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Nociception in mice: the influences exerted by a variety of barbiturate agonists and antagonists
1445 compartment and allowing for development of tolerance was fitted to the data (Holford, 1981; Porchet 1988). Results: Mean clonidine elimination t~/2 was not significantly influenced by naloxone treatment (7.3 h vs 9.9 h). Clonidine alone or with naloxone induces an equal maximal fall of MAP ( - 10 mmHg). SF drop is maximal ( - 80~) at 2 h, corresponding to clonidine Cma~. Clonidine with and without naloxone increases subjective and objective pain thresholds for at least 4 h (p < 0.01, ANOVA), peaking at 2 h. Naloxone has no effect on objective pain threshold but tends to increase subjective pain threshold (p = 0.08). An acute decrease in analgesia and SF drop is observed after a light standardized lunch taken at 3 h, contrasting with the sustained effect on MAP up to 8 h. The concentration-effect plot for MAP shows a distinct counter-clockwise hysteresis. The respective t~/2 keo are 42 mi~ (CV: 17~;) and 29 win (18~;) for clonidine alone and with naloxone. On the contrary almost collapsed hystereses are observed when SF and analgesia are plotted against clonidine concentration, thus confirming a rapid attenuation of these effects. The best fit is obtained with a model allowing an acute change of the linear relationship between effect and concentration after the third hour corresponding to meal time. None of the models postulating an acute development of tolerance a~equately fit the data. Conclusions: A single oral dose of clonidine induces a clear analgesia not mediated by the opioid peptide system. This effect is short-lived in comparison with the duration of hypotension. This is probably related to an acute postprandial change in pain sensitivity. The same observation can be made for SF.
References Solomon, R.E., Brody, M.J., Gebhart, C.F., 1989, J Pharmacol Exp Ther 251: 27. Holford, N.H.G, Sheiner, L.B., 1981, Clin Pharmacokinet 6: 429. Porchet, H.C., Benowitz, N.L., Sheiner, L.B., 1988, J Pharmacoi Exp Ther 244 231.
Nocicepfion in mice: the influences exe~ed by a variety of barbiturate agonists and antagonists Carrnody, J., Knodler, L. and Murray, S. School of Physiology and Pharmacology, Universityof New South Wales, Kensington (Sydney), 2033, Australia
For some time our laboratory has been interested in the question of barbiturate influences on nociception. Stimulated by conflicting reports in the literature, our own experiments found that pentobarbitone produced marked hyperalgesia, doubting nociception in mice with doses as low as 20~ of those required for hypnosis (Carmody et al., 1986). This effect seemed to have no relation to opiate receptors but it raised several other questions. These included: A would this result be seen with other nociceptive tests than the one which we used or could the disparity found in the litc~ature follow from test-specific results? B given the fact that pentobarbitone is a racemic mixture of a convulsant as well as an hypnotic isomer (Andrews et al., 1979), is such a hyperalgesic effect seen with other barbiturates, notably the "pure" hypnotics and the "pure" convulsants? C is this barbiturate action exerted at the "classic" GABA receptor (i.e. GABA^) where the receptor is part of a receptor-Cl- ionophore complex which generates inhibitory post-synaptic potentials? The experiments which attempted to answer these questions were done with virgin, naive Balb/C female mice, approximately 20 g in weight. Four nociceptive tests and four drugs have been used. Two of the tests could be classed as acute, thermal or superficial, while the other two n~Jght be deemed deep, chemical or inflammatory (and the latter might thus be considered the more clinically relevant). These tests were: (i) the tail-flick and (ii) the foot-flick tests, where the measurement is of the time for the appearance of a characteristic nocifensive motor response after exposure to the thermal stimulus (49, and 56 o, respectively); (iii) the abdominal constriction test where a count is made of the occurrence of characteristic abdominal constrictive-lordotic extensive movements after intraperitoneai mj~tion of an irritant substance (1 ~ acetic acid solution); and (iv) the formalin test which involves scoring (over a 0-3 range) of the extent to which a forelimb is "favoured" after the injection of 0.03 ml of 5~ formalin solution. Apart from pentobarbitone, the drugs were the purely hypnotic amylobarbitone, the purely convulsant 5-ethyl-5-(3'-methyl-but-
1¢46 2"-eny|)-barbituric acid (3M2B, which differs from a m y l o b a r b i t o n e only in having a terminal double b o n d in the 5-C substitution) a n d picrotoxin (a convulsant antagonist of G A B A at the receptor ionophore complex, Johnston et al., 1984). The results are heterogeneous and paradoxical, with picrotoxin the only drug to give a uniform result (analgcsia). They are summarised in the Table. Test
Pain ratio ~
1. Pentobarbitone footflick tailfliek formalin constriction Picrotoxin footflick tailfl~ formalin constriction
0.82 1.28 * 1.04 1.59 * 0.59 0.65 0.16 0.22
* * * *
Test 3. Amylobarbitone footflick tailflick formalin constriction 4. 3M2B footflick tailflick formalin constriction
Pain ratio = 1.57 1.39 0.77 4.90
* * * *
0.75 0.66 * 0.73 * 0.13 *
# The ratio is of the index of pain sensitivity in saline treated animals/drug treated animals. A ratio of 1.0 indicates that nociception is unchanged by the treatment. A value greater than 1.0 indicates (after the band of statistical error has been taken into account) h)T~,ralgesia, while a value significantly less than 1.0 indicates analgesia. * indicates a difference from 1.0 with a significance level of at least P < 0.05. There is no obvious pattern in these results, either with a particular drug or in the acute cf the chronic tests. These disparities imply that different pathways must subserve the different nociceptive test, s, while some but not all involve classic G A B A A receptors.
