European Journal of Pharrnaeology, 219 (1992) 113-116
113
f~ 1992 Elsevier Science Publishers B.V. All rights reserved 1)014-2999/92/$05.00
EJP 52575
Effects of two different reversible monoamine oxidase-A inhibitors on nociceptive thresholds in the rat M a u r o Bianchi, P a o l o M a n t e g a z z a a n d A l b e r t o E. P a n e r a i Department of Pharmacology, Unit~ersityof Milano, Via Vant~itelli32, 20129 Milano, Italy Received 4 March 1992, revised MS received 12 May 1992, accepted 19 May 1992
The acute effect of two different reversible inhibitors of monoamine oxidase-A on nociceptive thresholds was evaluated in the rat by the tail-flick and hot-plate tests. CGP 11305-A, a monoamine oxidase-A inhibitor that also blocks serotonin reuptake, elicited an increase of latency in the tail-flick and the hot-plate test. Ineffective doses of CGP 11305-A increased nociceptive thresholds when administered in combination with other serotoninergic agents, i.e. chlorimipramine or 5-hydroxytryptophan, at doses that were ineffective alone. CGP 22364-A, a pure inhibitor of monoamine oxidase-A, increased latency only in the hot-plate test. Both compounds decreased spontaneous locomotor activity at the doses effective in the hot-plate test, suggesting that the responses observed in this test are not related to a pure effect on nociceptive thresholds. The data suggest that the increase in serotonin availability induced by monoamine oxidase-A inhibition alone is not sufficient to affect nociceptive thresholds. Monoamine oxidase-A inhibitors; Nociception; Tail-flick test; Hot-plate test; 5-HT (5-hydroxytryptamine, serotonin)
1. Introduction There is increasing, recent clinical and experimental evidence in support of an important role for tricyclic antidepressant drugs in pain therapy. These drugs are effective in post-operative, cancer and neuropathic or stump pain (Tiengo et al., 1987; Ventafridda et al., 1990; Panerai et al., 1990). The most consistent results, both in clinical and animal experiments, were obtained with tricyclic antidepressants that potentiate the serotoninergic system, and this evidence was confirmed by the increase in nociceptive thresholds observed with the serotonin precursor 5-hydroxytryptophan (5-HTP) (Sacerdote et al., 1987). However, the use of tricyclic antidepressants is accompanied, especially in elderly patients, by severe side effects e.g. constipation, urinary retention, and dry mouth, that limit their use. Moreover, in non-depressed subjects, tricyclic antidepressants might also induce somnolence and mental confusion. Most recently, the new specific and reversible inhibitors of monoamine oxidase-A became available for psychiatric therapy, and seem to be as
Correspondence to: A.E. Panerai, Department of Pharmacology, University of Milano, Via Vanvitelli 32, 20129, Milano, Italy. Tel. 39.2.719 750, fax 39.2.730 470.
effective as some tricyclic antidepressants such as chlorimipramine (Civeira et al., 1990). Moreover, in psychiatric clinical trials, reversible monoamine oxidase-A inhibitors seem to provoke much fewer side effects than tricyclic antidepressants, expecially in the elderly (Versiani et al., 1990). The mechanism of action of reversible monoamine oxidase-A inhibitors resembles that of tricyclic antidepressants since they cause an increase in serotonin availability through the inhibition of its catabolism. Since serotonin is well known to play a pivotal role in the control of pain, we thought of investigating whether reversible monoamine oxidase-A inhibitors could, alone or in association with other serotoninergic agents, modify nociceptive thresholds. Moreover, we wanted to investigate whether, as reversible monoamine oxidaseA inhibitors and tricyclic antidepressants are apparently equally effective in depressive disorders, the increase in serotonin induced by the inhibition of monoamine oxidase-A activity was also sufficient to increase nociceptive thresholds. It is well known, in fact, that monoaminoxidases have only a minor role in the catabolism of biologic amines. For this reason, if reversible monoamine oxidase-A inhibitors were also effective on nociceptive thresholds, it would mean that minimal changes in the serotoninergic tone are sufficient to modulate pain.
