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Differential effect of pentazocine on primary cortical evoked potentials elicited by stimulation of the trigeminal tract and spinal cord pathways
European Journal of Pharmacology, 47 (1978) 465--467 © Elsevier/North-Holland Biomedical Press
465
Short communication DIFFERENTIAL EFFECT OF PENTAZOCINE ON PRIMARY CORTICAL EVOKED POTENTIALS ELICITED BY STIMULATION OF THE TRIGEMINAL TRACT AND SPINAL CORD PATHWAYS RUBEN SOTO-MOYANO, ALEJANDRO HERNANDEZ, SAMUEL RUIZ, HERNAN PEREZ and CARLOS PAEILE
Laboratorio de Neurofisiologfa y Bioffsica, Instituto de NutriciOn y Tecnologfa de los Alimentos, Universidad de Chile, Casilla 15138, Santiago 11, Chile Received 16 December 1977, accepted 20 December 1977
R. SOTO-MOYANO, A. HERNANDEZ, S. RUIZ, H. PEREZ and C. PAEILE, Differential effect ofpentazocine on primary cortical evoked potentials elicited by stimulation of the trigeminal tract and spinal cord pathways, European J. Pharmacol. 47 (1978) 465--467. The influence of pentazocine on primary cortical evoked potentials was studied in guinea pigs under pentobarbital anesthesia. P.entazocine (10 mg/kg, i.v.) increased the latency time of evoked responses to posterior limb stimulation, more than that of responses to lip stimulation. This result suggests that pentazocine decreases the velocity of nervous conduction. Pentazocine
Evoked potentials
Somesthetic cerebral cortex
1. Introduction Pentazocine (5 and 10 mg/kg, i.v.) increases significantly the latency time of the primary somesthetic cortical evoked responses elicited by electrical stimulation of the upper contralateral lip (Soto-Moyano et al., 1975). This effect of pentazocine, interpreted as a direct action on the primary trigeminal pain pathway (AS and C fibers of the trigeminal tract, bulbothalamic tract, thallamocortical fibers of primary protection), may be exerted either at the synaptic connections or on the fibers of the nervous tract. In this preliminary investigation the action of pentazocine on the primary pain spinal cord pathway (AS and C fibers of the sciatic nerve, neospinothalamic tract, thalamocortical fibers of primary projection) was studied and compared with the effect produced on the trigeminal tract. Both pathways have the same number of functionally similar synaptic steps but differ markedly in length. A comparison
of the changes in latency time induced by pentazocine in both pathways should provide better information about the levels where this action is exerted. 2. Materials and methods
Experiments were performed in 10 adult guinea pigs under sodium pentobarbital anesthesia (70mg/kg, i.p.), D-tubocurarine and artificial respiration. Animals weighed 400--500 g. The head was restrained in a Horsley--Clarke type stereotaxic apparatus and one cerebral hemi-cortex was exposed. The stimulus consisted of series of 10 rectangular electric shocks of 6 V, 0.4 msec and 0.25 Hz each, applied alternately to the contralateral posterior limb and to the contralateral upper lip through two stainless-steel needles, completely insulated except at their tips. Cortical evoked responses were recorded through a silver chloride electrode applied
466
R. SOTO-MOYANO ET AL.
directly to the SI area of the cerebral cortex corresponding to the posterior limb and the lip (Soto-Moyano and Kayser, 1973). Latency times were measured instantaneously with a digital latencymeter (Guillet, Kayser and Soto-Moyano, French Patent No. 7602524, 1976). The experimental group received 10 mg/kg of pentazocine by injection into the jugular vein. The mean latency time was measured before drug injection so that each animal served as its own control. It has been previously shown that the solvent used for pentazocine (lactic acid 1.2% and NaC1 0.28% in distilled water) does not modify the evoked potentials (Soto-Moyano et al., 1975). Results were expressed as variations (A) of the latency time of the evoked potentials with reference to the control measurement.
3. Results In agreement with previous reports (SotoMoyano et al., 1975), the latency time of the evoked cortical responses elicited by lip stimulation after pentazocine injection was increased (fig. 1 upper left). The evoked responses elicited by posterior limb stimulation after drug injection showed latency time increases even greater than those obtained by lip stimulation (fig. 1 upper right). Fig. 1 (lower) illustrates changes in the latency time of cortical evoked potentials elicited by limb and lip stimulation after pentazocine. The standard errors for each corresponding point in both curves show that there were significant differences in the effect of pentazocine in both neural pathways.