Rderenees Carmody, JJ., Jamieson, D.D. and dePoort~re, R.Y., 1986. Naunyn. Schmied. Arch. Pharmacol. 334, 193. Andrews, P.R., Jones, G.P. and Lodge, D: 1979. Eurcp. J. Pharmacol. 55, 115. Johnston, G.A.R., AHan, R.D. and Skerritt, J.H, 1984, GABA Receptors, in: Handbook of Neuroscience (2nd edition), ed Lajtha, A. (l~enurn Press, New York), p. 213.
P.we.325 ]
Evaluation oF ~
analgesic effect o| fluvoxamine on experimental acute and chronic pain
Mic6, J.A., Casas. J., G..,errez, M., G6mez-Cama, M.C., Valverde, O., Aracama, J.R., Elorza, J. and Gibert-Rahola, J. •
,.6-"
Unidad de Neuropsicofarmac-ologi~ Dpto. Neurociencias, Universidadde Cddiz, Spain Considerable evidence exits to implicate a role for the neurotransmitter serotonin (5HT) in the modulation of the nociceptive transmission (MESSING and LYTLE, 1977). Activation of the descending serotoninergic bulbospinal system produces inhibition of behavioral and dorsal horn neuronal response to noxious stimuli. For instance, increasing postsynaptic 5HT receptor activity by administration of selective 5 H T inhibitors may induce antinociception in mice, rats and humans. However, variable effects of 5 H T uptake inhibitors have been reported. Antinociception as well as no effect in the hot plate and tail frick tests have been demonstrated in mice and rats. Moreover, in mice, some selective 5HT uptake inhibitors produced hyperalgesia in the formal in test. Antidepressants with 5HT inhibiting properties have been used ~n the treatment of chronic pain ( W A L S H 1983). On the other hand, sex differences in the sensitivity of mice to ~:erctonin agonists have been reported, females are more susceptible than males (CARLSSON and CARLSSON 1988) The following experiments were undertaken to characterize the effects of
References Solomon, R.E., Brody, M.J., Gebhart, C.F., 1989, J Pharmacol Exp Ther 251: 27. Holford, N.H.G, Sheiner, L.B., 1981, Clin Pharmacokinet 6: 429. Porchet, H.C., Benowitz, N.L., Sheiner, L.B., 1988, J Pharmacoi Exp Ther 244 231.