114
2. Materials and methods
S p r a g u e - D a w l e y CD male rats, eight in each group, were used in all experiments. The rats, 200-250 g body weight, were housed for at least one week before the experiments at 22°C with a light: dark cycle of 14:10 h, with food and water ad libitum. All experiments were conducted in the morning, beginning at 09:00-09:30 h. We used C G P 11305-A ( ( 7 - B r - 5 - m e t h o x y - 2 benzofuryl)-piperidine; brofaromine, Ciba-Geigy, Origgio, Italy), a reversible monoamine oxidase-A inhibitor that, at doses 10 time higher than those effective on monoamine oxidase-A, also induces the inhibition of serotonin, but not of noradrenaline reuptake (Waldmeier et al., 1989), and CGP 22364-A (l-[l(phenyl)ethyl]-2-methyl-imidazol; Ciba-Geigy, Origgio, Italy), another reversible monoamine oxidase-A inhibitor, completely devoid of effects on serotonin or noradrenaline reuptake. Both drugs were administered alone at doses of 10, 20, 40, 60, 80 m g / k g , or at the dose of 10 m g / k g together with 5-HTP (Tript-OH, Sigma-Tam Pomezia, Italy) 25 m g / k g , or chlorimipramine (CIM) (Anafranil, Ciba-Geigy, Origgio, Italy) 10 m g / k g . All drugs were administered intraperitoneally (i.p.) immediately after measurement of basal tail-flick or hot-plate latency. Nociceptive thresholds had been measured by the tail-flick (the stimulus was a focussed light beam), and hot-plate (58°C) methods. The results are expressed as percentage of the maximal possible effect. Maximal possible effect expresses the equation [(TL-BL)/(ML-BL)] × 100, where BL is the mean basal latency (2.5-3.5 s for tail-flick, and 4.0-8.0 s for hot-plate) measured before the first treatment was applied; T L is the test latency measured after treatments; ML is the maximal latency accepted (8 s for tail-flick and 20 s for hot-plate), chosen in order to avoid tissue damage to the tail or the footpad respectively. The data were analyzed by means of the Kruskall-Wallis test and Dunnett's test for multiple comparisons. For the study of the effects of C G P 11305-A and 22364-A on spontaneous locomotor activity, the drugs were administered i.p. at the dose of 40 m g / k g (the minimum effective in the hot-plate test), and saline was administered to control rats. Rats were positioned in an Animex apparatus (L.K.B. Hagersten, Sweden), and locomotor activity was recorded over two consecutive periods of 3 min, at a time from drug administration corresponding to the maximal effect observed in the hot-plate test. The results were expressed as number of counts (movements of the animal), and evaluated statistically by means of Student's t-test. Since all the drugs used in the experiments, affecting the serotoninergic system, could modify the temperature of the tail, tail temperatures of rats treated with the highest dose of CGP 11305-A effective in the
lO0
~L
INl: --
-
80
2
I
60
\
I"
60
-
-
ilJ 'qG
I';
:ll
\11;
[,i;
I
*~ -
% HI'P
100
tO0
80
8O
+il
60
CGI'
CIM C(]P
1130,
60
2--
40
4O
/
,
/ c~
2O
k
11305/ A + CiM
+
/
c
- -
.... --
/ / \
I +
Saline b CGPII305-A CGP11305-A + CIM Saline~ CG P 11305-A + 5-HTP Saline o CGP22364-A
631+ 51 137± 23 ~ 395 ± 125 ~ 672+127 469 + 145 702+ 94 365 ± 52 ~"
i, Counts on Animex; mean ± S.D. b Peak time for effect on nociception T45, Animex counts: Tms-Ts p " Peak time for effect on nociception T(,0, Animex counts: T+,0-T(,6. a Peak time for effect on nociception Ti5 , Animex counts: TIs-T21. c p < 0.01 vs. respective control.
