Download The effect of morphine on the activity evoked in

Exp. Brain Res. 24, 473---484 (1976)
Experimental
Brain
Research
9 by Springer-Verlag1976
The Effect of Morphine on the Activity Evoked in Ventrolateral
Tract Axons of the Cat Spinal Cord*
I. J u r n a 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 tract 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. I n 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 tract 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 tract axons.
I t is concluded t h a t a spinal effect contributes to the analgesic action of
morphine.
Key words: Ventrolateral tract 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 t h a t electrical stimulation
of small diameter afferents (A& or C) in skin nerves evokes activity in axons of the
ventrolateral tract of the cat spinal cord, as does applying noxious stimuli to the
skin, and it was suggested that these axons are specifically nociceptive and involved in the process of pain perception.
I n a previous investigation (Grossmann and Jurna, 1974) the activity evoked
in ventrolateral tract 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 n e r v e was depressed b y a n i n t r a v e n o u s injection of m o r p h i n e in a
dose as low as 0.5 mg/kg. This p o i n t e d to a spinal site of action i n v o l v e d i n the
analgesic effect of morphine. I n t h e present s t u d y t h e n u m b e r of axons a c t i v a t e d
b y s t i m u l a t i o n of A6 afferents a n d t3sted u n d e r the influence of m o r p h i n e was
extended, a n d the effect of t h e drug was also assessed on v e n t r o l a t e r a l t r a c t
axons a c t i v a t e d b y C fibre s t i m u l a t i o n . I n this connection, two problems deserved
p a r t i c u l a r interest. One is t h a t of a p a r t i c i p a t i o n of m o n o a m i n e s in the effect of
m o r p h i n e at t h e spinal level, a n d this has been studied b y p r e t r e a t i n g the prep a r a t i o n s with reserpine. The other concerns the question as to whether m o r p h i n e
depresses sensory impulse t r a n s m i s s i o n in the spinal cord b y a c t i v a t i n g i n h i b i t o r y
p a t h w a y s descending from t h e lower m e d u l l a oblongata (Satoh a n d Takagi,
1971). As will be shown, t h e spinal depressant effect of m o r p h i n e on the a c t i v i t y
in v e n t r o l a t e r a l t r a c t axons is n o t directly d e p e n d e n t on changes of the monoa m i n e c o n t e n t in t h e spinal cord b u t m a y be m o d u l a t e d b y a n action of the drug
on s u p r a s p i n a l eentres.
Methods
The experiments were performed on 19 cats (2.0 3.3 kg body weight) operated under halothane 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 repetition 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, displayed 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~hepoints 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), naloxone 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 contralateral 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 stimulation). 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 contralateral A5 fibre stimulation, 2 by contralateral and 1 by ipsilateral C fibre stimulation). 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
A
B
NALOX. counts
MORPHINE
single
stimulus
repefiffve
5-6 20-21
~l~
6-7 21-22
stimuli
__
III
....... L
.......
0
0
215
sec
D
O
MORPHINE
•-5
singlestimulus
repetitive
100
stimuli
L
9-10
NALOX.
5-6 I0-11~
k_k
counts
115
o
215sec
Fig. 1. Effect of morphine and naloxone on impulse discharge evoked in axons of the ventrolateral tract by contralateral sural nerve stimulation in two spinal cats. Activation was produced 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 calibration (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 u n i t each a c t i v a t e d b y eontra- a n d ipsilateral C fibre stimulation). I t is e v i d e n t
t h a t m o r p h i n e did not exert a significantly stronger effect after t h e high t h a n
after t h e low dose.
Morphine 0.5 mg/kg produced only m i n i m a l changes, if any, in blood-pressure.
After the a d m i n i s t r a t i o n of 2 mg/kg a fall in t h e m e a n blood-pressure of 10--20 m m
t I g was observed which lasted 2---5 min.
Morphine and Ventrolateral Tract Axons
A
[3
S PINAL
O/o
$
40
=5
477
%
t
o
SPINAL, AFTER RESERPINE
/
~00-
80-
I
,,I
I
~
/
40u
"0
o
u
-80
I
I
I
I
0
5
20
30
E
V-]
0
,
5 m~n
c
antagonist
morphine
0
9
single stimulus
repetitive stimuli
morphine 2 mg/kg ,
and Iorfan 0.2 mg/l<g
~.
