive effects of 5-MeODMT (3 mg/kg) in the tail-flick and hot-plate tests and the antinociceptive effect of 8-OH-DPAT (0.5 mg/kg) in the hot-plate test were markedly reduced. The behavioral responses to i.th. 5-HT (4.0 micrograms) and SP (2.5, 5, and 10 ng) which include vigorous biting, licking and scratching of the caudal part of the body, were attenuated 90-120 min after withdrawal of 5-MeODMT treatment. It is suggested that repeated administration of 5-MeODMT downregulates the function of the 5-HT receptors mediating the antinociceptive effects of 5-MeODMT and 8-OH-DPAT. The rapid desensitization to the behavioral responses both to 5-HT and SP by 5-MeODMT pretreatment may reflect a functional interaction between 5-HT and SP in the spinal modulation of nociception.

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

PubMed1989

Antinociceptive effects of serotonergic reuptake inhibitors in mice.

The antinociceptive effects of three predominantly serotonergic reuptake inhibitors, alaproclate, citalopram and clomipramine, were examined in mice using the hot-plate, formalin and substance P tests. The effects were compared with those of the noradrenergic reuptake inhibitor, desipramine. Different profiles in the three nociceptive tests were found for all four drugs, using doses of 10 and 40 mg/kg. The selective serotonergic reuptake inhibitor, alaproclate, seemed to have the least antinociceptive effects, and was the only drug that was ineffective in the hot-plate test. The other selective drug, citalopram, had a stronger effect than alaproclate in the substance P test, but in the formalin test, both drugs were approximately equally effective. Clomipramine differed from citalopram by being more effective in the formalin test. These findings thus indicate that selective inhibitors of the uptake of 5-HT have weaker antinociceptive effects than less selective drugs. Desipramine seemed to be no less effective than the serotonergic drugs and was the most potent drug in the hot-plate test.

Alanine↗

PubMed1989

Desipramine in small doses induces antinociception in the increasing temperature hot-plate test, but not in the tail-flick test.

The data reported for the antinociceptive effect of tricyclic antidepressants are conflicting. In this investigation, the effect of acute intraperitoneal (i.p.) administration of desipramine (2 and 5 mg/kg) was studied in rats, using the tail-flick test with simultaneous measurement of tail-skin temperature, and the increasing temperature hot-plate test. A constant negative correlation between tail-flick latency and tail-skin temperature, as described earlier, was also found in this study. Different ambient temperatures influenced the results of the tail-flick test. At an ambient temperature of 24-25 degrees C, desipramine gave rise to an apparent antinociception in the tail-flick test, which was found to be caused by a relative fall in tail-skin temperature. At 21-22 degrees C, no change in tail-flick latency was found after the administration of desipramine. In the increasing temperature hot-plate test, however, a dose-dependent antinociceptive effect of desipramine was observed at both ambient temperatures. The strong influence of moderate differences in ambient temperature on the results of the tail-flick test may explain some of the conflicting results reported in the literature. Whenever this test is used, the temperature of the tail should be recorded and taken into account in the evaluation of the data.

Animals↗

PubMed1989

The apparent hyperalgesic effect of a serotonin antagonist in the tail flick test is mainly due to increased tail skin temperature.

It has been suggested that reduced activity in raphe-spinal serotonergic systems induces hyperalgesia. In rats, the serotonin antagonist metergoline (0.5 mg/kg intraperitoneally) reduced tail flick latency by 0.92 sec (p less than 0.001) and increased tail skin temperature by 2.4 degrees C (p less than 0.001) when measured 50 min after injection. Multiple regression analysis with tail flick latency as dependent variable and tail skin temperature and metergoline/vehicle as independent variables revealed a highly significant effect of tail temperature on tail flick latency. The increase of tail skin temperature explained a reduction of tail flick latency of 0.64 of the 0.92 sec observed [B = -0.267 +/- 0.034, t(37)= -7.75, p less than 0.0001]. When the effect on tail skin temperature was taken into account, metergoline reduced tail flick latency by 0.28 sec [B = -0.284 +/- 0.114, t(37) = -2.50, p less than 0.05]. Metergoline (0.5 and 2.0 mg/kg) did not significantly alter plantar paw skin temperature or the response temperature in the increasing temperature hot plate test. Thus, the observed effect of metergoline on tail flick latency is primarily due to an effect on tail skin temperature. The possibility exists that the remaining effect of metergoline may be due to inadequate correction for the skin temperature change, and it is concluded that the study provide no clear evidence for a tonic inhibition of nociception by serotonergic systems.

Animals↗

PubMed1989

An improved method for tail-flick testing with adjustment for tail-skin temperature.

The tail-skin temperature is an important factor in determining tail-flick latency to noxious radiant heat in rats and mice. A simple, non-invasive method for recording the tail-skin temperature during conventional tail-flick testing is described. The method is conveniently performed during conventional tail-flick testing. It does not require additional handling of the animals, and it is not stressful. The method utilizes a small-sized thermocouple which is brought in contact with the dorsal surface of the tail close to the area exposed to the radiant heat stimulus. A computer based system is used to record the temperature and control the tail-flick apparatus. Continuous monitoring of skin temperature showed that the temperature as measured 23 mm from the tip of the tail agreed well with skin temperature in the position where the beam was focused during tail-flick testing (13 mm from the tip). The skin temperature closer to the base of the tail (100 mm from the tip) showed considerably more deviation from the temperature 13 mm from the tip. Temperature measurements close to the heated area gave a higher degree of correlation between recorded temperature and tail-flick latencies than did temperature measurements closer to the base of the tail. These results provide further support for the contention that tail-skin temperature is an important factor when assessing nociception by means of the tail-flick test, and demonstrate that the temperature should be measured as close to the heated area as possible.

Animals↗