MILTON AND SABINE WENDLANDT

J. Physiol. (1971), 218, pp. 325-336 325
With 3 text-ftgurem
Printed in Great Britain
EFFECTS ON BODY
TEMPERATURE OF PROSTAGLANDINS OF THE A, E AND F
SERIES ON INJECTION INTO THE THIRD VENTRICLE OF
UNANAESTHETIZED CATS AND RABBITS
BY A. S. MILTON AND SABINE WENDLANDT
From the Department of Pharmacology,
The School of Pharmacy, University of London,
29/39 Brunswick Square, London WC1N lAX
(Received 19 April 1971)
SUAMMVARY
1. Prostaglandins were injected into the third ventricle of unanaesthetized
cats and rabbits whilst rectal temperature was recorded.
2. In cats prostaglandin E1 and E2 (PGE1 and PGE2) produced hyperthermia
which mostly began within a minute of injection and lasted
1 or more hours. With PGE1 the hyperthermia was shown to be dose
dependent between 10 ng and 10 ,tg (2.8 x 10-11 and 2.8 x 10- M). The
hyperthermia was associated with vigorous shivering, skin vasoconstriction
and piloerection. In several experiments a secondary rise in
temperature occurred a few hours after the injection but such an effect
was sometimes observed with control injections of 0-9 % NaCl solution
as well.
3. None of the other prostaglandins (A1, F1,, F2X) examined in cats had
an immediate or strong effect on temperature comparable to the hyperthermia
produced by PGE1 and PGE2.
4. In rabbits PGE1 (2fg) also caused hyperthermia which began
shortly after the injection and lasted for hours. PGF2a and PGA1, did not
affect temperature.
5. In cats it was seen that an intraperitoneal injection of 4-acetamidophenol
(paracetamol 50 mg/kg) did not affect the initial strong hyperthermia
produced by PGE1 and PGE2 but abolished the secondary rise.
6. The possibility is discussed that PGE1 plays a role as a central transmitter
or modulator in temperature regulation.

326
A. S. MILTON AND S. WENDLANDT
INTRODUCTION
The results of the present experiments show that the prostaglandin
E1 (PGE1) and E2 (PGE2) exert a strong hyperthermic effect when injected
in minute amounts into the third cerebral ventricle of the
unanaesthetized cat and rabbit.
Prostaglandins have been shown to be natural constituents of the central
nervous system of various species including cats and rabbits (Samuelsson,
1964; Coceani & Wolfe, 1965; Ambache, Brummer, Rose & Whiting,
1966; Horton & Main, 1967a). The distribution of the E and F series of
prostaglandins has been investigated in the central nervous system of the
dog by Holmes & Horton (1968 a), who found them not only in the cerebral
cortex, cerebrum and spinal cord, but also in those parts of the brain which
line the cerebral ventricles such as the hippocampus, caudate nucleus and
hypothalamus. They appear to be released from these structures into the
perfused cerebral ventricular system as shown in anaesthetized cats
(Feldberg & Myers, 1966) and dogs (Holmes, 1970). According to Holmes
the concentration of the E series of prostaglandins increases fourfold on
perfusion with 5-hydroxytryptamine. Prostaglandins were also detected
in superfusate from the cerebral and cerebellar cortex (Ramwell & Shaw,
1966; Wolfe, Coceani & Pace-Asciak, 1967).
No definite physiological function has so far been attributed to the
prostaglandins in the central nervous system but they have been shown
to modulate nerve cell activity (Avanzino, Bradley & Wolstencroft, 1966;
Hoffer, Siggins & Bloom, 1969; Kaplan, Grega & Buckley, 1968; Duda,
Horton & McPherson, 1968; Phillis & Tebecis, 1968) and to alter animal
behaviour, to produce signs of sedation, stupor and catatonia in cats, to
antagonize electrical and leptazol induced convulsions in rats and to
affect muscle tone and reflex activity in various species (for references see
Horton, 1968). The results of the present experiments suggest that PGE1
and PGE2 by their hyperthermic actions may play a role in temperature
regulation and that this may be one of their physiological functions in the
hypothalamus.
