Exp. Brain Res. 24, 473---484 (1976) Experimental Brain Research

�9 by Springer-Verlag 1976

The Effect of Morphine on the Activity Evoked in Ventrolateral Tract Axons of the Cat Spinal Cord*

I. Ju rna and W. Grossmann Institut ffir Pharmakologie und Toxikologie der Universit~t des Saarlandes, Homburg/Saar (I~RG)

Summary. The effect of morphine on the activity in ventrolateral t ract axons was studied in intercollicularly decerebrate cats with and without spinal section. Activity was elicited by electrical stimulation of At- and C-fibres in the sural nerves. In spinal animals, morphine injected intravenously in a dose as low as 0.5 mg/kg reduced the post-stimulus discharge of impulses recorded in ventrolateral t ract axons below the site of transection. The depression was not only abolished but reversed by levallorphan and naloxone. Pretreatment with reserpine did not diminish the effect of morphine. The effect of morphine was considerably weaker in deccrebrate cats. Reversible block of the spinal cord produced by cold revealed that morphine reduced inhibition from the brain stem controlling the impulse transmission to ventrolateral t ract axons.

I t is concluded tha t a spinal effect contributes to the analgesic action of morphine.

Key words: Ventrolateral t ract axons - - Morphine - - Morphine antagonists - - Analgesia.

Introduction

Noxious stimuli applied to the skin give rise to activity in A5 (Zotterman, 1939; Burgess and Perl, 1967; Perl, 1968) as well as in C afferents (Iggo, 1959, 1960; Hansel et al., 1960; Iriuchijima and Zotterman, 1960; Witt, 1962; Bessou and Perl, 1969; Van IIees and Gybels, 1972), activity which is associated with pain reception. Recently, Pomeranz (1973) demonstrated tha t electrical stimulation of small diameter afferents (A& or C) in skin nerves evokes activity in axons of the ventrolateral t ract of the cat spinal cord, as does applying noxious stimuli to the skin, and it was suggested that these axons are specifically nociceptive and involv- ed in the process of pain perception.

In a previous investigation (Grossmann and Jurna, 1974) the activity evoked in ventrolateral t ract axons in spinal eats by electrical stimulation of A& fibres

* This investigation was supported by the Sonderforschungsbereich 38 "Membranen" and the Stiftung Volkswagenwerk. The authors are indebted to Dr. l~erster of Endo Laboratories, :Brussels, for the generous supply of naloxone.

474 I. Jurna and W. Grossmann

in the sural nerve was depressed by an in t ravenous inject ion of morphine in a dose as low as 0.5 mg/kg. This pointed to a spinal site of action involved in the analgesic effect of morphine. I n the present s tudy the n u m b e r of axons ac t ivated by s t imula t ion of A6 afferents and t3sted under the influence of morphine was extended, and the effect of the drug was also assessed on ventrolateral t rac t axons act ivated by C fibre s t imulat ion. I n this connection, two problems deserved par t icular interest. One is tha t of a par t ic ipat ion of monoamines in the effect of morphine at the spinal level, and this has been studied by pre t reat ing the pre- parat ions with reserpine. The other concerns the quest ion as to whether morphine depresses sensory impulse t ransmiss ion in the spinal cord by ac t iva t ing inhib i tory pa thways descending from the lower medul la oblongata (Satoh and Takagi, 1971). As will be shown, the spinal depressant effect of morphine on the ac t iv i ty in ventrolateral t rac t axons is not directly dependent on changes of the mono- amine content in the spinal cord bu t may be modula ted by an act ion of the drug on supraspinal eentres.

Methods

The experiments were performed on 19 cats (2.0 3.3 kg body weight) operated under halo- thane anesthesia and decerebrated at the intercollicular level. The spinal cord was exposed from Th n to L~ for the recording of activity from axons in the ventrolateral tract; 9 animals were spinalized at the level of Th10, and in 5 the spinal cord was additionally exposed from Th 7 to Thlo for reversible spinalization by cooling the spinal cord. In the latter experiments, two separate pools of paraffin oil were formed covering the spinal card. The rural nerves were isolated over a length of 8--10 era, mounted on pairs of recording and stimulation electrodes and cut distal to the site of stimulation. After completion of the surgical procedures anesthesia ceased, and the preparations were immobilized with gallamine triethiodide and artificially respired. The temperature in the rectum and of the paraffin oil covering the lumbar and (when not cooled) the thoracic spinal cord, and the rural nerves was maintained between ~7 ~ and 38 ~ In order to produce spinal block, water at 4 ~ was perfused through a thin polyethylene tube coiled around the thoracic spinal cord and, in addition, the warm oil was exchanged for oil of a temperature of 10--12 ~ Blood-pressure was recorded in one of the carotid arteries; the mean pressure ranged from 120 to 180 mm gg. Drugs were injected by a cannula inserted into one of the jugular veins.

