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Antispasticity drugs Mechanisms of action.

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NEUROLOGICAL PROGRESS
Antispasticity D m . : Mechanisms of Action
Robert A. Davidoff, MD
Several different drugs are now used, or are potentially useful, to peat patients with spasticity. Although these
compounds vary in their actions on spinal neurons and reflex arcs, it is possible to formulate reasonable hypotheses
regarding their modes of action. The benzodiazepines bind to specific benzodiazepine receptors linked to classic yaminobutyric acid (GABA) receptors located on the terminals of primary afferent fibers. This binding results in an
increased affinity of the GABA receptor for the amino acid, an augmented flux of chloride ions across the terminal
membrane, and an increase in the amount of presynaptic inhibition. Baclofen activates GABABreceptors putatively
located on the same terminals. Activation of these receptors retards the influx of calcium ions into the terminals,
thereby reducing the evoked release of excitatory amino acids and possibly other transmitters. Progabide and its
metabolites act on both classic and GABABreceptors. Glycine works on specific inhibitory receptors located on spinal
interneurons and motoneurons. The phenothiazines act on the brainstem to alter the function of fusimotor fibers.
Phenytoin and carbamazepine reduce the afferent output of muscle spindles. Dantrolene diminishes the activation of
the contractile process in muscle fibers by reducing the release of calcium ions from the sarcoplasmic reticulum. This
review summarizes the data supporting these concepts.
Davidoff RA: Antispasticity drugs: mechanisms of action. Ann Neurol 17:107-116, 1985
Many authorities [39, 78, 98; cf. 791 have defined
spasticity as a disorder of motor function characterized
by a velocity-sensitive increase in resistance to passive
stretch of muscles accompanied by hyperactive tendon
reflexes. However, increased stretch reflexes constitute only one aspect of the multiple deficits in motor
function following upper motor neuron lesions. From
the point of view of patients’ symptoms and complaints, other symptoms are generally more important
than hypertonia. In fact, there is evidence that in some
spastic patients the hypertonus and exaggerated stretch
reflexes are not even causally related to the abnormal
motor performance 11231. In many patients, movement is significantly restrained by the cocontraction of
agonists and antagonists, or by a dyssynergic pattern of
muscle contraction {761. In other patients, exaggerated
andor spontaneous and involuntary flexion reflexes
(flexor spasms) are the major obstacles to function
11311. In almost all patients with spasticity, paresis or
loss of dexterity, or both, contribute importantly to
patients’ inability to function. Moreover, since the clinical presentation of spasticity depends upon the locus
(e.g., spinal cord, brainstem, cerebrum) and extent of
injury to the central nervous system (CNS), one encounters several different clinical patterns ofsspasticity
{793. As a corollary, there is no reason to believe that
the same pathophydiological abnormalities are present
in all cases of spasticity or that the same therapeutic
agents will be equally effective in all patients.
From the Neurology Service, Veterans Administration Medical
Center, and Department of Neurology, University of Miami School
of Medicine, Miami, FL 33101.
The focus of this review will be on the modes of
action of drugs and other compounds that either are
currently used for the treatment of patients with spasticity or that have potential value in the treatment of
such patients. Because most, if not all, the essential
mechanisms required for the development of spasticity
are present within the spinal cord itself, and because
the subject has been extensively reviewed from other
perspectives [16, 20, 32, 1511, the emphasis in this
report will be on basic pharmacological effects exerted
on spinal neurons and on the peripheral reflex apparatus.
Physiological and Pharmacological Background
When supraspinal control over spinal cord activity is
loit, segmental reflexes begin to change. Such alterations are responsible for many of the phenomena o b
served.in patients with spasticity. The function of any
or all of the neuronal structures involved in various
reflex arcs may be affected: included can be peripheral
sensory receptors, primary afferent fibers and their
presynaptic terminals, excitatory and inhibitory interneurons, alpha motoneurons innervating skeletal muscle, and gamma motoneurons (fusimotor neurons)
innervating the intrafusal muscle fibers in muscle spindles. As a corollary, drugs that relieve spasticity act in
various ways to decrease the excitability of spinal
reflexes. They may lower the sensitivity of peripheral
sensory receptors (dantrolene, phenothiazines), reduce
Address reprint requests to Dr Davidoff, Department ot Neurology,
Po Box 016960, University of Miami School of Medicine, Miami,
FL 33101.
Received June 28, 1984, and in revised form Sept 6. Accepted for
publication Sept 10, 1984.
107
the release of excitatory transmitter from the presynaptic terminals of primary afferent fibers (baclofen,
diazepam, progabide), inhibit excitatory interneurons
intercalated in reflex pathways and alpha motoneurons
innervating muscle (glycine), interfere with the contractile response of skeletal muscle (dantrolene), or
diminish the remaining supraspinal facilitatory effects
exerted on presynaptic terminals, interneurons, and
motoneurons (phenothiazines).