Nocicepfion in mice: the influences exe~ed by a variety of barbiturate agonists and antagonists Carrnody, J., Knodler, L. and Murray, S. School of Physiology and Pharmacology, Universityof New South Wales, Kensington (Sydney), 2033, Australia
For some time our laboratory has been interested in the question of barbiturate influences on nociception. Stimulated by conflicting reports in the literature, our own experiments found that pentobarbitone produced marked hyperalgesia, doubting nociception in mice with doses as low as 20~ of those required for hypnosis (Carmody et al., 1986). This effect seemed to have no relation to opiate receptors but it raised several other questions. These included: A would this result be seen with other nociceptive tests than the one which we used or could the disparity found in the litc~ature follow from test-specific results? B given the fact that pentobarbitone is a racemic mixture of a convulsant as well as an hypnotic isomer (Andrews et al., 1979), is such a hyperalgesic effect seen with other barbiturates, notably the "pure" hypnotics and the "pure" convulsants? C is this barbiturate action exerted at the "classic" GABA receptor (i.e. GABA^) where the receptor is part of a receptor-Cl- ionophore complex which generates inhibitory post-synaptic potentials? The experiments which attempted to answer these questions were done with virgin, naive Balb/C female mice, approximately 20 g in weight. Four nociceptive tests and four drugs have been used. Two of the tests could be classed as acute, thermal or superficial, while the other two n~Jght be deemed deep, chemical or inflammatory (and the latter might thus be considered the more clinically relevant). These tests were: (i) the tail-flick and (ii) the foot-flick tests, where the measurement is of the time for the appearance of a characteristic nocifensive motor response after exposure to the thermal stimulus (49, and 56 o, respectively); (iii) the abdominal constriction test where a count is made of the occurrence of characteristic abdominal constrictive-lordotic extensive movements after intraperitoneai mj~tion of an irritant substance (1 ~ acetic acid solution); and (iv) the formalin test which involves scoring (over a 0-3 range) of the extent to which a forelimb is "favoured" after the injection of 0.03 ml of 5~ formalin solution. Apart from pentobarbitone, the drugs were the purely hypnotic amylobarbitone, the purely convulsant 5-ethyl-5-(3'-methyl-but-
1¢46 2"-eny|)-barbituric acid (3M2B, which differs from a m y l o b a r b i t o n e only in having a terminal double b o n d in the 5-C substitution) a n d picrotoxin (a convulsant antagonist of G A B A at the receptor ionophore complex, Johnston et al., 1984). The results are heterogeneous and paradoxical, with picrotoxin the only drug to give a uniform result (analgcsia). They are summarised in the Table. Test
Pain ratio ~
1. Pentobarbitone footflick tailfliek formalin constriction Picrotoxin footflick tailfl~ formalin constriction
0.82 1.28 * 1.04 1.59 * 0.59 0.65 0.16 0.22
* * * *
Test 3. Amylobarbitone footflick tailflick formalin constriction 4. 3M2B footflick tailflick formalin constriction
Pain ratio = 1.57 1.39 0.77 4.90
* * * *
0.75 0.66 * 0.73 * 0.13 *
# The ratio is of the index of pain sensitivity in saline treated animals/drug treated animals. A ratio of 1.0 indicates that nociception is unchanged by the treatment. A value greater than 1.0 indicates (after the band of statistical error has been taken into account) h)T~,ralgesia, while a value significantly less than 1.0 indicates analgesia. * indicates a difference from 1.0 with a significance level of at least P < 0.05. There is no obvious pattern in these results, either with a particular drug or in the acute cf the chronic tests. These disparities imply that different pathways must subserve the different nociceptive test, s, while some but not all involve classic G A B A A receptors.
Rderenees Carmody, JJ., Jamieson, D.D. and dePoort~re, R.Y., 1986. Naunyn. Schmied. Arch. Pharmacol. 334, 193. Andrews, P.R., Jones, G.P. and Lodge, D: 1979. Eurcp. J. Pharmacol. 55, 115. Johnston, G.A.R., AHan, R.D. and Skerritt, J.H, 1984, GABA Receptors, in: Handbook of Neuroscience (2nd edition), ed Lajtha, A. (l~enurn Press, New York), p. 213.
P.we.325 ]
Evaluation oF ~
analgesic effect o| fluvoxamine on experimental acute and chronic pain
Mic6, J.A., Casas. J., G..,errez, M., G6mez-Cama, M.C., Valverde, O., Aracama, J.R., Elorza, J. and Gibert-Rahola, J. •
,.6-"
Unidad de Neuropsicofarmac-ologi~ Dpto. Neurociencias, Universidadde Cddiz, Spain Considerable evidence exits to implicate a role for the neurotransmitter serotonin (5HT) in the modulation of the nociceptive transmission (MESSING and LYTLE, 1977). Activation of the descending serotoninergic bulbospinal system produces inhibition of behavioral and dorsal horn neuronal response to noxious stimuli. For instance, increasing postsynaptic 5HT receptor activity by administration of selective 5 H T inhibitors may induce antinociception in mice, rats and humans. However, variable effects of 5 H T uptake inhibitors have been reported. Antinociception as well as no effect in the hot plate and tail frick tests have been demonstrated in mice and rats. Moreover, in mice, some selective 5HT uptake inhibitors produced hyperalgesia in the formal in test. Antidepressants with 5HT inhibiting properties have been used ~n the treatment of chronic pain ( W A L S H 1983). On the other hand, sex differences in the sensitivity of mice to ~:erctonin agonists have been reported, females are more susceptible than males (CARLSSON and CARLSSON 1988) The following experiments were undertaken to characterize the effects of