The rural nerves were stimulated electrically with a pair of platinum wire electrodes. Stimulation was performed either with single rectangular pulses or with trains of 300 pulses/see and 10--20 msec duration. The duration of the rectangular pulses was 0.05 msee and the repeti- tion rate of the single pulses or pulse trains 0.25 tIz. Compound action potentials were recorded with bipolar platinum wire electrodes placed at a distance of 6--8 cm proximal from the stimulating electrodes. Potentials cf axons in the ventrolateral tract were recorded from the left side at the level of L1--L s with steel electrodes (tip diameter 1 #m; resistance 5--10 M~2) connected to an electrometer (W-P Instruments Model M-4AI~M), and were amplified, dis- played on a cathode ray oscilloscope and evaluated with an averaging computer (Fabri-Tek 1062; the number of computer addresses used was 512 or 1024) after having been stored on tape (Philips Aria-Log 7).

The experiments were not started until 1 hr had passed after discontinuing the anesthesia. When the effect of morphine on the activity of an axon had been tested, current (500--600 nA for 15--30 see) was passed through the electrGde and the tip position determined histologically by Prussian blue staining. The localization of l~he points recorded from when testing the effect of morphine is presented in :Fig. 2C.

The drugs used were halothane (~luothane | l~hein-Pharma, Heidelberg), gallamine triethiodide (l~laxedil | Boehringer, Ingelheim/t~hein, morphine hydroehloride (Merck,

Morphine and Ventrolateral Tract Axons 475

Darmstadt), levallorphan tartrate (Lorfan | Hoffmann-La Roche, Grenzach/Baden), nal- oxone hydrochloride (Narcan | Endo Laboratories, Brussels) and reserpine (Sedaraupin | Boehringer, Mannheim).

Results

Compound Action Potentials

The threshold for the sural nerve fibres giving rise to the early component of the compound action potential was 0.15--0.4 V; the thresholds for A5 and C fibres ranged between 1.3--1.5 V and 6--8 V, respectively. The conduction velocity of A3 and C fibres in the sural nerve was determined by measuring the lateneies between the stimulus artifact and the peak of the respective compound action potentials. The conduction velocity of A5 fibres in 19 preparations was 21.7 +_ 3.0 m/see (mean value ~ standard deviation) and that of the C fibres 1.26_+ 0.24 m/see./Viorphine (0.5 and 2 mg/kg) injected intravenously did not influence the compound action potentials.

Activity o/ Ventrolateral Tract Axons in Spinal Preparations

In 9 preparations recordings were obtained from 12 axons in the lei~ ventrolaterM tract activated by contra- or ipsilateral stimulation of A5 and C fibres in the sural nerves. The latency of impulss discharges following AS-afferent stimulation was 13.3_+8.4 msec (mean value -/- standard deviation; 6 units activated by contra- lateral and 1 by ipsilateral stimulation), a value in accord with the latencies determined by Pomeranz (i973). The latency after C fibre stimulation was 121.1 + 51.3 msec (3 units activated by contralateral and 2 by ipsilateral stimu- lation). Trains of pulses produced a stronger activation than did single stimuli (rig'. 1). Morphine. Morphine in doses of 0.5 and 2 mg/kg reduced the number of impulses discharged by ventrolateral tract axons on stimulation of Ac~ and C fibres with either single or trains of pulses (Fig. 1B and D). There was no difference in the effect of morphine on the activity elicited by stimulation of A5 or C fibres, or by ipsi- or contralateral activation. The curves in Fig. 2A present the mean values (per cent of controls) of the impulse discharges following single and repetitive stimuli after the administration of both doses of morphine, irrespective of from where the activity was evoked. Twenty rain after the injection of morphine 0.5 mg/kg the number of impulses evoked by single stimuli was reduced by 50.3 _+ 25.1 ~ of the control, and that following repetitive stimulation was reduced by 41.1 • 17.4 (6 determinations made in each group; 3 units activated by contra- lateral A5 fibre stimulation, 2 by contralateral and 1 by ipsilateral C fibre stimu- lation). At the same interval after administration, morphine 2 mg/kg reduced the activity following single stimuli by 53.3_+ 20.6, and that following repetitive~ stimuli by 58.3_+ 17.7~o of the control (6 determinations made in each group;: 3 units activated by eontralaterM and 1 by ipsilateral A5 fibre stimulation;