11305-A was effective at doses lower than those effective in the tail-flick test. Figure 4 shows that in the hot-plate test also doses of CGP 11305-A and 5-HTP (left panel) or C1M (right panel) that were ineffective alone, induced a significant increase of nociceptive thresholds when administered together. In contrast, the association of CGP 22364-A and the serotoninergic drugs did not elicit any effect (data not shown). Table 1 shows that the treatment with the highest dose of CGP-11305-A, or the combination of the reversible monoamine oxidase-A inhibitors and serotoninergic agents at doses effective in the tail-flick test did not modify tail temperature. Table 2 shows that the two reversible monoamine oxidase-A inhibitors alone at the dose of 40 mg/kg, or in combination with serotoninergic agents, decreased spontaneous locomotor activity.
\
l,
2O
Counts ~'
,L_I
/
/
Treatment
\
4. Discussion
U 0
0
+ +1
+0
4,%
60
75)
90
]5
~0
45
60
7O
90
'rime (min) Fig. 4. Effect of the association of ineffective doses of CGP-11305-A (10 m g / k g ) with an ineffective dose of 5-hydroxytryptophan (5-HTP, 25 m g / k g ) (left panel), or with an ineffective dose of chlorimipramine (CIM, 10 m g / k g ) (right panel) on nociceptive threshold in the rat on the hot-plate. The values are means+_S.D. * P < 0,01 vs. 5 - H T P or CIM.
Our data do not support the hypothesis that, in spite of the minimal increase in serotoninergic tone induced by reversible monoamine oxidase-A inhibitors, these drugs might be as efficacious as tricyclic antidepressants on nociception. In fact, only CGP 11305-A, that at the dose of 60 and 80 m g / k g combined reversible monoamine oxidase-A inhibitor and serotonin reup-
TABLE 1 Effect of C G P 11305-A alone or associated with 5-hydroxytryptophan or chlorimipramine on tail-skin temperatures. CGP = CGP11305-A; 5-HTP = 5-hydroxytryptophan; CIM = Chlorimipramine. Treatment
Before treatment
CGP 11305-A CGP + 5-HTP C G P + CIM
26.6± 1.0 a.b 24.8 + 0.7 26. l ± 1.1
~' Mean ± S.D. b R o o m temperature = 24°C,
TlS
T3 u
-1-45
T611
26.7±1.1 25.4+0.9 26.9±1.0
26.7±1.4 26.0±1.1 25.7±0.9
26.3±1.0 25.8±1.0
27.0±1.5 24.9±0.7 25.3±0.8
26.8±1.2
Tv5 26.2+0.9 25.5±0.9 26.4±1.0
116
take inhibitory effects, was capable of increasing the nociceptive threshold in the tail-flick test. In the same test, CGP 11305-A when administered together with the serotonin precursor 5-HTP or the tricyclic antidepressants CIM induced an increase in nociceptive threshold at doses at which both drugs were ineffective. Since tail temperature was not affected by the treatments, we conclude that the effect elicited by CGP 11305-A is a true analgesic effect. This does not hold for the effect of CGP 11305-A and C G P 22364-A on hot-plate latency. In fact, it appears clear from the results of the Animex test that both drugs, either alone or in combination with serotoninergic agents, induce a drastic decrease in spontaneous Locomotor activity. It can be concluded that reversible monoamine oxidase-A inhibitors do not elicit a sufficient increase of serotonin to be good candidates as analgesic drugs when used alone, at least after acute administration. In fact, the pure reversible monoamine oxidase-A inhibitors 22364-A is ineffective, while CGP 11305-A, that also blocks serotonin reuptake, is effective only at high doses. However, C G P 11305-A might still be a useful drug in pain therapy since low doses of this reversible monoamine oxidase-A inhibitor allow the administration of lower than commonly used doses of other drugs that increase the serotoninergic tone, such as 5-HTP or tricyclic antidepressants, and so reduce some of their typical side effects. Finally, the association of C G P 11305-A with drugs that induce an increased or sustained release of sero-