METHODS
Cats and Dutch rabbits of either sex weighing between 2-5 and 3-5 kg were used.
Cannulation of third ventricle. The cats were anaesthetized with pentobarbitone
sodium (40 mg/kg i.P.). The head of the cat was held in a stereotaxic apparatus, the
eardrums being protected by rubber caps fitted onto the earbars. Under aseptic
conditions, a hole 1-5 mm in diameter was drilled through the bone in the midline
and 12-5 mm anterior to the interaural line. A stainless-steel guide cannula (20-gauge
needle tubing) with a rubber-capped cannula head was lowered through the hole in
the skull to 6 mm above the interaural line. This placed the guide cannula in the

PROSTAGLANDINS AND BODY TEMPERATURE 327
third ventricle at the level of the anterior hypothalamus. The co-ordinates were
taken from the stereotaxic atlas of the cat brain by Snider & Niemer (1961).
The rabbits were anaesthetized with paraldehyde (1-5 ml./kg i.P.) and a rubbercapped
cannula similar to that used in the cat was implanted into the third
ventricle 7-5 mm posterior to the coronal suture and to a depth of 13-5 mm from the
surface of the skull.
Correct implantation of the cannula in both cat and rabbit was apparent by the
pulsatile flow of c.s.f. from a needle inserted into the rubber cap of the cannula.
Once flow was established the cannula was fixed to the bone with acrylic cement
anchored by two stainless-steel screws screwed into the skull. Benzyl-penicillin
powder was sprinkled on to the wound and 2000 units were injected intramuscularly
daily for 3 days. The cannula and cannula holder were heat sterilized and flushed
with pyrogen-free saline before implantation. The animals were allowed to recover
for at least a week before being used for experiments.
Temperature measurement. The experiments were performed at an ambient temperature
of 20-22° C unless otherwise stated. The cats moved about freely in the
cage while the rabbits were restrained in a rabbit holder. Temperature was
measured with a thermistor probe (Yellow Springs 400) inserted about 8 cm into
the rectum and held in position with adhesive tape. Temperature was monitored
continuously by a Honeywell multi-channel chart recorder. The temperature responses
were plotted on graph paper with time (1 cm = 1 hr) as abscissa, and temperature
change (2 cm = 10 C) as ordinate. The number of cm2 between the curve
and the base line was counted and divided by two, to give a thermal response index
(TRI). Each unit of TRI is equivalent therefore to a 1° C change lasting for 1 hr.
Administration of drugs. Solutions were injected into the third ventricle via a
polyethylene tube attached to a cannula made of 27-gauge stainless-steel needle
tubing. Both tube and cannula were filled with the solution and the cannula was
passed through the rubber diaphragm of the previously implanted guide cannula.
A flange around the inner cannula prevented it from extending more than 1-0 mm
beyond the tip of the outer guide cannula. A control injection of 5 ,I. pyrogen-free
0-9 % NaCl solution was given 1-2 hr before each prostaglandin injection. The
prostaglandins were injected in a volume of 5 or 10 Al. Immediately after the injection
the cannula was flushed with 5 Id. sterile 0 9 % NaCl solution.
In several experiments in which the effect of Paracetamol (4-acetamidophenol;
4-Ac) on the hyperthermia produced by PGE1 and PGE2 was examined it was
injected I.P. in a dose of 50 mg/kg. The 4-Ac was dissolved in 2-0 ml of hot 0-9 % NaCl
solution containing 20 % propylene glycol and, before injection, made up with
0 9 % NaCl solution to 4 ml. A similar volume of propylene glycol saline containing
no 4-Ac was used for control injections.