Many of our most cherished concepts about the
pathophysiological nature of spasticity are based oh
deductions drawn from experiments on decerebrate
cats. Because some of the phenomena observed in
such animals superficially resemble those seen in patients with spasticity, it has been assumed that the
physiological abnormalities thought to be responsible
for the hypertonus of decerebrate rigidity are also responsible for the increased muscle tone seen in human
spasticity. Accordingly, hyperactivity of the fusimotor
system has been regarded as the major cause of the
increased muscle tone seen in human spasticity 11211.
However plausible this concept, recent evidence
makes reassessment necessary because microneurographic recordings of single muscle spindle afferents in
human beings have produced no evidence of overactivity of afferent spindle discharges or of the fusimotor
system in patients with spasticity 1171. On the other
hand, the intensity of the muscular activity is usually
proportional to the velocity of stretch in spastic patients
1181, an indication that the velocity sensitivity of the
muscle spindle has influence on the spastic condition.
Descending pathways powerfully inhibit interneurons intercalated in the polysynaptic reflex and in
inhibitory pathways. This realization has resulted in
new emphasis being placed on the likelihood that altered interneuronal function accounts for many of the
abnormalities in spasticity. In humans with spasticity,
the polysynaptic flexor reflex is exaggerated 11321, and
in animals with chronic spinal cord lesions, transmission in polysynaptic excitatory spinal pathways activated by muscle stretch or by electrical stimulation
of high threshold muscle and cutaneous nerves is
facilitated 1681. Postsynaptic inhibitory pathways involving interneurons have been found to be depressed
in patients with spasticity t1451, but paradoxically, in
animals these same pathways have been found to be
more efficient 1681. Some data also show that spinal
transection changes the excitability of motoneurons
1541.
Substantial alterations in the mechanisms that control transmitter release from presynaptic terminals of
primary afferent fibers have been demonstrated. For
example, in patients with spasticity there is evidence of
a change in the excitability of, and release of transmitter from, afferent terminals (presynaptic inhibition).
108 Annals of Neurology
Voi 17 No 2 February 1985
Thus, presynaptic inhibition affecting afferent fibers
from muscle spindles appears inadequate 15, 381, although again the information available from animal experiments is conflicting (see 169, 971).
Most hypotheses about the pathophysiological
mechanisms of spasticity or about the action of drugs
on the spinal cord are based on observations made
during acute animal experiments. The validity of these
hypotheses, however, may be limited because spasticity is not usually an acute symptom, but rather a syndrome that in most cases develops gradually and persists indefinitely. This well-known clinical observation
buttresses mounting experimental evidence that over
time a complex series of plastic changes alters the intact portions of the CNS. For example, existing circuits
and pathways may become modified by any or all of
the following processes: nerve fibers uninjured by the
pathological process may sprout 1961, denervation
supersensitivity may develop 11031, transsynaptic degeneration may occur, and synapses that are normally
ineffective in producing excitation may “open up”
1991. Nervous systems altered by plastic changes must
surely function in ways differing from those of normal
individuals. In turn these changes may affect the action
of drugs in ways that are not necessarily predictable
from experiments performed in intact animals. Nonetheless, it is clear that most drugs used in spastic patients work in various ways on the synapses. To understand the mechanisms by which these drugs work, it is
necessary to identify the substances that function as
transmitters at spinal synapses.
Neurotransmitters in the Spinal Cord
Glycine and y-aminobutyric acid (GABA) have been
identified as the major inhibitory transmitters in the
spinal cord TlOl, 1501. There is good evidence that
glycine is the transmitter released by inhibitory interneurons responsible for reciprocal inhibition and by
Renshaw cells responsible for recurrent inhibition.
GABA may also be involved in postsynaptic inhibition
at synapses in the spinal cord (e.g., [26]), but its most
important function in the spinal cord is the mediation
of presynaptic inhibition. Presynaptic inhibition, a
powerful mechanism operating at the spinal level to
suppress sensory signals arriving from muscle and
cutaneous receptors, can be produced by discharges in
various afferent and supraspinal inputs to the spinal
cord 1341. It is believed that specific synapses located
on the terminals of primary afferent fibers are the substrate for presynaptic inhibition. Activation of specific
receptors on afferent terminals by GABA, the transmitter secreted by these synapses 1991, results in a
decrease in the amount of excitatory transmitter released by impulses in primary afferent fibers 1431 with
a consequent reduction of the amplitude of the excita-
tory postsynaptic potentials (EPSPs) produced in motoneurons and interneurons by afferent signals.
GABA receptors have been studied thoroughly by
electrical measurements of physiological events and by
chemical determinations of the binding of various
ligands to membrane preparations of CNS tissues 133,
50, l05}. There appear to be at least two major types
of GABA receptors: (1) the classic receptors (GABAA
type) which can be activated by GABA and by some
GABA agonists (e.g., muscimol) and which are
blocked by the specific GABA antagonist bicuculline;
and (2) the nonclassic receptors (GABAB type) which
are activated by GABA, but not by the majority of
recognized GABA-mimetics, and which are not affected by bicuculline Ell, 131. Both types are present
in the spinal cord [lo, 131 and both types are thought
to be located on afferent terminals of myelinated and
unmyelinated fibers [1171. Evidence presently available favors the role of GABAA receptors in presynaptic inhibition.