tonin, such as fenfluramine or reserpine, might be worth further investigation. References Civeira, J., S. Cervera, J. Giner, S.R. Alcln. K. ttcllstern, 11. Malanowski, R. Wirz and K. Klar, 1990, Moclobcmidc versus clomipramine in the treatment of depression: a multiccntrc study in Spain, Acta Neurol. Stand. 82, 48s. Eide, P.K. and A. Tjolsen, 1988, Effect of serotonin receptor antagonists and agonists on the tail-flick response in mice involve altered tail-skin temperature, Neuropharmacology 27, 889. Panerai, A.E., G. Monza, P. Movilia, M. Bianchi, B.M. Francucci and M. Tiengo, 1990, A randomized, within patient, cross-over. placebo-controlled trial on the efficacy and tolcrability of the tricyclic antidepressants chlorimipramine and nortryptilinc in central pain. Acta Neurol. Scand, 82, 34, Sacerdote, P., A. Brini, P, Mantegazza and A.E. Panerai, 1987, A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs, Pharmacol. Biochcm. Behav. 26, 153. Tiengo, M., B. Pagnoni, A. Calmi, M. Rigoli, P.C. Braga and A.E. Panerai, 1987, Clomipramine compared with pentazocinc as unique treatment in postoperative pain, Int. J. Clin. Pharmacol. Res. 7, 141. Ventafridda, V., M. Bianchi, C. Ripamonti, P. Sacerdote, F. l)e Conno. E. Zecca and A.E. Panerai, 1990, Studies on the effects of the antidepressant drugs on the antinociceptive action of morphine and plasma morphine in rat and mare Pain 43, 155. Versiani, M., A.E. Nardi, I.L.V. Figueira and M. Stabl, It,~90, Tolcrability of moclobemide, a new reversible inhibitor of monoamine oxidase-A, compared with other antidepressants and placebo, Acta Neurol. Scand. 82, 24s. Waldmeier, P.C. and K. Stocklin, 1989, The reversible M A O inhibitor, CGP 11305-A, inhibits serotonin uptake in viw~, Eur. J. Pharmacol. 169, 197.
113
f~ 1992 Elsevier Science Publishers B.V. All rights reserved 1)014-2999/92/$05.00
EJP 52575
Effects of two different reversible monoamine oxidase-A inhibitors on nociceptive thresholds in the rat M a u r o Bianchi, P a o l o M a n t e g a z z a a n d A l b e r t o E. P a n e r a i Department of Pharmacology, Unit~ersityof Milano, Via Vant~itelli32, 20129 Milano, Italy Received 4 March 1992, revised MS received 12 May 1992, accepted 19 May 1992
The acute effect of two different reversible inhibitors of monoamine oxidase-A on nociceptive thresholds was evaluated in the rat by the tail-flick and hot-plate tests. CGP 11305-A, a monoamine oxidase-A inhibitor that also blocks serotonin reuptake, elicited an increase of latency in the tail-flick and the hot-plate test. Ineffective doses of CGP 11305-A increased nociceptive thresholds when administered in combination with other serotoninergic agents, i.e. chlorimipramine or 5-hydroxytryptophan, at doses that were ineffective alone. CGP 22364-A, a pure inhibitor of monoamine oxidase-A, increased latency only in the hot-plate test. Both compounds decreased spontaneous locomotor activity at the doses effective in the hot-plate test, suggesting that the responses observed in this test are not related to a pure effect on nociceptive thresholds. The data suggest that the increase in serotonin availability induced by monoamine oxidase-A inhibition alone is not sufficient to affect nociceptive thresholds. Monoamine oxidase-A inhibitors; Nociception; Tail-flick test; Hot-plate test; 5-HT (5-hydroxytryptamine, serotonin)
1. Introduction There is increasing, recent clinical and experimental evidence in support of an important role for tricyclic antidepressant drugs in pain therapy. These drugs are effective in post-operative, cancer and neuropathic or stump pain (Tiengo et al., 1987; Ventafridda et al., 1990; Panerai et al., 1990). The most consistent results, both in clinical and animal experiments, were obtained with tricyclic antidepressants that potentiate the serotoninergic system, and this evidence was confirmed by the increase in nociceptive thresholds observed with the serotonin precursor 5-hydroxytryptophan (5-HTP) (Sacerdote et al., 1987). However, the use of tricyclic antidepressants is accompanied, especially in elderly patients, by severe side effects e.g. constipation, urinary retention, and dry mouth, that limit their use. Moreover, in non-depressed subjects, tricyclic antidepressants might also induce somnolence and mental confusion. Most recently, the new specific and reversible inhibitors of monoamine oxidase-A became available for psychiatric therapy, and seem to be as
Correspondence to: A.E. Panerai, Department of Pharmacology, University of Milano, Via Vanvitelli 32, 20129, Milano, Italy. Tel. 39.2.719 750, fax 39.2.730 470.