Preparation of pyrogen-free prostaglandin solutions. Stock solutions of the prostaglandins
in methanol were stored at - 150 C. A sterile solution suitable for
intraventricular injection was prepared from the stock solution by the following
procedure. The methanol was evaporated using a rotary evaporator with a water bath
temperature of 400 C. The pure prostaglandin residue was dissolved in sterile pyrogen-free
0 9 % NaCl solution and passed through a GS 0-22 ,m 'Millipore' filter before
injection. The 'Millipore' filter was sufficiently fine to remove any particulate matter
including bacteria. The filtered solution was stored at - 150 C until required, and
was thawed and warmed to room temperature before injection. All glassware and
the 'Millipore' filter unit were autoclaved before use.

328
A. S. MILTON AND S. WENDLANDT
RESULTS
Cats
PGE1. As shown in Table 1, the injection, at room temperature (20-
220 C), of PGE1 in doses between 10 ng and 10 ,sg produced a dose dependent
rise in temperature. Temperature began to rise after a latent period
which was independent of the dose and varied between 30 sec and 3 min
(mean of twelve experiments 1 min). On the other hand, the time at which
the maximum rise was attained and the duration of the rise were dose
dependent as shown in columns 6 and 7 of Table 1. The threshold dose
&
+2
E +1
U
C
C
lOng 100 ng 1 0 Ig
0 1 2 3 4 5 0 1 2 3 4 5
Hours Hours
(day 1) (day 5)
Fig. 1. Rectal temperature of the unanaesthetized cat. At the arrows
injections into the third ventricle of PGE1 in the doses as indicated. The
first two injections were made on the same day, the third injection 5 days
later.
was about 10 ng (2-8 x 10-11 M). Fig. 1 illustrates the effect of this dose and
of two larger ones on the same cat. The rise produced by 10 ng was
0. 30 C, by 100 ng 1.10 C and by 1 fig, given 5 days later, 20 C.
The rises were associated with skin vasoconstriction as evidenced by the
coldness of the ears, nose and paws, and by shivering. It was vigorous and
widespread after the larger doses of PGE1. As the temperature reached its
maximum, shivering decreased and finally ceased. With doses of 1 and
10ong piloerection occurred regularly during the vigorous shivering; with
smaller doses piloerection was not regularly observed. After 1 and 10 FuZg
the vigorously shivering cat was usually sitting quietly in the cage with
the head lowered, the eyes closed and the forepaws tucked under the body.
In this condition, some cats responded to touch and external stimuli,

No. of
expts.
3
3
2 3
PROSTAGLANDINS AND BODY TEMPERATURE 329
others were unresponsive and appeared stuporous, but there were no
definite signs of catatonia. In a few cats defaecation and diarrhoea were
observed. Ear twitching was a frequent occurrence with all doses injected.
Sometimes a secondary rise in temperature occurred. It developed
gradually either before or after the temperature had returned to the preinjection
level, reached its maximum after about 5 hr and lasted up to
11 hr. During this rise, shivering reappeared and the cat sat in the cage
with eyes closed in a manner similar to that observed during a fever produced
by an intraventricular injection of 5-HT or bacterial pyrogen.
A late rise was sometimes observed also with control injections of saline
solution.
TABLE 1. Temperature response (mean values) in the unanaesthetized cat to
intraventricular injection of PGE1. TRI (thermal response index)
Dose of
PGE1
(#g)
0-01
0-10
0-50
1-00
la^ 1%
4-Ac
50 mg/kg
I.P.
1 IUIUU -
1 0-20 Injected 30 min
before PGE1
2 1-00 Injected 90min
before PGE1
1 1-00 Injected 30 min
after PGE1
1 10-00 Injected 30 min
before PGE1
1 10-00 Injected 50 min
after PGE1
2 050 -
Time Dura-
Latency Max. to max. tion of
of temp. temp. temp. temp.
response increase increase response
(min) (0C) (min) (min)
1-2 0.4 17 80
1-3 0-9 38 100
0-5 1-3 50 165
1-0 1-6 50 205
0-5 2-0 55 300
0-5 1.0 55 200
TRI
0-5
1-6
2-2
3-2
5-9
2-0
Ambient
temp.