476 I. Jurna and W. Grossmann

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Fig. 1. Effect of morphine and naloxone on impulse discharge evoked in axons of the ventro- lateral tract by contralateral sural nerve stimulation in two spinal cats. Activation was pro- duced with single (upper row in each set of recordings) and repetitive (lower row) stimuli. The activity in A and B was elicibed by stimulation with a strength 1.6 times threshold for A~ fibres and that in C and D by stimulation with a strength 4.2 times threshold for C fibres. The upper tracings in each recording of A and C present the activity recorded from axons in the ventrolateral tract, the lower tracings the compound action potentials recorded from the sural nerve. Time calibration (horizontal bars) (A) 20 msec and (C) 100 msee; voltage cali- bration (vertical bars) in upper tracings of A and C, 100 pV and in lower tracings, 500 pV. (B) Post-stimulus histograms of impulses discharged by the unit in A, and D that of the unit in C before drug administration and after morphine (0.5 mg/kg) and naloxone (NALOX., 0.05 mg/kg). Each histogram in B and D is the result of 12 consecutive responses; the vertical scales on the right give the number of counts stored in each address of the computer memory (the number of computer addresses was 1024), the horizontal scales the time (sec) after the single stimulus or the last stimulus of the stimulus train. Note the different calibration of counts in B. The numbers on top of each recording indicate the time in min after drug injection at which the histograms were recorded

1 un i t each ac t ivated by eontra- and ipsilateral C fibre st imulation). I t is evident tha t morphine did not exert a significantly stronger effect after the high t h a n

after the low dose. Morphine 0.5 mg/kg produced only min imal changes, if any, in blood-pressure.

After the admin is t ra t ion of 2 mg/kg a fall in the mean blood-pressure of 10--20 m m t Ig was observed which lasted 2---5 min.

Morphine and Ventrolateral Tract Axons 477

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Fig. 2. Effect of morphine on the impulse activity of ventrolateral tract axons evoked by sural nerve stimulation. The curves in A and B give the mean values of the change in the number of impulses discharged to contra and ipsilateral Ag and C fibre stimulation with single and repetitive pulses induced by morphine and morphine antagonists as a per cent of the control discharges (Ordinates). (A) Spinal preparations. Abscissa: time in rain after the injection of morphine (0.5 and 2 mg/kg) and after the injection ofnaloxone (0.05 mg/kg) and levallorphan (0.2 mg/kg). Each point on the curves presents the mean value of 6 determinations (open and filled circles, open and filled triangles). (B) Spinal preparations, control values 30 rain after the injection of reserpine (6--7 mg/kg). Abscissa: time in rain after the injection of morphine (0.5 mg/kg) and naloxone (0.05 mg/kg). Each point on the curves presents the mean value of 4: determinations. The arrows in A and ]3 indicate the moment of drug injection. (C) Locali- zation of points recorded from when testing the effect of morphine

Morphine Antagonists. When the morphine antagonis ts leval lorphan and naloxone were injected after the effect of morphine had fully developed, the depression of the ac t iv i ty in ventrolateral t rac t axons was abolished and ~he ac t iv i ty even in- creased beyond the control level (Fig. 1B and D, Fig. 2A). I n three exper iments

478 I. Jurna and W. Grossmann

levallorphan 0.2 mg/kg, and in two naloxonc 0.05 mg/kg injected before morphine did not influence the activity of ventrolateral tract axons. Monoamine Depletion. To test whether the depressant effect of morphine depends on unimpaired monoaminergic impulse transmission in the spinal cord, reserpine (6--7 mg/kg) was injected intravenously to 4 preparations, after a testing injection of morphine. At the time when morphine was tested again (30 rain after reserpine), the mean blood-pressure had fallen to 100--110 mm Hg, a marked bradycardia was present, and the monoamine content in the central nervous system was presumably considerably reduced (Carlsson, 1966).