effective as some tricyclic antidepressants such as chlorimipramine (Civeira et al., 1990). Moreover, in psychiatric clinical trials, reversible monoamine oxidase-A inhibitors seem to provoke much fewer side effects than tricyclic antidepressants, expecially in the elderly (Versiani et al., 1990). The mechanism of action of reversible monoamine oxidase-A inhibitors resembles that of tricyclic antidepressants since they cause an increase in serotonin availability through the inhibition of its catabolism. Since serotonin is well known to play a pivotal role in the control of pain, we thought of investigating whether reversible monoamine oxidase-A inhibitors could, alone or in association with other serotoninergic agents, modify nociceptive thresholds. Moreover, we wanted to investigate whether, as reversible monoamine oxidaseA inhibitors and tricyclic antidepressants are apparently equally effective in depressive disorders, the increase in serotonin induced by the inhibition of monoamine oxidase-A activity was also sufficient to increase nociceptive thresholds. It is well known, in fact, that monoaminoxidases have only a minor role in the catabolism of biologic amines. For this reason, if reversible monoamine oxidase-A inhibitors were also effective on nociceptive thresholds, it would mean that minimal changes in the serotoninergic tone are sufficient to modulate pain.
114
2. Materials and methods
S p r a g u e - D a w l e y CD male rats, eight in each group, were used in all experiments. The rats, 200-250 g body weight, were housed for at least one week before the experiments at 22°C with a light: dark cycle of 14:10 h, with food and water ad libitum. All experiments were conducted in the morning, beginning at 09:00-09:30 h. We used C G P 11305-A ( ( 7 - B r - 5 - m e t h o x y - 2 benzofuryl)-piperidine; brofaromine, Ciba-Geigy, Origgio, Italy), a reversible monoamine oxidase-A inhibitor that, at doses 10 time higher than those effective on monoamine oxidase-A, also induces the inhibition of serotonin, but not of noradrenaline reuptake (Waldmeier et al., 1989), and CGP 22364-A (l-[l(phenyl)ethyl]-2-methyl-imidazol; Ciba-Geigy, Origgio, Italy), another reversible monoamine oxidase-A inhibitor, completely devoid of effects on serotonin or noradrenaline reuptake. Both drugs were administered alone at doses of 10, 20, 40, 60, 80 m g / k g , or at the dose of 10 m g / k g together with 5-HTP (Tript-OH, Sigma-Tam Pomezia, Italy) 25 m g / k g , or chlorimipramine (CIM) (Anafranil, Ciba-Geigy, Origgio, Italy) 10 m g / k g . All drugs were administered intraperitoneally (i.p.) immediately after measurement of basal tail-flick or hot-plate latency. Nociceptive thresholds had been measured by the tail-flick (the stimulus was a focussed light beam), and hot-plate (58°C) methods. The results are expressed as percentage of the maximal possible effect. Maximal possible effect expresses the equation [(TL-BL)/(ML-BL)] × 100, where BL is the mean basal latency (2.5-3.5 s for tail-flick, and 4.0-8.0 s for hot-plate) measured before the first treatment was applied; T