20-22° C
20-22° C
20-22° C
20-22° C
20-22° C
20-22° C
3-0 1-8 45 180 3.5 20-220 C
0-5 2-8 40 230 5.9 20-220 C
0-5 3-0 40 330 9-0 20-220 C
0-5 2-5 55 270 6-4 20-220 C
2-0 1.1 85 205 2-3 360C
In two experiments, 0-5 ,ug PGE1 was injected while the cats were kept
at an ambient temperature of 360C; they showed the behavioural responses
characteristic of heat dissipation, such as fur licking, lying on the
side with legs outstretched and panting. Nevertheless, the injections produced
a rise in temperature of about the same extent as in the experiments
carried out at room temperature, but the rise developed more
gradually and shivering was much weaker. The results of these two
experiments are included in Table 1 (bottom line).
As shown in Table 1, an I.P. injection of 4-Ac, 50 mg/kg, did not reduce
the immediate hyperthermic effects produced by intraventricular injec-

330 A. S. MILTON AND S. WENDLANDT
tion of 0*2-10 ,tg PGE1 whether this antipyretic drug was given before or
after PGE1. In fact, the hyperthermias induced by PGE1 appeared to be
accentuated. For instance, in the experiment of Fig. 2, 4-Ac was injected
30 min before the intraventricular injection of 10 jug PGE1 which produced
a particularly large rise of 30 C. On the other hand the prolonged
U0
I-
0
41
40
Q. 39
SE
u
'4J
9C)
38
37
0 5
Hours
10
Fig. 2. Temperature record of an unanaesthetized cat. At the first arrow
marked 4-Ac, 50 mg/kg was injected i.P. and at the arrow marked PGE1,
10 #ag PGE1 was injected into the third ventricle (same experiment as given
on third line from bottom in Table 1).
secondary rise observed sometimes after an injection of PGE1 was
abolished by the 4-Ac injection, the temperature began to fall after a
latency of about 15 min and fell even below the level recorded before the
PGE1 injection. Normal temperature was either not affected by an i.P.
injection of 4-Ac, 50 mg/kg, or it fell by not more than half a degree.
The accentuation of the immediate and the abolition of the late hyperthermias
were due to the 4-Ac and not to the solvent because these

PROSTAGLANDINS AND BODY TEMPERATURE 331
effects were not obtained with control injections of propylene glycol-O9 %
NaCl solution. The aboliton of the late rise resembled the similar effect
previously observed with 4-Ac on the fever produced by intraventricular
injections of 5-HT or bacterial pyrogen (Milton & Wendlandt, 1968).
PGE2. This prostaglandin was injected intraventricularly in doses of
1 and 5 jug only. Both doses raised temperature and produced behavioural
effects similar to those observed with PGE1. The rise in temperature was
of immediate onset and reached a maximum within an hour; temperature
then either returned to the pre-injection level within 3-4 hr, or, after
having begun to fall, rose again and this secondary rise lasted up to 10 hr.
41
UO 40-
I 39
E
X 4-Ac \
, 38 mG t 2 X-
0 4-Ac
_ I
5
~
10
~ ~
15
~ ~~~~~~~~ I I
20
Hours
Fig. 3. Rectal temperature of the unanaesthetized cat. At the first and third
arrow i.P. injections of 4-Ac, 50 mg/kg; at the second arrow intraventricular
injections of 5 ,ug PGE2.