9
single stimulus
repetitive stimuli
morphine 0.5mg/kg and
naloxone 0-05 mg/kg
0
activated by stimulation of
9 A5-fibres
contralateral
" C-f~bres
9
AS-fibres
0
C-fibres
5
morphine
15
0
5 m~n
naloxone
9
single stimulus
9
repetitive stimuli
ipsilateral
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) Localization of points recorded from when testing the effect of morphine
Morphine Antagonists. W h e n the m o r p h i n e a n t a g o n i s t s levallorphan a n d n a l o x o n e
were i n j e c t e d after the effect of m o r p h i n e h a d fully developed, the depression of
the a c t i v i t y in ventrolateral t r a c t axons was abolished a n d ~he a c t i v i t y even increased b e y o n d the control level (Fig. 1B a n d D, Fig. 2A). I n three e x p e r i m e n t s
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 morphine and pretreatment with reserpine, whereas the reduction in the number of
impulses discharged to repetitive stimulation was significantly greater after pretreatment 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 reduced 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. It proved difficult to determine the latency of the impulse discharge evoked
b y 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 preparations, 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
MORPHINE
NALOXONE 0 . 0 5 m g / k g
0.5 m g / k g
responseto
slnDle
stimulus
warmed
cord
479
114-15
19-20:
,i.,,[,,,, . , ,~L, ,,
4-5
L~
4-5
""
' II1~
9 -10
9-t0
cooled
cord
response to
repetitive
stimuli
wormed
cord
t5-16
20-21
5-6
~
5-6
10-11
counts
cord
o
F-o
f
1.25 sec
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), particular 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 stimulation 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 poststimulus 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). It 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 selected axons. This accounts for the difference in the results obtained, i.e. for the consistent 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. It seems, therefore, 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 preparation (Fig. 3, warmed cord) is due to an activation of descending facilitation. It
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 ascending 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 depressant 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 impulses discharged by single units during a longer period after stimulation. Moreover, 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 facilitatory 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 transmission 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 poststimulus 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 tract 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. If 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. Obviously, the importa:~ce of monoamines for the analgesia following the administration 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.
l~eferences
Albus, K., Schott, M., tterz, A. : Interaction between morphine and morphine antagonists
after systemic and intraventricular application. Europ. J. Pharmacol. 12, 53--64 (1970)
And6n, N.-E. : Effect of reserpine and other drugs on the monoaraine metabolism with special
reference to the CNS. Ann. Med. exp. l%nn. 46, 361--366 (1968)
Morphine and Ventrolateral Tract Axons
483
Bessou, P., Perl, E. R. : Response of cutaneous sensory units with myelinated fibers to noxious
stimuli. J. Neurophysioh 32, 1025-1043 (1969)
Brown, A.G. : Effects of descending impulses on transmission through the spinoeervical tract.
J. Physiol. (Lond.) 219, 103--125 (1971)
Burgess, P. 1~., Perl, E. 1~. : Myelinated afferent fibres responding specifically to noxious stimulation of the skin. J. Physiol. (Lond.) 190, 541--562 (1967)
Carlsson, A. : Drugs which block the stgrage of 5-hydroxytryptamine and related amines.
In: Handbook of Experimental Pharmacology, Vol. 19, pp. 529--592. Berlin-HeidelbergNew York: Springer 1966
Grossmann, W., Jurna, I. : Depression by morphine of activity in the ventrolateral tract
evoked from cutaneous A-fibres. Europ. J. Pharmaeol. 29, 171--174 (1974)
Grossmann, W., Jurna, I., Nell, T., Theres, C. : The dependence of the anti-noeiceptive effect
of morphine and other analgesic agents on spinal motor activity after central monoamine
depletion. Europ. J. Pharmacol. 24, 67--77 (1973)
I-Iagbarth, K.-E., Kerr, D.I.B. : Central influences on spinal afferent conduction. J. Neurophysiol. 17, 295--307 (1954)
Hensel, H., Iggo, A., Witt, I. : A quantitative study of sensitive cutaneous thermoreeeptors
with C afferent fibres. J. Physiol. (Lond.) 153, 113--126 (1960)
Herz, A., Albus, K., Mety~, J., Schubert, P., Teschemacher, Hi. : On the central sites for the
antinoeiceptive action of morphine and fentany]. Neuropharmacol. 9, 539--551 (1970)
Iggo, A. : Cutaneous heat and cold receptors with slowly conducting (C) afferent fibres. Quart.