Figure 2B presents the mean changes in the number of impulse discharges produced by morphine 0.5 mg/kg and naloxone 0.05 mg/kg in the four experiments after pretrcatment with reserpine. At 15 min after the injection of morphine the activity of the ventrolateral tract axons following single stimuli was reduced by 59.5+9.0, and that following repetitive stimulation was reduced by 87.3 +-7.8% of the control number of impulses discharged (4 determinations made in each group ; 1 unit each activated by contra- and ipsilateral A~ and r fibre stimulation). There was no significant difference between the mean values following activation by single stimuli 20 min after morphine without reserpine, and 15 min after mor- phine and pretreatment with reserpine, whereas the reduction in the number of impulses discharged to repetitive stimulation was significantly greater after pre- t reatment with reserpine (p<0.005, Student's t-test) than in its absence. After pretreatment with reserpine the mean values of the number of impulses discharged to repetitive stimulation 15 min after morphine was also significantly more re- duced than that following single stimuli (p<0.01 ; Fig. 2B). Thus, reserpinization of the preparations appeared to potentiate the depressant effect of morphine on the activity elicited by repetitive stimulation.

Naloxone administered after reserpine and morphine increased the number of impulse discharges beyond the control level (Fig. 2B).

Activity o] Ventrolateral Tract Axons in Decerebrate Preparations

The effect of morphine on the activity in ventrolateral tract axons was studied in 5 intercollieularly decerebrate preparations in which the spinal cord remained intact. I t proved difficult to determine the latency of the impulse discharge evoked by A5 and C fibre stimulation because of relatively large variations in the responses.

Morphine (0.5 and 2 mg/kg) produced no clear effect on the impulse activity in ventrolateral tract axons. In 8 of 11 units tested the post-stimulus activity was reduced, and in 3 units it was increased. This resulted in a large scattering of the individual values. Thus, in contrast to experiments performed in spinal pre- parations, it was unpredictable whether morphine depressed or increased the activity in ventrolateral tract axons of the decerebrate cat.

Activity in Decerebrate Preparations with Cold Block o/the Spinal Cord

The striking difference in the effect of morphine on the activity of ventrolateral tract axons in spinal and dccerebrate preparations suggests that the drug not only affects impulse transmission from A5 and C fibres to the neurones of the ascending

~Iorphine and Ventrolatera] Tract Axons 479

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Fig'. 3. Effect of morphine and spinal block on the impulse discharge in a ventrolatera] tract axon evoked by sara] nerve stimulation. The activity was recorded at L 1 without (warmed cord) and during spinal block produced by cooling the cord at the level of ThT--Thz0 (cooled cord). Activation was produced with single (upper two rows of histograms) and repetitive (lower two rows of histograms) stimuli. The activity was evoked by contralateral stimulation with a strength 2.2 times threshold for Aft fibres. Twelve consecutive responses each were stored after stimulation. The vertical scale gives the number of counts stored in each address of the computer memory (the number of computer addresses was 512) and the horizontal scale the time (see) after the single stimulus or the last stimulus of the train. The numbers on top of each histogram indicate the time in rain after drug injection at which the responses were recorded

pathway under study, but also influences the the activity of neurones in the brain stem controlling ascending impulse activity via descending pathways (Hagbarth and Kerr, 1954; Taub, 1964; Wall, 1967; Brown, 1971). Reversible spinal block produced by cold in decerebrate cats has revealed that the brain stem inhibits the responses of dorsal horn cells to cutaneous stimuli (Wall, 1967) and those in the spinocervical tract to noxious stimuli (Brown, 1971). I t might well be that ventrolateral tract neurones are also subject to descending inhibition, and that morphine by depressing this inhibition releases the activity in the ascending axons and thus counteracts its inhibitory effect on spinal impulse transmission. To test this hypothesis experiments were performed in which reversible spinalization was produced by applying cold to the cord cranial to the recording site.

I t was found that during cold block the activity in some ventrolateral tract axons was higher, and that in others lower than before cooling the thoracic spinal cord. This indicates that inhibitory as well as facilitatory influences from the braizl stem control the impulse transmission to ventrolatera] tract axons. Since it has been proposed that the inhibitory effect of small doses of morphine on spinal sensory transmission is mainly due to a stimulant effect of the drug on descending inhibitory influences from the lower brain stem (Satoh and Takagi, 1971), parti- cular interest was directed to axons showing increased activity when the spinal cord was cooled. These experiments on fibres selected according to release from

33 Exp. Brain 1%es. Vol. 24

480 I. Jurna and W. Grossmann

inhibition by reversible spinal block were performed oll 8 axons (3 activated by contralat~ral and 2 activated by ipsilateral A~ afferent stimulation; 3 activated by eontralateral C afferent stimulation) in 5 preparations. Figure 3 exemplifies the result obtained.