As with PGE1 the initial rise was not abolished or attenuated by 4-Ac
which, however, had an antagonizing effect on the secondary rise. A typical
experiment is illustrated in Fig. 3, which shows that the injection of 5 #ug
PGE2 given 1 hr after an i.p. injection of 50 mg/kg 4-Ac caused a rise of
over 20 C. During the following 4 hr, temperature returned to nearly preinjection
level, but then began to rise again. This secondary rise was suppressed
by another injection of 4-Ac and temperature fell during the
following 5 hr. The occurrence of the secondary rise in spite of the first
4-Ac injection is explained by the fact that the action of 4-Ac lasts for a
few hours only. In the experiment of Fig. 3 the effect of the second 4-Ac
injection also began to wear off after a little over 5 hr. In other experiments
in which the 4-Ac was given after the prostaglandin injection,
during the initial rise, the result was the same. The initial rise continued
while a secondary rise when it occurred was delayed.
PGFO12,. Intraventricular injections of 1 or 1O ,tg of this prostaglandin
produced no immediate effect on temperature in some cats, small rises in

332
A. S. MILTON AND S. WENDLANDT
others and, in a few, rises of nearly 10 C. These rises differed from those
produced by PGE1 and PGE2 in that they were not associated with
shivering and skin vasoconstriction. The injections, however, produced
restlessness and diarrhoea. The effect of an i.P. injection of 4-Ac, 50 mg/kg,
was examined in two cats in which the PGF1. injection had previously
caused a small, immediate, but long-lasting rise. In the one cat in which
the 4-Ac was injected 50 min before the PGF,. a rise did not occur, in the
other, in which the 4-Ac was injected 50 min after the PGF1Q, the rise
which had occurred was not affected.
PGF2a. Intraventricular injections of 100 ng, 1 and 10 jug PGF2a had
either no immediate effect on temperature or it rose 0.2-0.5° C. These
small hyperthermias, however, may not have been due to the PGF2a since
temperature fluctuations of this magnitude occurred spontaneously.
PGAJ. Intraventricular injections of 1 and 10 ,ug PGA1 had no immediate
effect on temperature, but in some cats temperature began to rise
after a latency of about 30 min, then rose 20 C or more during the following
3 hr and remained elevated for another 12 hr. In two cats in which such
late rises had been observed, the injections of PGA1 were repeated on
another day but preceded by an intraperitoneal injection of 4-Ac, 50 mg/
kg given 30 min earlier. In the one the rise did not occur, in the other it
occurred but after a delay of 5 hr.
Rabbit
A few experiments were made in this species and only with the three
prostaglandins PGE1, PGF2a and PGA1. Intraventricular injections of
1 ,ug of either PGF2cz or PGA1 had no effect on temperature. On the other
hand, PGE1 raised temperature as in cats, but the effect appeared to be
more prolonged. An intraventricular injection of 2 ,ug produced a rise of
about 1° C associated with skin vasoconstriction and slight shivering.
Temperature began to rise within a minute of the injection, continued to
rise for about 1 hr and remained high for up to 14 hr. An i.V. injection of
20 ,ug PGE1 produced no rise in temperature which on the contrary fell
slightly and the fall was associated with skin vasodilation.
DISCUSSION
Although central actions of prostaglandins are not confined to the
E series (see Horton, 1969) definite hyperthermias were only produced
with PGE1 and PGE2. The hyperthermias which occurred almost immediately
after the injections of these prostaglandins are central effects
since they did not occur when PGE1 was injected I.v. into rabbits in a dose
ten times greater than that which produced strong hyperthermia on intra-

PROSTAGLANDINS AND BODY TEMPERATURE
333
ventricular injection. If the hyperthermias were the result of vasodilatation
in regions of the brain adjacent to the third ventricle one would have
expected PGA1, to have a similar effect since, like PGE1 and PGE2, it is
a potent vasodilator (Horton, 1969). However, it did not produce the
immediate hyperthermia when injected into the third ventricle.
The hyperthermias produced by PGE1 and PGE2 are most likely due to
an action on the preoptic anterior hypothalamus* the region on which the
monoamines noradrenaline, adrenaline and 5-HT act when they produce
their effects on temperature. The temperature effects of the prostaglandins,
however, differ from those of the monoamines in two ways. Firstly,
the prostaglandins are more potent, they act in nanograms whereas
micrograms of the amines are needed to affect temperature on their intraventricular
injection. Secondly, the temperature effects produced by
PGE1 are similar in cats and rabbits, whereas opposite effects are produced
by the amines in these two species.
