Reviews of Physiology, Biochemistry and Pharmacology, Volume 71

167 Pages·1974·5.896 MB·English

by  Eckhart Simon (auth.)

Reviews of
17 Physiology,
yrtsimehcoiB dna
ygolocamrahP
formerly
Ergebnisse der Physiologie, biologischen
Chemie und experimentellen Pharmakologie
Editors
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With 70 Figures
Springer-Verlag
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Contents
Temperature Regulation: The Spinal Cord as a Site of Extra-
hypothalamic Thermoregulatory Functions. By E. ,NOMIS
Bad Nauheim/Federal Republic of Germany. With 23 Fig-
ures . . . . . . . . . . . . . . . . . . . . . . . .
Galactosamine Hepatitis: Key Role of the Nucleotide Defi-
ciency Period in the Pathogenesis of Cell Injury and Cell
Death. By K. REKCED and D. ,RELPPEK Freiburg/Federal
Republic of Germany. With 81 Figures ........ 77
Recent Concepts of Intestinal Fat Absorption. By R.K.
,RENKCO San Francisco/USA and K.J. ,REHCAB~HssI
Boston/USA. With 02 Figures . . . . . . . . . . . . 701
Author Index . . . . . . . . . . . . . . . . . . . . . 741
Subject Index . . . . . . . . . . . . . . . . . . . . . 851
List of Contributors
,REKCED K., Prof. Dr., Biochemisches Institut der Universit/it
7800 Freiburg/Federal Republic of Germany
,REHCABLESSI K. J., Prof. Dr., Harvard Medical School, The Mas-
sachusetts General Hospital, Boston, MA 02114/USA
,RELPPEK D., Prof. Dr., Biochemisches Institut der Universifftt
7800 Freiburg/Federal Republic of Germany
,RENKCO R. K., Dr., Department of Medicine, University of Cali-
fornia, School of Medicine, San Francisco, CA 94143/USA
,NOMIS E., Prof. Dr., Max-Planck-Institut fiir Physiologische und
Klinische Forschung, W. G. Kerckhoff Institut, 6350 Bad Nau-
heim/Federal Republic of Germany
Rev. Physiol.Biochem. Pharmacol., Vol. 17
© by Springer Verlag 1974
Temperature Regulation: The Spinal Cord as a Site
of Extrahypothalamic Thermoregulatory Functions
ECKHART SIMON*
Contents
.1 Spinal Mechanisms of Temperature Regulation . . . . . . . . . . . . . . . . 2
1.1. Extrahypothalamic Deep Body Thermosensitivity in the Spinal Canal ....... 2
1.1,1. First Evidence for Thermosensitive Structures in the Spinal Canal . . . . . . . . 3
1.1.2. Methods of Spinal Thermal Stimulation . . . . . . . . . . . . . . . . . . . 4
1.1.3. Location of Spinal Thermosensitive Structures . . . . . . . . . . . . . . . . . 5
1.2. Specifity and Spectrum of Thermoregulatory Effector Responses Induced by Spinal
Thermal Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.2.1. Shivering and Shivering Thermogenesis . . . . . . . . . . . . . . . . . . . . 8
1.2.2. Non-Shivering Thermogenesis (NST) . . . . . . . . . . . . . . . . . . . . . 41
1.2.3. Skin Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
1.2.4. Panting, Thermal Tachypnea, Respiratory Evaporative Heat Loss . . . . . . . . 8 t
1.2.5. Sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.2.6. Piloerection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.2.7. Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2l
1.3. Neuronal Correlates of Spinal Thermosensitivity . . . . . . . . . . . . . . . . 26
1.3.1. Temperature Effects on Efferent Spinal Neurons . . . . . . . . . . . . . . . . 28
1.3.2. Temperature Effects on Ascending Spinal Neurons . . . . . . . . . . . . . . . 30
1.3.3. Cellular Mechanismso f Neuronal Thermosensitivity . . . . . . . . . . . . . . 34
1.4. Synopsis of Thermoregulatory Functions Established at the Spinal Level ..... 83
1.4.1. Input Function: The Spinal Cord as a Temperature Sensor . . . . . . . . . . . 38
1.4.2. Controller Function: The Spinal Cord as a Site of Subsidiary Control Functions in
Temperature Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . 40
1.4.3. Output Function : The Spinal Cord as an Output Amplifier . . . . . . . . . . . 14
,2 The Role of the Spinal Temperature Sensor in Temperature Regulation ...... 42
2.1. Comparative Evaluation of the Effectivity of the Spinal Temperature Sensor .... 43
2.1.1. Relationship between Stimulus Intensity and Effector Response . . . . . . . . . 44