Relatively little activity was evoked in the ventrolateral tract axon by stimu- lation with single pulses and trains of pulses (Fig'. 3, warmed cord). During cooling of the spinal cord, the impulse activity following single and r.ep3titive stimuli was markedly increased (Fig. 3, cooled cord). Morphine 0.5 mg/kg reduced the post- stimulus impulse discharge during spinal block (4--5 and 9--10 rain as well as 5--6 and 10--11 rain after the injection), as it regularly did in preparations with the spinal cord transeeted. Warming the spinal cord did not further depress the activity, as might have been expected from an activation of descending inhibition, but increased it (warmed cord, 14--15 and 19--20 rain as well as 15--16 and 20--21 rain after the injection). This result is similar to that obtained by cooling the thoracic spinal cord before the administration of morphine and suggests that descending inhibition is depressed by morphine. The release by morphine from descending inhibition of the activity in the axons must be even stronger than it appears in the histograms, because morphine inhibits simultaneously impulse transmission from cutaneous afferents (Fig. 3, cooled cord). I t should be recalled that, in contrast to the experiments performed on dee.~rebrate preparations without reversible spinal block, this series of experiments wa~ carried out on select- ed axons. This accounts for the difference in the results obtained, i.e. for the con- sistent increase of activity in the axons inhibited from the brain stem and released by cold block, and for the depression predominantly observed after morphine in non-selected axons (eL preceding section).

NMoxone (0.05 mg/kg) injected immediately after the responses from 20--2I min aider morphine had been recorded increased the post-stimulus activity during cold block beyond the level of activity before the administration of morphine (Fig. 3, cooled cord). However, it reduced the number of impulse discharges when the spinal cord was warmed. Actually, in Fig. 3 (warmed cord) the response to repetitive stimuli after naloxone was less than before morphine. I t seems, there- fore, that naloxone reverses the depressant effect of morphine not only on spinal impulse transmission but also on descending inhibition so that eventually the latter prevails.

Two axons activated by eontralateral Aft fibre stimulation, and found to be less active during cold block of the spinal cord, showed a reduced post-stimulus activity after the administration of morphine. The number of impulses discharged after morphine was practically the same when the thoracic spinal cord was cooled or warmed, which indicates that morphine depressed the descending facilitation of the axons. This result excludes the possibility that the increased activity in ventrolateral tract axons after morphine in the non-spinal decerebrate prepara- tion (Fig. 3, warmed cord) is due to an activation of descending facilitation. I t Mso suggests that the experiments on deeerebrate preparations without spinal block (ef. preceding section), in which morphine reduced the activity of 8 axons and increased that of 3, were p~rformed on 8 axons controlled by descending facilitation.

morphine and Ventrolatera] Tract Axons ~81

Discussion

Applying noxious stimuli to the skin as well as electrical stimulation of Ac~ and C fibres evokes activity in ipsi- and contralateral specific nociceptive axons ascend- ing in the ventrolateral tract of the cat spinal cord (Pomeranz, 1973). Morphine in a dose as low as 0.5 mg/kg depressed the activity evoked in such axons not only by contralateral (Grossmann and Jurna, 1974) but also by ipsilateral Ac~ fibre stimulation. Moreover, the drug reduced the number of impulse discharges in axons exclusively activated by ipsi- and contralateral C fibre stimulation. The high dose tested (2 mg/kg) did not produce a stronger effect than the low dose (0.5 mg/kg), which is very near that employed in medical practice to produce analgesia in humans (10 rag/70 kg) and below the one currently administered in mammals to inhibit nocieeptive reflexes (2 mg/kg). A similar high sensitivity to low doses of morphine of responses evoked by stimulation of small diameter afferents has been reported by Koll et al. (1963). Since morphine exerts a depres- sant action in spinal preparations, it seems justified to assume that the analgesic effect of the drug implies a spinal site of action. Such conclusion may also be reached from the observation (Le Bars et al., 1974) that morphine decreas3d the activity of interneurones in lamina V (Rexed, 1964~) of the spinal cord dorsal horn, which are involved in the transmission of impulses elicited by painful stimuli (Liebeskind et al., 1973; Oliveras et al., 1974=).