1
8
LiP LIMB
O----O
7,
,r- -¢
6,
/
5/
4+ 3
5
10
20
30
40
50
60
70
Fig. 1. Influence of pentazocine (10 mg/kg) on the latency time of primary cortical evoked potentials in guinea pigs. Upper left: Evoked responses elicited by lip stimulation. Upper right: Evoked responses elicited by posterior limb stimulation. 1 designates evoked potentials before pentazocine injection (control) and 2, evoked potentials after 10 mg/kg of pentazocine. Lower: Variation of latency (A, msec, ordinate) of evoked potentials elicited by lip (G ~,) and posterior limb (o . . . . . . o) stimulation after the i.v. injection of pentazocine. The S.E.M. for each point is shown by the vertical bars. p < 0,005 in relation to control (Student's t-test). Abscissa: time (rain).
PENTAZOCINE ON CORTICAL EVOKED POTENTIALS 4. Discussion This effect of pentazocine may, as mentioned above, be produced either at the synaptic connections of the primary pain pathway or on the fibers of the nervous tract. With respect to the first alternative, the drug may be acting directly on the synaptic relays or through the control mechanisms which regulate the afferent impulses at the level of the dorsal horn of the spinal cord (Hagbarth and Kerr, 1954) and its bulbar homologue (Hern~ndez--Pe6n and Hagbarth, 1955). Pentazocine may also act on the ventrobasal thalamic nuclei (Ogden, 1960) or on the cerebral cortex. However, the primary trigeminal pain pathway and the primary spinal cord pain pathway have the same number (Bowsher and Albe-Fessard, 1965) of functionally similar synaptic steps. Therefore, if the action of pentazocine were exerted at the synaptic level, no significant differences in latency time variations should be found. Our results may be interpreted as suggesting that pentazocine exerts its effect by decreasing the velocity of nervous conduction possibly through slowing of membrane depolarization or repolarization. Such a hypothesis would be consistent with the greater delay in the spinal cord pathway compared to the trigeminal, owing to greater length of the former. The hypothesis is further supported by the observation t h a t pentazocine induces bradycardia (Gavend and Gavend, 1969; SotoMoyano et al., 1975) and decreases the conduction velocity of action potentials in cardiac muscle (P~rez-Olea et al., 1976). As cell membranes of excitable tissues have similar functional characteristics, preliminary observations were carried out on isolated frog sciatic nerve and supported the hypothesis (Paeile and Molgo, 1976, unpublished observation). For these reasons, we suggest that the effect of pentazocine is not restricted to the pain conduction pathway. It must be clarified whether the drug acts preferentially on myelinated or on unmyelinated nerve fibers. In fact morphine, another central analgesic, reduces only the c o m p o u n d action potentials
467 of the A5 and C fibers (Jurna and Grossmann, 1977). If this were the case with pentazocine our interpretation should be different. However caution might be advisable in the analysis of these results, since a possible effect at the synaptic level cannot be totally dismissed. Hypoxia is excluded as a cause of these effects since pentazocine does not m o d i f y blood pCO2, pO2, oxygen saturation and pH (Soto-Moyano et al., 1975).
Acknowledgements We are grateful to Dr. O. Brunser for his help in the preparation of the manuscript. This work was supported by Grant No. 3237 from the University of Chile. References Bowsher, D. and D. Albe-Fessard, 1965, The anatomophysiological basis of somatosensory discrimination, Intern. Rev. Neurobiol. 8, 35. Gavend, M. and M.R. Gavend, 1969, Etude exp~rimentale de Faction de quelques analeptiques l'4gard de la d~pression respiratoire et cardiovasculaire provoqu~e par la pentazocine, Th~rapie 24,353. Hagbarth, K.E. and D.I.B. Kerr, 1954, Central influences on spinal afferent conduction, J. Neurophysiol. 17,295. Hern~ndez-Pe6n, R. and K.E. Hagbarth, 1955, Interaction between afferent and cortically induced reticular responses, J. Neurophysiol. 18, 44. Jurna, I. and W. Grossmann, 1977, The effect of morphine on mammalian nerve fiber, European J. Pharmacol. 44,339. Ogden, T.E., 1960, Cortical control of thalamic somato-sensory relay nuclei, Electroenceph. Clin. Neurophysiol. 12,621. P~rez-Olea, J., M. Quevedo and C. Paeile, 1976, Efecto depresor cardfaco de la pentazocina, Proc. VI Congreso Latinoamericano de Farmacologfa, Buenos Aires, p. 86. Soto-Moyano, R. and D. Kayser, 1973, Potentials ~voqu~s par la stimulation des l~vres et des gencives chez le cobaye, J. Physiol. (Paris) 66,447. Soto-Moyano, R., D. Kayser, Y. Grail, A. Hern~ndez, S. Ruiz and C. Paeile, 1975, Effect of pentazocine on the evoked potentials recorded in the primary somesthetic cortical areas of guinea pigs, Brain Res. 88,475.