2.1.2. Changes of Core Temperature Induced by Spinal Thermal Stimulation ...... 52
2.2. Evidence for Continuous Signalling of Spinal Cord Temperature in the Range of
Physiological Core Temperature Variations . . . . . . . . . . . . . . . . . . 55
2.2.1. Signals of Ascending Spinal Thermosensitive Neurons . . . . . . . . . . . . . 56
2.2.2. Thresholds of Effector Activation . . . . . . . . . . . . . . . . . . . . . . 56
2.2.3. Shifts of Core Temperature . . . . . . . . . . . . . . . . . . . . . . . . . 57
3. Characteristics of the Temperature Regulation System . . . . . . . . . . . . . 58
3.1. Multiplicity of Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
3.2. Multiplicity of Controllers . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.3. Multiplicity of Effectors . . . . . . . . . . . . . . . . . . . . . . . . . . 63
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
* Max-Planck-Institut for Physiologische und Klinische Forschung--W. G. Kerckhoff-Institut,
D-6350 Bad Nauheim, Germany.
2 .E NOMIS :
The investigations concerning the role of central nervous structures in tem-
perature regulation may be considered as having proceeded during the last decade
along two converging conceptual lines which have originally emerged from
opposing points of view. One of thesec onceptsw hich can be traced to the classical
discoveries of RUOBRAB (1912) and of DIMHCSNESI and LHERK (1912) had proposed
that the hypothalamus represents the only center of temperature regulation
existing within the central nervous system. Both the control of the thermoregula-
tory effector activities and the perception of core temperature as the controlled
variable were exclusively ascribed to this particular section of the brain stem.
The second concept had been introduced in the discussion about the central
nervous functions in temperature regulation by REUAHT (1939). It emphasized the
functional character of nervous control centers and proposed that the specific
thermoregulatory control functions, though governed by the hypothalamus, are
established in principle by structures widespread in the central nervous system.
The numerous experimental efforts which have been stimulated by these
opposing concepts during the last ten years have led to their gradual approach
and eventual coalescence. The analyses of hypothalamic functions in temperature
regulation have positively confirmed the great importance of this section of the
brain stem as a control center and a central temperature sensor, but have also
indicated that the hypothalamus alone cannot account for the entire information
about deep body temperature. On the other hand, substantial evidence has
accumulated that extrahypothalamic central nervous structures contribute signi-
ficantly to the regulation of body temperature. The experiments which have
demonstrated the existence of thermosensitive structures in the spinal cord have
been comprehensively described by REUAHT (1970). The crucial role of this dis-
covery in defiensittaebllyi shing central extrahypothalamic thermoregulatory func-
tions has been pointed out recently by REUAHT and NOMIS (1972). It is the aim
of this report to review the investigations on the spinal cord and those related
studies which have formed the experimental basis for the concept of multiple
representation of thermoregulatory control functions in the central nervous
system.
1. Spinal Mechanisms of Regulation Temperature
1.1. Extrahypothalamic Deep Body Thermosensitivity in the Spinal Canal
The investigations which have led to the discovery of thermosensitive structures
within the spinal cord may be reckoned among the numerous experimental efforts
to establish the function of extrahypothalamic deep body thermoreceptors in
temperature regulation. These efforts which were characterized by REUAHT )2691(
as the search for the "glomus caroticum of temperature regulation" had been
stimulated by conflicting results concerned with the thermoreceptive function of
the hypothalamus.
