Norepinephrine, dopamine and serotonin in experimental spinal cord trauma: current status
SEROTONIN IN 0
By RO BERT A. BRODNER 0
GEORGE J. DOHRMANN 0
0 Department of Neurosurgery, Mount Sinai School of Medicine, New York, N. Y. I0029 and Section of Neurosurgery, Department of Surgery, Yale University School of Medicine , New Haven, Connecticut , U.S.A
This is a review on norepinephrine, dopamine and serotonin withregard to their actionfollowing spinal cord injuries which reveals the controversies on this subject. THE role of neurochemical factors in the pathophysiology of experimental spinal cord trauma has been widely studied, and recently considerable attention has been focused on the biogenic amines (Dohrmann, I972; Osterholm, 1974). Much of the available data is inconsistent, with conflicting resultsbeing reportedboth in the basic pathophysiological studies as well as in the treatment studies. The importance of a potentially reversible pathochemical substratein spinal cord injury and its possible therapeutic implications are clear. The continued controversy concerning the role of the monoamines, norepinephrine, dopamine and serotonin,in spinal cord trauma has clouded the data and has renderedinterpretation most difficult. In this paper, the function of monoamines in neural trauma is reviewed and the data discussed.
Norepinephrine; dopamine; serotonin
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bolic response,resulting in release of transmitter substances,particularly norepine-?
phrine. These substances are thought to induce toxic vasospasm, hypoxia and
subsequentnecrosis of the tissue.
The pathogenic effect of norepinephrine on the traumatised spinal cord as
describedby Osterholm and Mathews (1972) has not been confirmed in the work
of others. Several investigators (see Table I), have failed to find a significant
elevation of norepinephrine in spinal cord tissue following trauma in cats, dogs or
(Naftchiet ai. , 1974; Hedeman et ai. , 1974; Rawe et ai. , 1974; de la Torre
et al. , 1974; Bingham et al. , 1975; Tsubokawa et ai. , 1975; Zivin et ai. , 1976)
la Torre et al. (1974) did not observean elevation in norepinephrine levels following
a soo g-cm spinal cord contusion. Alpha-methyl tyrosine (AMT), an inhibitor of
catecholamine synthesis, did not appear to improve the rate of motor recovery or
alter histopathologicalchanges in cats when given IS mins post-trauma(de la Torre
etai. , 1974). Naftchiet ai. (1974), Hedemanetai. (1974) and Tsubokawaetal. (197S}
also failed to find any significant elevation in norepinephrine concentration
following experimental spinal cord injury. Schoultz et al. (1976) found a norepine?
phrine elevation at the trauma site I hour after a 400 g-cm contusion of the feline
spinal cord. No increase in norepinephrine concentration was noted, however,
following experimental injury of adrenalectomised cats. The authors hypo?
thesised that the origin of the elevated spinal cord norepinephrine seen I hour
post-trauma was more related to a peripheral adrenal contribution and increased
blood levels than to intrinsic cord sources. In a study of catecholamine levels in
the spinal cords of monkeys following 300 g-cm trauma, Bingham et ai. (197S)
noted a progressive decrease in norepinephrine levels for 4 hours after trauma.
Rawe et al. (1974) reported no increase in norepinephrine levels at the site of
impact after a soo g-cm contusion. Despitethe efficacyof AMT to reduce nore?
pinephrine to low levels, there was no significant differencein functional neuro?
logical recovery after trauma between AMT treated animals and controls
et ai. , 1974)
. In addition, reserpine, a potent anti-norepinephrine agent, produced
no significant post-traumatic improvement
(Rawe et al. , 1974)
tyrosine was found to increase the rate of motor recovery after experimental
spinal cord injury in sheep by Yeo et al. (197S), although there was no significant
Concentration of catecholamines in the spinal cord after experimental spinal cord
Author and year
Osterholmand Mathews (1972) Cat
de la Torre et al. (1974) Dog, cat
Naftchi et al. (1974) Cat
Hedeman et al. (1974) Dog, cat
Rawe et al. (1974) Cat
Bingham et al. (1975) Monkey
Tsubokawa et al. (1975) Dog
Zivin et al. (1976)
Schoultz et al. (1976)
Unchanged * All measurements are at impact site.
difference in the extent of functional return at the end of 12 weeks. A recent
report by Zivin et al. (1976) separately studied post-traumatic monoamine altera?
tions in the contused grey and white matter. Their resultsshowed norepinephrine
to be decreased at the impact site in both the grey and white matter.
Concomitant with norepinephrine studies, another catecholamine, dopamine,
has been investigated relative to its possiblerole in the pathophysiology of spinal
(Osterholm and Mathews, 1972; Naftchi et al., 1974; Hedeman et al.,
1974; de la Torre et al., 1974; Bingham et al., 1975; Zivin et al., 1976)
Osterholm and Mathews (1972) found dopamine to be decreased by a factor of 4
at the site of spinal cord impact within I hour after trauma. Other investigators
have noted no significant alteration in dopamine concentration in the contused
(de la Torre et al., 1974; Bingham et al., 1975; Zivin et al., 1976)
Naftchi et al. (1974) and Hedeman et al. (1974) reported a significant elevation in
dopamine concentration following experimental spinal cord injury. The latter
authors (Hedeman et al., 1974) also observed that the use of haloperidol, pre?
dominantly a dopaminergic blocker, lent a high degree of clinicopathological
protection to the injured canine spinal cord, and hypothesised that the trauma?