465
Short communication DIFFERENTIAL EFFECT OF PENTAZOCINE ON PRIMARY CORTICAL EVOKED POTENTIALS ELICITED BY STIMULATION OF THE TRIGEMINAL TRACT AND SPINAL CORD PATHWAYS RUBEN SOTO-MOYANO, ALEJANDRO HERNANDEZ, SAMUEL RUIZ, HERNAN PEREZ and CARLOS PAEILE
Laboratorio de Neurofisiologfa y Bioffsica, Instituto de NutriciOn y Tecnologfa de los Alimentos, Universidad de Chile, Casilla 15138, Santiago 11, Chile Received 16 December 1977, accepted 20 December 1977
R. SOTO-MOYANO, A. HERNANDEZ, S. RUIZ, H. PEREZ and C. PAEILE, Differential effect ofpentazocine on primary cortical evoked potentials elicited by stimulation of the trigeminal tract and spinal cord pathways, European J. Pharmacol. 47 (1978) 465--467. The influence of pentazocine on primary cortical evoked potentials was studied in guinea pigs under pentobarbital anesthesia. P.entazocine (10 mg/kg, i.v.) increased the latency time of evoked responses to posterior limb stimulation, more than that of responses to lip stimulation. This result suggests that pentazocine decreases the velocity of nervous conduction. Pentazocine
Evoked potentials
Somesthetic cerebral cortex
1. Introduction Pentazocine (5 and 10 mg/kg, i.v.) increases significantly the latency time of the primary somesthetic cortical evoked responses elicited by electrical stimulation of the upper contralateral lip (Soto-Moyano et al., 1975). This effect of pentazocine, interpreted as a direct action on the primary trigeminal pain pathway (AS and C fibers of the trigeminal tract, bulbothalamic tract, thallamocortical fibers of primary protection), may be exerted either at the synaptic connections or on the fibers of the nervous tract. In this preliminary investigation the action of pentazocine on the primary pain spinal cord pathway (AS and C fibers of the sciatic nerve, neospinothalamic tract, thalamocortical fibers of primary projection) was studied and compared with the effect produced on the trigeminal tract. Both pathways have the same number of functionally similar synaptic steps but differ markedly in length. A comparison
of the changes in latency time induced by pentazocine in both pathways should provide better information about the levels where this action is exerted. 2. Materials and methods
Experiments were performed in 10 adult guinea pigs under sodium pentobarbital anesthesia (70mg/kg, i.p.), D-tubocurarine and artificial respiration. Animals weighed 400--500 g. The head was restrained in a Horsley--Clarke type stereotaxic apparatus and one cerebral hemi-cortex was exposed. The stimulus consisted of series of 10 rectangular electric shocks of 6 V, 0.4 msec and 0.25 Hz each, applied alternately to the contralateral posterior limb and to the contralateral upper lip through two stainless-steel needles, completely insulated except at their tips. Cortical evoked responses were recorded through a silver chloride electrode applied
466
R. SOTO-MOYANO ET AL.
directly to the SI area of the cerebral cortex corresponding to the posterior limb and the lip (Soto-Moyano and Kayser, 1973). Latency times were measured instantaneously with a digital latencymeter (Guillet, Kayser and Soto-Moyano, French Patent No. 7602524, 1976). The experimental group received 10 mg/kg of pentazocine by injection into the jugular vein. The mean latency time was measured before drug injection so that each animal served as its own control. It has been previously shown that the solvent used for pentazocine (lactic acid 1.2% and NaC1 0.28% in distilled water) does not modify the evoked potentials (Soto-Moyano et al., 1975). Results were expressed as variations (A) of the latency time of the evoked potentials with reference to the control measurement.
3. Results In agreement with previous reports (SotoMoyano et al., 1975), the latency time of the evoked cortical responses elicited by lip stimulation after pentazocine injection was increased (fig. 1 upper left). The evoked responses elicited by posterior limb stimulation after drug injection showed latency time increases even greater than those obtained by lip stimulation (fig. 1 upper right). Fig. 1 (lower) illustrates changes in the latency time of cortical evoked potentials elicited by limb and lip stimulation after pentazocine. The standard errors for each corresponding point in both curves show that there were significant differences in the effect of pentazocine in both neural pathways.