Morphine caused less depression of the activity in ventrolateral tract axons in intereollicularly decerebrate preparations with an intact spinal cord than in spinal animals. This result is in accord with the observation of Le Bars et al. (1974) made with lamina V cells, who ascribed the weaker effect of morphine to the presence of a strong inhibition of the cells in the decerebrate non-spinal cat. Actually, morphine even increased the post-stimulus activity in ventrolateral tract axons as did cold block applied to the spinal cord above the site of recording. This is contrary to what might have been expected if morphine enhanced descending inhibitory influences on spinal sensory transmission (Satoh and Takagi, 1971). Such action has been proposed on account of the finding that morphine exerted a weaker effect in spinal than in decerebrate preparations on the potentials evoked in the ventrolateral tract by splanchnic nerve stimulation. One explanation for the discrepancy in the results may be that these latter authors performed their study on a potential of relatively short duration built up by more than one unit, whereas in the present exp?riments measurements were carried out on the im- pulses discharged by single units during a longer period after stimulation. More- over, it is very likely that the pentothal anesthesia employed in most of those experiments changed the function of the pathways involved in pain perception in a fundamental way. Depression by morphine of descending inhibitory and facili- ta tory influences evoked by repetitive stimulation of adequate brain stem areas was observed when recording the impulse discharge from muscle spindle afferents (Jurna, 1966), and likewise bulbospinal inhibition of monosynaptie reflex activity is reduced by morphine (Sinclair, 1973). On account of the present results it must be assumed that the depressant effect of morphine on the impulse trans- mission from cutaneous afferents to ventrolateral tract axons is counteracted by a depressant effect on inhibition descending from the brain stem and controlling the spinal impulse transmission.

33*

482 I. Jurna and W. Grossmann

In spinal animals, both morphine antagonists levallorphan and naloxone not only antagonized the depressant effect of morphine but increased the post- stimulus activity beyond that recorded before the administration of morphine. This might have been due to an excitatory effect of the morphine antagonists (Jacob et al., 1974), but no significant increase in the ventrolateral t ract activity was observed when the drugs were administered before an injection of morphine had been made. t~eversal of the depressant effect of morphine on the inhibition descending from the brain stem may also account for the result that naloxone given after morphine to decerebrate preparations with a warm thoracic spinal cord reduced the activity increased by morphine.

Pretreatment with reserpine did not diminish the effect of morphine on the activity in ventrolateral tract axons in spinal animals. The effect of morphine develop?d somewhat more slowly, but the depression of the activity following rep~lAtive stimulation was even enhanced. I f it is assumed that reserpine in the dose used produced a considerable lowering of the concentration of monoamines in the central nervous system in the interval between its administration and the injection of morphine and naloxone, i.e. within 30--45 min (Carlsson, 1966), and that impulse transmission in monoaminergic synapses depends on an intact monoamine incorporation into the storage granules (And6n, I968), monoamines do not seem to play a primary role in the depressant effect of morphine on the impulse transmission to ventrolateral tract axons in spinal eats. On account of the disappearance of the anti-noeieeptive effect of morphine observed in numerous investigations after central monoamine depletion (for a survey of the literature cf. Grossmann e$ al., 1973; Vogt, 1974) it has been proposed that the analgesic effect of morphine is dependent on or mediated by central monoamines. Ob- viously, the importa:~ce of monoamines for the analgesia following the administra- tion of morphine in intact animMs must be sought with pathways other than that investigated in the present experiments.

The activity in ventrolateral tract axons was not blocked by morphine in the spinal preparation but only reduced to about one half of the control activity. This suggests that morphine must act on supraspinal ccntres as well to produce 'complete' analgesia. On account of their results obtained with intraventricular injections of small doses of morphine, tIerz and coworkers (Herz et al., 1970; Albus et aI., 1970 ; Tcschemaeher et al., 1973 ; Vigouret et al., 1973) proposed that the effects on reactions (including pain) elicited by noxious stimuli are mediated by structures adjacent to the fourth ventricle.

From the results presented it may be concluded that a depressant effect of morphine on nociceptive spinal impulse transmission participates in the analgesic action of morphine and that this effect is modulated by descending activity also influenced by morphine.

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Morphine and Ventrolateral Tract Axons 483

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Received October 13, 1975

Prof. Dr. I. Jurna Institut ffir Pharmakologie und Toxikologie der Universit~t des Saarlandes D-6650 Homburg/Soar Federal Republic of Germany