related dopamine elevation may induce intramedullary vasoconstriction through
an alpha-adrenergic mechanism which is blocked by this agent. The administra?
tion of AMT 15 mins after injury did not prevent dopamine elevation and afforded
no clinical or microscopic protection
(Hedeman et al., 1974)
. The lack of efficacy
of AMT may be explained by the early and rapid post-trauma elevation of dopa?
mine which would precede the onset of AMT action
(Hedeman et al., 1974)
Twenty-four hour pretreatment with AMT, however, suppressedall spinal cord
catecholamines, and did prevent trauma-induced dopamine elevation
et al., 1974)
Serotonin, a vasoactive biogenic amine, has been reportedincreased following
central nervous system trauma both experimentally
(Osterholm et al., 1969;
Tsubokawa et al., 1975; Zivin et al., 1976)
and clinically (Misra et al., 1967) (Table
II). Osterholm et al. (1969) demonstrated significant elevation of serotonin in the
brain and cerebrospinal fluid (CSF) after experimental cerebral trauma in cats.
Elevated serotonin levels were noted in the traumatised canine spinal cord by
Tsubokawa et al. (1975), who correlated these levels with the onsetof vasoconstric?
tion of the cord vessels and reduced vascular perfusion. Zivin et al. (1976)
reported an increase in the white matter serotonin concentration both rostral and
caudal to the impact lesion. Other investigators, however, have been unable to
confirm serotonin elevation after neural trauma
(de la Torre et al., 1974; Naftchi
et al., 1974; Brodner et al., 1977)
Brodner et al. (1976) have noted a significant decrease in the intramedullary
serotonin levels 30 mins after injury, and have also reported a significant rise in
CSF serotonin I hour after experimental spinal cord trauma. This elevation in
CSF serotonin has been correlated with the appearance of vasoconstriction and
reduced perfusion in the intramedullary microcirculation of the contused spinal
cord (Brodner et al., 1975). The authors postulatedthat release of serotoninduring
platelet aggregation and clot lysis in the subarachnoid space following trauma is
responsible for the observedvascular changes.
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Experimental central nervous system trauma: concentration of serotonin in tissue
* All measurements are at impact site.
t Measurements are from cerebrum and brain stem.
t No change at5 min, 15 min 1, 4 and 12 hours post-trauma;decreased (p= <0'05)
at 30 min after injury.
? Increased (p = <0'025) at I hour post trauma.
IIIncreased in white matter;decreased in grey matter.
Osterholm et al. (1969) have shown that minute quantItIeS of serotonin
injected intracerebrally cause severe neurological alterations and cerebral oedema.
They hypothesisedthat, when released from an intracellular site, serotonin acts on
other neurons to cause post-traumatic neurological damage. De la Torre et al.
(1974) used higher concentrations of serotonin for intracerebral injection of cats
and monkeys and found no alteration in either neurological or behavioural para?
Serotonin may play an important role in the propagation and development of
the spinal cord lesion following trauma. All arguments advanced favouring
norepinephrine as a mediator of secondary spinal cord injury could apply equally to
serotonin. If pretreatment with reserpine retards damage, serotonin depletion
may be an important factor. Howitt and Turnbull (1972) did not find methyser?
gide, a serotonin antagonist, to be effectivein lessening the effectsof spinal cord
injury. Pretreatment with parachlorophenylalanine (PCPA) has been shown by
Brodner and Roth (1977) to increase perfusion and improve the microcirculatory
dynamics of the traumatised spinal cord. Similarly, Nemecek et al. (197.5) have
reported functional improvement in the experimentally contused rabbit spinal
cord after pretreatment with PCPA.
The findings to date do not supportthe hypothesisthat the catecholamines,
norepinephrine and dopamine, play a direct and major role in the pathophysiology
of spinal cord trauma. Similarly, the place that serotonin may have in this process
is unclear. Factors contributing to the inconsistencies in biochemical and histo?
chemical studiesof spinal cord injury are the limitations of the models and methods
used as well as technical problemswith the measurement of biogenic amines. Of
concern is the high variability in normal and post-traumatic catecholamine values.
Variability is all the more prominent in the traumatised animals because of the lack
of standardisation of the spinal cord trauma model using the weight-dropping
technique (Dohrmann & Panjabi, 1976), and the lack of control of the major
physiological parameters at the time of injury (Brodner et al., 1976).
The status and function of monoamines in experimental spinal cord trauma
remains a subject of controversy and continued debate. The norepinephrine
hypothesishas been severely weakened by its lack of reproducibility. Dopamine
results are too variable to draw meaningful conclusions. The role of serotonin
particularly with reference to its vasoactive properties and the physiological
importance of its effects,remains to be determined.
Le role et la fonction des monoamines dans les traumatismes expenmentaux de la
moelle epiniere restent l'objet de controverses et de debats continuels. L'hypothese de la
norepinephrine a ete considerablement affaiblie par son manque de reproductibilite. Les
resultats de la dopamine sont trop variables pour permettre de tirer des conclusions valables.
Le role de la serotonine, en particulier concernant ses proprietes vasoactives et l'importance
physiologique de ses effets, reste a determiner.
Der Status und die Funktion von Monoaminen in experimentell verursachten Riicken?
marksverletzungen ist umstritten. Die Norepinephrinhypothesis wurde erheblich gesch?
wacht durch den Mangel an Reproduzibilitat. Dopamine Resultate sind zu variabel, urn
giiltige Schliisse zu ermoglichen. Die Rolle von Serotonin beziiglich seiner vasoaktiven
Wirkung ist noch zu untersuchen.
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