gnomA eht snoitagitsevni hcihw dah dehsilbatse tnanimoderp eht role fo eht sumalahtopyh
ni erutarepmet ,noitaluger most denimaxe stceffe eht of snoisel ni or snoitcesnart of eht niarb
mets (for secnerefeR ees ,YDRAH .)1691 There erew a only wef latnemadnuf reports hcihw
Temperature Regulation 3
described thermoregulatory reactions induced by thermaslt imulation of the brain stem ,RUOBRAB(
1912; ,OTOdrlHSAH 1915; ECNIRP and HAHN, 1918) or of the hypothalamus NUOGAM( et al.,
1938; YAWGNIMEH et al., 1940; NOTAEB et al., 1941). Proceeding from these experiments it
was taken for granted that core temperature was perceived exclusively by temperature sensors
located in the preoptic and anterior hypothalamic region REGNIZNEB( et al., 1691 ; ,YDRAH .)1691
However, the systematic exploration of the thermoreceptive function of the hypothalamus
which was started by the investigations of M6RXS (1950a, b) had only in part supported this view.
On the one hand, the great influence of hypothalamic temperature on the activity of many
thermoregulatory effectors was convincingly demonstrated. On the other hand, several obser-
vations were made which reinforced some of the early doubts of REUAHT (1939) about the
exclusive role of the hypothalamus in central temperature perception. For instance, a high degree
of hypothalamic heat and cold sensitivity could be demonstrated in conscious dogs by LEMMAH
et al. (1960) and by Fusco et al. (1961). But the gradual lessening of effector activity during
sustained hypothalamic temperature displacements seemed to indicate the existence of deep
thermoreceptors outside of the thermally stimulated area. In particulart,h e diversity of findings
concerning heat and cold sensitivity increased the doubts about the concept that central tem-
perature reception was restricted to the hypothalamus. While heating of the preoptic and anterior
hypothalamic region consistently elicited heat defence reactions ,MORTS( 1950a; NOV RELUE
and ,GREBRED6S 1958; NAMEERF and DAvis, 1959; LEMMAH et al., 1960; Fosco et al., 1961),
equivocal results were obtained when the effects of cooling were studied. Negative results and
weak or transitory effects as well as definite cold defence reactions in response to cooling of
the brain or hypothalamus were reported by different investigators ,MORXS( 1950b; NAMEERF
and DAvis, 1959; REFEOHNOD et al., 1959; ZXEB et al., 1960; ,LEDNERB 1960; LEMMAH et al.,
1960; LIM, 1960; NOSSREDNA et al., 1962; YENWOD and ,MARTTOM 1962). While these con-
flicting results still did not question the predominant role of the hypothalamus in central tem-
perature perception, they favoured theories of temperature regulation in which any central
cold perception was denied REGNIZNEB( et al., 1961). But this view contrasted with the well-
established observation that cooling of the whole body core when the skin was warm regularly
evoked strong cold defence reactions in dogs TENNOXAHC( and ,EHCNAT 1957a, b; SHCAWLLAH
et al., 1691 a). This discrepancy greatly stimulated the search for extracerebral deep body thermo-
receptors and it is obvious why this search was concentrated, at that time, on the effector re-
sponses to central cooling ,SIEFTALB( 1960; ,HGILB 196t; SHCAWLLAH et al., 1961 b; YENWOD
and ,MARTTOM 1962).
HALLWACHS et al. (1961b) who cooled the whole extracerebral body core in
anesthetized dogs after thermal isolation of the head were the first to demon-
strate definite cold defence reactions in response to deep body cooling at elevated
skin and brain temperatures. Subsequent investigations by RAUTENBERG et al.
(1963a, b) and by NOM1S et al. (1963a) in anesthetized dogs confirmed a central
cold sensitivity both in the brain and in the extracerebral body core. These results
initiated the systematic search for the extracerebral deep cold sensitive structures
which finally led to the spinal canal as a site of specific extrahypothalamic thermo-
sensitivity.