L is the test latency measured after treatments; ML is the maximal latency accepted (8 s for tail-flick and 20 s for hot-plate), chosen in order to avoid tissue damage to the tail or the footpad respectively. The data were analyzed by means of the Kruskall-Wallis test and Dunnett's test for multiple comparisons. For the study of the effects of C G P 11305-A and 22364-A on spontaneous locomotor activity, the drugs were administered i.p. at the dose of 40 m g / k g (the minimum effective in the hot-plate test), and saline was administered to control rats. Rats were positioned in an Animex apparatus (L.K.B. Hagersten, Sweden), and locomotor activity was recorded over two consecutive periods of 3 min, at a time from drug administration corresponding to the maximal effect observed in the hot-plate test. The results were expressed as number of counts (movements of the animal), and evaluated statistically by means of Student's t-test. Since all the drugs used in the experiments, affecting the serotoninergic system, could modify the temperature of the tail, tail temperatures of rats treated with the highest dose of CGP 11305-A effective in the
lO0
~L
INl: --
-
80
2
I
60
\
I"
60
-
-
ilJ 'qG
I';
:ll
\11;
[,i;
I
*~ -
% HI'P
100
tO0
80
8O
+il
60
CGI'
CIM C(]P
1130,
60
2--
40
4O
/
,
/ c~
2O
k
11305/ A + CiM
+
/
c
- -
.... --
/ / \
I +
Saline b CGPII305-A CGP11305-A + CIM Saline~ CG P 11305-A + 5-HTP Saline o CGP22364-A
631+ 51 137± 23 ~ 395 ± 125 ~ 672+127 469 + 145 702+ 94 365 ± 52 ~"
i, Counts on Animex; mean ± S.D. b Peak time for effect on nociception T45, Animex counts: Tms-Ts p " Peak time for effect on nociception T(,0, Animex counts: T+,0-T(,6. a Peak time for effect on nociception Ti5 , Animex counts: TIs-T21. c p < 0.01 vs. respective control.
11305-A was effective at doses lower than those effective in the tail-flick test. Figure 4 shows that in the hot-plate test also doses of CGP 11305-A and 5-HTP (left panel) or C1M (right panel) that were ineffective alone, induced a significant increase of nociceptive thresholds when administered together. In contrast, the association of CGP 22364-A and the serotoninergic drugs did not elicit any effect (data not shown). Table 1 shows that the treatment with the highest dose of CGP-11305-A, or the combination of the reversible monoamine oxidase-A inhibitors and serotoninergic agents at doses effective in the tail-flick test did not modify tail temperature. Table 2 shows that the two reversible monoamine oxidase-A inhibitors alone at the dose of 40 mg/kg, or in combination with serotoninergic agents, decreased spontaneous locomotor activity.
\
l,
2O
Counts ~'
,L_I
/
/
Treatment
\
4. Discussion
U 0
0
+ +1
+0
4,%
60
75)
90
]5
~0
45
60
7O
90
'rime (min) Fig. 4. Effect of the association of ineffective doses of CGP-11305-A (10 m g / k g ) with an ineffective dose of 5-hydroxytryptophan (5-HTP, 25 m g / k g ) (left panel), or with an ineffective dose of chlorimipramine (CIM, 10 m g / k g ) (right panel) on nociceptive threshold in the rat on the hot-plate. The values are means+_S.D. * P < 0,01 vs. 5 - H T P or CIM.