J. exp. Physiol. 44, 362--370 (1959)
Iggo, A. : Cutaneous mechanoreceptors with afferent C-fibres. J. Physiol. (Lond.) 152, 337--353
(1960)
Iriuchijima, J., Zo~terman, Y. : The specificity of afferent cutaneous C-fibres in mammals.
Acta physiol, scand. 49, 267--278 (1960)
Jacob, J.J., Tremblay, E.C., Colombel, M.-C. : Facilitation de r~actions nociceptives par la
naloxone chez la souris e~ chez le rat. Psychopharmaeologia (Berl.) a7, 217--223 (1974)
Jurna, I. : Inhibition of the effect of repetitive stimulation on spinal motoneurones of the cat by
morphine and pethidine. NeuropharmaecJ. 5, 117--123 (1966)
Koli, W., Haase, J., Block, G., Mfihlberg, B. : The predilective action of small doses of morphine
on noeieeptive spinal reflexes of low spinal cats. Neuropharmacol. 2, 57--65 (1963)
Le Bars, B., Mdndtrey, D., Conseiller, C., Besson, J.M.: Effects of morphine on lamina V
cells in the cat dorsal horn: comparison between spinal and decerebrate preparations. J.
Pharmaeol. (Paris) 5, Suppl. 2, 58 (1974)
Liebeskind, J.C., Guilbaud, G., Besson, J.M., Oliveras, J.L.: Analgesia from electrical
stimulation of the periaqueduc~al gray matter in the cat: behavioural observations and
inhibitory effects on spinal cord interneurons. Brain Res. 50, 4 4 1 ~ 4 6 (1973)
Oliveras, J.L., Besson, J.M., Guilbaud, G., Liebeskind, J.C. : Behavioural and electrophysiological evidence of pain inhibition from midbrain stimulation in the cat. Exp. Brain Res.
20, 3 2 4 4 (1974)
Perl, E.R. : Myelinatcd afferent fibres innervating the primate skin and their response to
noxious stinmli. J. Physiol. (Lond.) 197, 593--615 (1968)
Pomeranz, B. : Specific nocieeptive fibers projecting from spinal cord neurons to the brain: a
possible pathway for pain. Brain Res. 50, 447~451 (1973)
gexed, B. : Some aspects of the cytoarchitectonies and synaptology of the spinal ccrd. Progr.
Brain Res. 11, 58--90 (1966)
Satoh, M., Takagi, H. : Enhancement by morphine of the central descending inhibitory influence on spinal sensory transmission. Europ. J. Pharmaeol. 14, 60--65 (1971)
Sinclair, J.G. : ~{orphine and meperidine on bulbospinal inhibition of the mcnosynaptic
reflex. Europ. J. Pharmacol. 21, 111--114 (1973)
Taub, A. : Local, segmental and supraspinal interaction with a dorsolateral spinal cutaneous
afferent system. Exp. Neurol. 10, 357--374 (1966)
Teschemacher, Hj., Schubert, P., FIerz, A. : Autoradiographic studies concerning the supraspinal site of the aninoeiceptive action of morphine when inhibiting the hindleg flexor
reflex in rabbits. Neuropharmacol. 12, 123--131 (1973)
484
I. Jurna and W. Grossmann
Van Hees, J., Gybels, J.M. : Pain related to single afferent C fibres from human skin. Brain
Res. 48, 397~400 (1972)
Vigourct, J., Teschemacher, Itj., Albus, K., Herz, A. : Differentiation between spinal and
supraspinal sites of action of morphine when inhibiting the hindleg flexor reflex in rabbits.
Neuropharmacol. 12, 111--121 (1973)
Vogt, M. : The effect of lowering the 5-hydroxytryptamine content of the rat spinal cord on
analgesia produced by morphine. J. Physiol. (Lond.) 236,483~498 (1974)
Wall, P.I). : The laminar organization of dorsal horn and effects of descending impulses. J.
Physiol. (Loud.) 188,403--423 (1967)
Witt, I. : Aktivitgt einzelner C-Fasern bei sehmerzhaften und nieht sehmerzhaften Hautreizen. Acta neuroveg. (Wien) 24, 208--219 (1962)
Zotterman, u : Touch, pain and tickling: an eleetrophysiologieal investigation on cutaneous
sensory nerves. J. Physiol. (Lond.) 95, 1--28 (1939)
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