1.1.1. First Evidence for Thermosensitive Structures in the Spinal Canal
The responses of two thermoregulatory effector systems to selective temperature
changes within the spinal canal of anesthetized dogs furnished the first evidence
for thermal susceptibility with an apparently specific function in a circumscribed
region of the extrahypothalamic body core. Fig. 1 firstly demonstrates the activa-
tion of metabolic heat production due to shivering which was induced by selective
cooling of the spinal canal at elevated core and skin temperatures. Secondly,
the course of the skin temperature measured at the paw indicates that skin blood
flow was reduced by cold stimulation within the spinal canal (SIMON et al., 1963 b).
4 E. NOMIS
ml ml Tair 28 °C
9
8
oxygen
consumption
7
&
6
MWMvM shivering
14
.~.~*t~r~ "-" Tbrai n
°C
. . . ~ . : ~ I ~ . ~ .-.Tre c
~l~:l'll:~';i" ~ ""~ -- . .Taort a
39
37
/ "*.+~+~ +~+ / \ .... Tskin trunk
\ %.
%+ ÷ + +Tskin hindpaw
35
33
v
\
29 F///////////z'/~ ~/////////2 A///////////z
I I I I I I I I
0 30 60 90 120 150 180 2t0 rain
Fig. l. Selective cooling (black bars) within the lower thoracic and lumbar spinal canal of an
anesthetized dog by means of conditions. ambient at thermode warm peridural perfused a water
oxygen and consumption increased Shivering era indued by lowering spinal canal erutarepmet
in spite of elevated, rising extraspinal core .serutarepmet The fall of skin at temperature the
wap spinal during cooling indicates cutaneous vasoconstriction. NoMrS( et al., 1963b)
Further investigations in anesthetized dogs confirmed that selective lowering of
the spinal canal temperature regularly evoked cold shivering in the absence of
any other central or peripheral cold stimuli (SIMON et al., 1964). GREBNETUAR
and SIMOy (1964) also demonstrated an appropriate interaction between external
and central cold stimuli and cold and warm stimuli applied to the spinal canal.
Shivering which had been evoked by peripheral or by general body cooling was
further enhanced by spinal canal cooling and was reduced or abolished by spinal
canal warming. Subsequently, SIMON et al. (1965) showed that shivering could
be regularly induced in unanesthetized dogs by selective cooling within the spinal
canal at thermoneutral ambient conditions (Fig. 2).
1.1.2. Methods of Spinal Thermal Stimulation
Perfusion of parts of the spinal subarachnoidal space with artificial liquor of
various temperatures was originally employed as the method of thermal stimula-
Regulation Temperature 5
C*
163
0~
/
23
Fig. .2 Electromyograms recorded from the fore and hind Iegs (lower traces of the recording)
of a conscious dog demonstrating shivering induced by selective cooling of the spinal canal
at thermoneutral ambient conditions (Ta= 32 C). ° A peridural thermode extending from the
second cervical vertebra to the sacral bone is perfused with water of ° C. 22 Upper traces:
constant rectal and changing spinal canal temperatures. NOMIS( et al., 1965)
tion. Later on, double-barrelled, U-shaped thermodes of polyethylene tubing were
inserted in the peridural space and were perfused with water of varying tempera-
ture. Although greater transverse temperature gradients were produced in the
spinal canal by thermode stimulation, this became the standard stimulation
method since chronically implanted thermodes were tolerated well and allowed
experiments in unanesthetized preparations. Variations of the method concerned
the number and the length of the thermodes. Only a few experiments are reported
in which metal thermodes instead of the flexible polyethylene tubings were used
(GulEU and HARDY, 1970a, b). Indirect spinal canal cooling and heating by means
of thermodes located outside of but adjacent to the spinal canal was performed
in a limited number of experiments (BROCK and WONNENBERC, 1967a, b). Elec-
trical, radiofrequency or resistor heating was occasionally employed (BROCK and
WUNNENBERG, 1966; W1JNNENBERG and BROCK, 1968a, 1970; DUCLAUX et al.,
1973).