In addition to the immediate rise in temperature, the injections of PGE1
or PGE2 produced a secondary late and long-lasting rise which differed
from the immediate hyperthermia with regard to its sensitivity to 4-Ac.
Whereas the immediate rise was not affected by an intraperitoneal injection
of 4-Ac, the late rise was antagonized. Such a late rise occurred sometimes
also with control intraventricular injections of saline solution alone
and has been described by other authors as well (Feldberg, Myers & Veale,
1970). It is therefore possible that when it occurs in response to an injection
of PGE1 or PGE2, it is an unspecific effect and not due to the prostaglandins.
This would readily account for the fact that it was affected differently
by 4-Ac from the immediate hyperthermia. Otherwise one
would have to assume that the hyperthermic effect of PGE1 and of PGE2
consists of two components, only one of which, the late one, is sensitive to
4-Ac. Further, the finding that the immediate rise was not abolished by
4-Ac shows that it differs from the hyperthermias produced by intraventricular
injections of either 5-HT or pyrogen, as these rises are abolished
by 4-Ac (Milton & Wendlandt, 1968).
Horton (1964) and Horton & Main (1965, 1967b) did not observe shivering
or piloerection when they injected PGs of the E series into the
lateral ventricles of the unanaesthetized cat, but they observed stupor and
catatonia. They usually injected larger doses than those used in the present
experiments. This would not explain why they did not observe shivering
and piloerection. Stupor and catatonia on the other hand may be an effect
seen regularly only with larger doses.
Although the PGs not belonging to the E series did not produce sig-
* The site has recently been confirmed for PGE1 by W. Feldberg & D. Saxena
(personal communication).

334
A. S. MILTON AND S. WENDLANDT
nificant effects on temperature, one of them, PGF,,, often produced
diarrhoea when injected intraventricularly into a cat. In this species
diarrhoea and defaecation were occasionally also obtained with intraventricular
injections of PGE1. These effects recall the findings of Horton,
Main, Thompson & Wright (1968) that ingestion of PGE1 by humans results
in severe diarrhoea. These authors attribute this effect to a direct
action of PGE1 on the gastro-intestinal tract, whereas the effect produced
in cats with intraventricular PGF1. is probably of central origin.
The fact that PGE1 which is a natural constituent of the hypothalamus
and is released into the c.s.f. affects body temperature when applied in
nanograms by the intraventricular route, raises the question of its function
as a central mediator or modulator of temperature responses. The
threshold dose for producing hypothermia on intraventricular injection
compares favourably with the amounts present in the hypothalamus
which are about 60 ng/g tissue (Holmes & Horton, 1968 a) and with the
rate of release into the c.s.f. which is between 1 and 5 ng/min (Holmes,
1970). The comparison becomes even more favourable because only a
fraction of the PGE1 injected intraventricularly is taken up by the brain,
as was shown by Holmes & Horton (1968b) with tritium labelled PGE1.
Further, not only the rapid onset of the hyperthermia but also its relatively
short duration on intraventricular injection accords well with a
transmitter or modulator function of this acid lipid in temperature regulation.
In favour of such a function is also the finding that the immediate
rise in temperature was unaffected by 4-Ac, because in contrast to the
fever produced by pyrogen neither normal temperature (Rosendorff &
Cranston, 1968) nor the elevated body temperature produced by cooling
the hypothalamus or raising the ambient temperature (Cranston, Hellon,
Rawlins & Rosendorff, 1970) are affected by antipyretics. However, more
evidence is required concerning the release of PGE1 in relation to body
temperature before a physiological function in temperature regulation
can be attributed to PGE1.
If prostaglandins are involved in temperature regulation, then bacterial
pyrogen or 5-HT injected into the central nervous system may
raise body temperature by augmenting synthesis and release of prostaglandins.