1
8
LiP LIMB
O----O
7,
,r- -¢
6,
/
5/
4+ 3
5
10
20
30
40
50
60
70
Fig. 1. Influence of pentazocine (10 mg/kg) on the latency time of primary cortical evoked potentials in guinea pigs. Upper left: Evoked responses elicited by lip stimulation. Upper right: Evoked responses elicited by posterior limb stimulation. 1 designates evoked potentials before pentazocine injection (control) and 2, evoked potentials after 10 mg/kg of pentazocine. Lower: Variation of latency (A, msec, ordinate) of evoked potentials elicited by lip (G ~,) and posterior limb (o . . . . . . o) stimulation after the i.v. injection of pentazocine. The S.E.M. for each point is shown by the vertical bars. p < 0,005 in relation to control (Student's t-test). Abscissa: time (rain).
PENTAZOCINE ON CORTICAL EVOKED POTENTIALS 4. Discussion This effect of pentazocine may, as mentioned above, be produced either at the synaptic connections of the primary pain pathway or on the fibers of the nervous tract. With respect to the first alternative, the drug may be acting directly on the synaptic relays or through the control mechanisms which regulate the afferent impulses at the level of the dorsal horn of the spinal cord (Hagbarth and Kerr, 1954) and its bulbar homologue (Hern~ndez--Pe6n and Hagbarth, 1955). Pentazocine may also act on the ventrobasal thalamic nuclei (Ogden, 1960) or on the cerebral cortex. However, the primary trigeminal pain pathway and the primary spinal cord pain pathway have the same number (Bowsher and Albe-Fessard, 1965) of functionally similar synaptic steps. Therefore, if the action of pentazocine were exerted at the synaptic level, no significant differences in latency time variations should be found. Our results may be interpreted as suggesting that pentazocine exerts its effect by decreasing the velocity of nervous conduction possibly through slowing of membrane depolarization or repolarization. Such a hypothesis would be consistent with the greater delay in the spinal cord pathway compared to the trigeminal, owing to greater length of the former. The hypothesis is further supported by the observation t h a t pentazocine induces bradycardia (Gavend and Gavend, 1969; SotoMoyano et al., 1975) and decreases the conduction velocity of action potentials in cardiac muscle (P~rez-Olea et al., 1976). As cell membranes of excitable tissues have similar functional characteristics, preliminary observations were carried out on isolated frog sciatic nerve and supported the hypothesis (Paeile and Molgo, 1976, unpublished observation). For these reasons, we suggest that the effect of pentazocine is not restricted to the pain conduction pathway. It must be clarified whether the drug acts preferentially on myelinated or on unmyelinated nerve fibers. In fact morphine, another central analgesic, reduces only the c o m p o u n d action potentials
467 of the A5 and C fibers (Jurna and Grossmann, 1977). If this were the case with pentazocine our interpretation should be different. However caution might be advisable in the analysis of these results, since a possible effect at the synaptic level cannot be totally dismissed. Hypoxia is excluded as a cause of these effects since pentazocine does not m o d i f y blood pCO2, pO2, oxygen saturation and pH (Soto-Moyano et al., 1975).
Acknowledgements We are grateful to Dr. O. Brunser for his help in the preparation of the manuscript. This work was supported by Grant No. 3237 from the University of Chile. References Bowsher, D. and D. Albe-Fessard, 1965, The anatomophysiological basis of somatosensory discrimination, Intern. Rev. Neurobiol. 8, 35. Gavend, M. and M.R. Gavend, 1969, Etude exp~rimentale de Faction de quelques analeptiques l'4gard de la d~pression respiratoire et cardiovasculaire provoqu~e par la pentazocine, Th~rapie 24,353. Hagbarth, K.E. and D.I.B. Kerr, 1954, Central influences on spinal afferent conduction, J. Neurophysiol. 17,295. Hern~ndez-Pe6n, R. and K.E. Hagbarth, 1955, Interaction between afferent and cortically induced reticular responses, J. Neurophysiol. 18, 44. Jurna, I. and W. Grossmann, 1977, The effect of morphine on mammalian nerve fiber, European J. Pharmacol. 44,339. Ogden, T.E., 1960, Cortical control of thalamic somato-sensory relay nuclei, Electroenceph. Clin. Neurophysiol. 12,621. P~rez-Olea, J., M. Quevedo and C. Paeile, 1976, Efecto depresor cardfaco de la pentazocina, Proc. VI Congreso Latinoamericano de Farmacologfa, Buenos Aires, p. 86. Soto-Moyano, R. and D. Kayser, 1973, Potentials ~voqu~s par la stimulation des l~vres et des gencives chez le cobaye, J. Physiol. (Paris) 66,447. Soto-Moyano, R., D. Kayser, Y. Grail, A. Hern~ndez, S. Ruiz and C. Paeile, 1975, Effect of pentazocine on the evoked potentials recorded in the primary somesthetic cortical areas of guinea pigs, Brain Res. 88,475.