Due to the anatomy of the spinal canal, quantitative evaluation of stimulus intensity proved
to be difficult. Considerable transverse temperature gradients were built up when stimulation
was performed by means of thermodes. Especially in bigger species these gradients were found
to exceed 01 ° C if onlyo ne thermode was used ELSILRAC( and ,MARGNI 3791 .)b These difficulties
can partly be overcome by implanting several thermodes, however, their number is limited
by the small size of the peridural space. At present, no satisfactory technical solution to the
problem of how to uniformly stimulate the spinal canal has been found. In order to estimate
average stimulus intensities applied by thermode perfusion at given perfusion temperatures
and flow rates, multiple temperature measurements at arbitrary points within the spinal canal
were made to permit calculation of "mean spinal cord temperatures" NESSEJ( and ,REYAM .)1791
These average temperatures gave at least reproducible estimations of the stimulus intensity.
In other investigations spinal canal temperature was disregarded. Stimulus intensity was simply
defined by the temperature of the perfusion fluid.
1.1.3. Location of Spinal Thermosensitive Structures
When the temperature within the spinal canal is experimentally lowered, cold
shivering becomes visible in anesthetized dogs within 1-2 rain (SIMON et al., 1964)
and can be detected by electromyography in conscious dogs within less than
6 . ENOM~S :
1 min NOM1S( et al., 1965). Smaller animals like the rabbit AKASOK( et al., 1967;
AKASOK and ,NOMIS 1968a) and the pigeon ,GREBNETUAR( 1969) respond within
a few seconds to this thermal stimuluTsh.i s quick activation of thermoregulatory
effector responses indicates that the stimulated thermosensitive structures are
located within or close to the spinal canal. The term "spinal thermosensitivity"
has been chosen to define those extra-hypothalamic deep thermosensitive struc-
tures which are directlya ffected by the temperature of the spinal canal thermode.
Responses evoked by reducing spinal canal temperature below its normal level
have been regarded as indicating "cold" sensitivity, while the effects of warming
the spinal canal to temperatures above normal have been ascribed to spinal
"warm" sensitivity. Both terms will be used in the following discussion in a
purely discriptive manner; that is, they are not meant to anticipate a decision
about the thermal coefficients of the thermosensitive structures mediating the
responses to warming and cooling.
The first observations in dogs, especially those obtained during spinal cooling
by means of subarachnoidal perfusion, indicated that spinal thermosensitivity
was more or less equally distributed over the whole length of the spinal canal.
This corresponded to the obseration that the effects of spinal cold and warm
stimulation in dogs NOM~S( et al., 1964) and pigeons ,GREBNETUAR( 1969)increased
with the length of the thermodes. In contrast, KC?tRB and GREBNENNOW (1966)
found spinal heat sensitivity in guinea pigs to be concentrated in the lower cervical
and upper thoracic segments of the spinal canal (Fig. .)3 In the pig the cervical
part of the spinal canal was also found to be more sensitive to spinal thermal
stimulation than the lumbar and sacral sections ELSILRAC( and ,MARGNI 1973b).
It is obvious that a part of the central nervous system, the spinal cord, is
directly affected by thermal stimulation within the spinal canal. This suggests
that the thermally sensitive structures might be localized within the spinal cord
itself. The first support for this assumption was obtained from investigations
of RERUEM et al. (1967). In dogs with chronical bilateral transection of the dorsal
roots of the lumbosacral spinal cord; selective cooling of this deafferentiated
section of the spinal cord was still effective in evoking cold tremor. NNAMSSULK
(1969) who investigated this question with neurophysiological methods found
no evidence for activation of afferent dorsal root fibers by thermal stimulation
within the spinal canal. Thus, it is most likely that spinal thermosensitivity is
based on temperature dependent spinal neurons or neuronal circuits as it is the
case with hypothalamic thermosensitivity.
1.2. Specifity and Spectrum of Thermoregulatory Effector Responses
Induced by Spinal Thermal Stimulation
Activation and inhibition of shivering by changes of spinal cord temperature
as observed in the first explorative studies on spinal thermosensitivity indicated
but did not prove its specific function in temperature regulation. Temperature
effects on signal transmission in the spinal cord which had repeatedly been de-
scribed in the past (see Paragraph 1.3.1.) were apparently non-specific, but could
have at least partly accounted for the motor reaction of cold induced muscle