In the light of this concept, antipyretic drugs may lower a fever
by preventing this increase in synthesis and release of prostaglandins.
This would explain why the antipyretic 4-Ac effectively antagonizes a
fever produced by TAB vaccine and by 5-HT but not a fever due to
PGEs.
The ability of PGE1 to raise temperature when injected into the third
ventricle in minute amounts may explain a hyperthermia seen by Myers
(1967) in his cross-perfusion experiments. He found that when a monkey

PROSTAGLANDINS AND BODY TEMPERATURE 335
was made to shiver by being placed in a cooled chamber its cerebrospinal
fluid, removed from the third and transfused into the third ventricle of
another monkey kept at room temperature, raised the temperature of the
recipient. The same result was obtained by transfusing the effluent obtained
from perfusing the anterior hypothalamus with a push-pull cannula
(Myers, Kana & Beleslin, 1969). Like 5-HT the c.s.f. from the third ventricle
and the effluent from the push-pull cannula contracted the rat
stomach strip preparation. When these fluids were assayed against 5-HT,
it was found that the 5-HT content of these fluids obtained from a cooled
monkey was manifestly greater than when obtained from a monkey kept
at room temperature. Yet even the increased 5-HT amounts found in
these fluids from the cooled monkey appear still to have been insufficient
to produce the hyperthermia by cross-perfusion in the recipient monkey.
If however part of the 5-HT activity was due to PGE1 to which the rat
stomach strip is sensitive as well, the hyperthermia of the cross-perfusion
experiments would be fully accounted for because the amount of PGE1
required to raise temperature in these conditions would at least be a
hundred times smaller than that of 5-HT.
ADDENDUM
That aspirin-like drugs can inhibit prostaglandin synthesis and that
this may be its mechanism of action was suggested in a paper by J. R.
Vane entitled 'Inhibition of prostaglandin synthesis as a mechanism of
action of aspirin-like drugs' which appeared in Nature New Biology, 231,
232-235 (1971).
REFERENCES
AMBACHE, N., BRUMMER, H. C., ROSE, J. G. & WHITING, L. (1966). Thin layer chromatography
of spasmogenic unsaturated hydroxy acids from various tissues.
J. Physiol. 185, 77-78P.
AVANZINO, G. L., BRADLEY, P. B. & WOLSTENCROFT, J. H. (1966). Actions of prostaglandins
E1, E2, F2X on brain stem neurones. Br. J. Pharmac. 27, 157-163.
COCEANI, F. & WOLFE, L. S. (1965). Prostaglandins in brain and the release of prostaglandin-like
compounds from the cat cerebellar cortex. Can. J. Physiol. Pharmac.
43, 445-450.
CRANSTON, W. I., HELLON, R. F., RAWLINS, M. D. & ROSENDORFF, C. (1970). The
action of salicylate on a non-infective fever. J. Physiol. 207, 18P.
DUDA, P., HORTON, E. W. & MCPHERSON, A. (1968). The effects of prostaglandins
E1, F1,, and F2. on monosynaptic reflexes. J. Physiol 196, 151-162.
FELDBERG, W. & MYERS, R. D. (1966). Appearance of 5-hydroxytryptamine and
an unidentified pharmacologically active lipid in effluent from perfused cerebral
ventricles. J. Physiol. 184, 832-853.
FELDBERG, W., MYERS, R. D., VEALE, W. L. (1970). Perfusion from cerebral ventricle
to cisterna magna in the unanaesthetized cat. Effect of calcium on body
temperature. J. Physiol. 207, 403-416.

336
A. S. MILTON AND S. WENDLANDT
HOFFER, B. J., SIGGINS, G. R. & BLOOM, F. E. (1969). Prostaglandins E1, E2,
antagonize norepinephrine effects on cerebellar Purkinje cells: microelectrophoretic
study. Science, N.Y. 166, 1418-1420.