Our data do not support the hypothesis that, in spite of the minimal increase in serotoninergic tone induced by reversible monoamine oxidase-A inhibitors, these drugs might be as efficacious as tricyclic antidepressants on nociception. In fact, only CGP 11305-A, that at the dose of 60 and 80 m g / k g combined reversible monoamine oxidase-A inhibitor and serotonin reup-
TABLE 1 Effect of C G P 11305-A alone or associated with 5-hydroxytryptophan or chlorimipramine on tail-skin temperatures. CGP = CGP11305-A; 5-HTP = 5-hydroxytryptophan; CIM = Chlorimipramine. Treatment
Before treatment
CGP 11305-A CGP + 5-HTP C G P + CIM
26.6± 1.0 a.b 24.8 + 0.7 26. l ± 1.1
~' Mean ± S.D. b R o o m temperature = 24°C,
TlS
T3 u
-1-45
T611
26.7±1.1 25.4+0.9 26.9±1.0
26.7±1.4 26.0±1.1 25.7±0.9
26.3±1.0 25.8±1.0
27.0±1.5 24.9±0.7 25.3±0.8
26.8±1.2
Tv5 26.2+0.9 25.5±0.9 26.4±1.0
116
take inhibitory effects, was capable of increasing the nociceptive threshold in the tail-flick test. In the same test, CGP 11305-A when administered together with the serotonin precursor 5-HTP or the tricyclic antidepressants CIM induced an increase in nociceptive threshold at doses at which both drugs were ineffective. Since tail temperature was not affected by the treatments, we conclude that the effect elicited by CGP 11305-A is a true analgesic effect. This does not hold for the effect of CGP 11305-A and C G P 22364-A on hot-plate latency. In fact, it appears clear from the results of the Animex test that both drugs, either alone or in combination with serotoninergic agents, induce a drastic decrease in spontaneous Locomotor activity. It can be concluded that reversible monoamine oxidase-A inhibitors do not elicit a sufficient increase of serotonin to be good candidates as analgesic drugs when used alone, at least after acute administration. In fact, the pure reversible monoamine oxidase-A inhibitors 22364-A is ineffective, while CGP 11305-A, that also blocks serotonin reuptake, is effective only at high doses. However, C G P 11305-A might still be a useful drug in pain therapy since low doses of this reversible monoamine oxidase-A inhibitor allow the administration of lower than commonly used doses of other drugs that increase the serotoninergic tone, such as 5-HTP or tricyclic antidepressants, and so reduce some of their typical side effects. Finally, the association of C G P 11305-A with drugs that induce an increased or sustained release of sero-
tonin, such as fenfluramine or reserpine, might be worth further investigation. References Civeira, J., S. Cervera, J. Giner, S.R. Alcln. K. ttcllstern, 11. Malanowski, R. Wirz and K. Klar, 1990, Moclobcmidc versus clomipramine in the treatment of depression: a multiccntrc study in Spain, Acta Neurol. Stand. 82, 48s. Eide, P.K. and A. Tjolsen, 1988, Effect of serotonin receptor antagonists and agonists on the tail-flick response in mice involve altered tail-skin temperature, Neuropharmacology 27, 889. Panerai, A.E., G. Monza, P. Movilia, M. Bianchi, B.M. Francucci and M. Tiengo, 1990, A randomized, within patient, cross-over. placebo-controlled trial on the efficacy and tolcrability of the tricyclic antidepressants chlorimipramine and nortryptilinc in central pain. Acta Neurol. Scand, 82, 34, Sacerdote, P., A. Brini, P, Mantegazza and A.E. Panerai, 1987, A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs, Pharmacol. Biochcm. Behav. 26, 153. Tiengo, M., B. Pagnoni, A. Calmi, M. Rigoli, P.C. Braga and A.E. Panerai, 1987, Clomipramine compared with pentazocinc as unique treatment in postoperative pain, Int. J. Clin. Pharmacol. Res. 7, 141. Ventafridda, V., M. Bianchi, C. Ripamonti, P. Sacerdote, F. l)e Conno. E. Zecca and A.E. Panerai, 1990, Studies on the effects of the antidepressant drugs on the antinociceptive action of morphine and plasma morphine in rat and mare Pain 43, 155. Versiani, M., A.E. Nardi, I.L.V. Figueira and M. Stabl, It,~90, Tolcrability of moclobemide, a new reversible inhibitor of monoamine oxidase-A, compared with other antidepressants and placebo, Acta Neurol. Scand. 82, 24s. Waldmeier, P.C. and K. Stocklin, 1989, The reversible M A O inhibitor, CGP 11305-A, inhibits serotonin uptake in viw~, Eur. J. Pharmacol. 169, 197.