HoTes, S. W. (1970). The spontaneous release of prostaglandins into the cerebral
ventricles of the dog and the effect of external factors upon this release. Br. J.
Pharmac. 38, 653-658.
HOLTES, S. W. & HORTON, E. W. (1968a). The identification of four prostaglandins
in dog brain and their regional distribution in the central nervous system.
J. Physiol. 195, 731-740.
HOLmRs, S. W. & HORTON, E. W. (1968b). The fate of tritium labelled prostaglandin
E1 injected in amounts sufficient to produce central nervous effects in
cats and chicks. Br. J. Pharmacy. 34, 32-37.
HORTON, E. W. (1964). Actions of prostaglandins E1, E2, and E3 on the central nervous
system. Br. J. Pharmac. 22, 189-192.
HORTON, E. W. (1968). The Prostaglandins: Recent Advances in Pharmacology, 4th
edn., pp. 185-213, ed. RoBsoN, J. M. & STACEY, R. S.
HORTON, E. W. (1969). Hypotheses on physiological roles of prostaglandins.
Physiol. Rev. 49, 122-161.
HORTON, E. W. & MAIN, I. H. M. (1965). Differences in the effects of prostaglandin
F2, a constituent of cerebral tissue, and prostaglandin E1, on conscious cats and
chicks. Int. J. Neuropharmac. 4, 65-69.
HORTON, E. W. & MAIN, I. H. M. (1967 a). Identification of prostaglandins in central
nervous tissues of the cat and chicken. Br. J. Pharmac. 30, 582-602.
HORTON, E. W. & MAIN, I. H. M. (1967b). Further observations on the central nervous
actions of prostaglandins F2. and E1. Br. J. Pharmac. 30, 568-581.
HORTON, E. W. & MAIN, I. H. M., THoMPsoN, C. J. & WRIGHT, P. M. (1968). Effects
of orally administered prostaglandin E1 on gastric secretion and gastro-intestinal
motility in man. Gut 9, 655-658.
KAPLAN, H. R., GREGA, G. J. & BUCKLEY, J. P. (1968). Evidence of the central
cardiovascular action of prostaglandin E1. Pharmacologist 9, 223.
MILTON, A. S. & WENDLANDT, S. (1968). The effect of 4-acetamidophenol in reducing
fever produced by the intracerebral injection of 5-hydroxytryptamine and pyrogen
in the conscious cat. Br. J. Pharmac. 34, 215P.
MYERS, R. D. (1967). Release of chemical factors from the diencephalic region of the
unanaesthetized monkey during changes in body temperature. J. Physiol. 188,
50-s1 P.
MYERS, R. D., KANA, A. & BELESLIN, D. (1969). Evoked release of 5-HT and NEFA
from the hypothalamus of the conscious monkey during thermoregulation.
Experientia 25, 705-706.
PHiLLIs, J. W. & TEBECIS, A. K. (1968). Prostaglandins and toad spinal cord responses.
Nature, Lond. 217, 1076-1077.
RAMWELL, P. W. & SHAw, J. E. (1966). Spontaneous and evoked release of prostaglandins
from cerebral cortex of anesthetized cats. Am. J. Physiol. 211,125-133.
ROSENDORFF, C. & CRANSTON, W. I. (1968). Effects of salicylate on human temperature
regulation. Clin. Sci. 35, 81-91.
SAMUELSSON, B. (1964). Identification of a smooth muscle-stimulating factor in bovine
brain. Biochem. biophys. Acta 84, 218-219.
SNIDER, R. S. & NIEMER, W. T. (1961). A Stereotaxic Atlas of the Cat Brain. Chicago:
The University of Chicago Press.
WOLFE, L. S., COCEANI, F. & PACE-AscIAx, C. (1967). Brain prostaglandins and
studies of the action of prostaglandins on the isolated rat stomach. In Proceedings
2nd Nobel Symposium, pp. 265-275. Stockholm: Almqvist and Wiksell.