The GABAA receptor is thought to consist of a
complex supramolecular structure composed of several
independent but interconnected molecular subunits:
1. GABA recognition site: The recognition site binds
tritiated (3H)GABA; the site has properties (e.g.,
saturability, displacement by GABA agonists and
antagonists) expected of a synaptic GABA receptor. Multiple binding sites with differing affinities
have been described [lO5], but it is not known with
certainty if the multiple sites for C3H}GABA binding represent separate receptors or reflect changes
in the conformation of the same receptor protein
that can exist in more than one state.
2. Chloride ion channel (chloride ionophore). The
predominant effect produced by activation of the
GABAA recognition site is opening of chloride
channels. This increased ionic conductance, which
allows diffusion of chloride ions across the neuronal
membrane according to the electrochemical gradient, is responsible for the physiological inhibitory
effects of GABA. On afferent terminals, GABAA
receptor activation leads to a net efflux of chloride
ions that produces a depolarization (primary afferent depolarization) thought to be the causal event
in presynaptic inhibition E41).
3. Benzodiazepine (BZD) site. C3H}Diazepam and
other BZDs bind to brain and spinal cord membranes in a high-affinity, stereospecific, saturable
manner {93, 1421. BZD receptors are thought to
be localized in most GABAergic synapses and to
have a regulatory action on the affinity of the recognition site for GABA. It is probable, however, that
GABAA and BZD receptors are not always closely
linked [Zl, 881.
Our knowledge of the GABAB receptor is less clear
[131. For example, GABAB receptors are thought to
be located on presynaptic terminals, but there is evidence that they may also be present on neuronal dendrites [l 11. In either case, however, we lack definitive
information about an association of GABAB receptors
with GABAergic synapses. Little is known about the
ionic events associated with GABAB receptor activation, even though indirect evidence suggests that
GABAB receptors on primary afferent neurons are
coupled to calcium channels [41, 42, 921.
L-Glutamate and L-aspartate have been proposed as
transmitters released from terminals of large-diameter,
myelinated primary afferent fibers, and from excitatory
interneurons, respectively [l 18, 1241. In contrast, unmyelinated primary sensory neurons may secrete peptides. In particular, the peptide substance P is thought
to be a transmitter released by a population of unmyelinated afferents excited by noxious peripheral stimuli
and involved in pain conduction 115, 661. These afferent terminals that secrete L-glutamate and substance P
are subject to GABA-mediated presynaptic inhibition.
Amino acids and peptides are not the only spinal
transmitters. The spinal cord receives projections of
noradrenergic, dopaminergic, and serotonergic fibers
descending from the brainstem C2, 871. These descending monoaminergic fibers facilitate locomotion
and control the gain of stretch and flexor reflexes presumably by affecting the transmission of impulses from
primary afferent fibers [11, the excitability of interneurons [72), and the discharges of fusimotor neurons
[23, 521 and interneurons {72}.
Antispasticity Agents
Benzodiazepines
The earliest clue to the action of the BZDs was provided by the now classic study of Schmidt and his
colleagues [ 1291 that demonstrated that diazepam increased presynaptic inhibition in cats. Their findings
have been both amply confirmed 1114, 127, 1387 and
extended to human beings [73, 1461. Because GABA
is assumed to be the transmitter responsible for this
form of inhibition, such results indicate that the BZDS
affect GABA-mediated synaptic events. This view is
strengthened by observations that pharmacological elevation of spinal cord GABA levels increases the effects of BZDs on presynaptic inhibition and that
blockade of GABA synthesis decreases the expected
augmentation of inhibition by the BZDs E55, 1141. In
addition, low concentrations of BZDs increase inhibition, and also increase the effects of exogenously applied GABA on neurons from other areas of the CNS
where GABA is thought to be a transmitter (e.g., [5l,
70, 1481). Moreover, BZDs specifically enhance
GABAergic effects and do not affect synaptic events
Neurological Progress: Davidoff: Antispasticity Drugs
109
mediated by other transmitters such as glycine [29,
1291. The effect of BZDs on GABA-mediated events
is largely caused by direct augmentation of the postsynaptic actions of GABA E85). In particular, the presynaptic terminals of afferent fibers are depolarized by
GABA, an action enhanced by even low doses of
BZDs C102, 1331.
The molecular mechanisms underlying these observations have been the object of intense study.
Biochemical studies indicate that BZDs heighten the
affinity of the binding of GABA to GABAA receptors
on CNS membranes 153, 134, 1351. The increased
GABA binding increases the frequency with which
chloride channels open in response to a given amount
of GABA {133, 139). In turn, this produces an augmented chloride current. These observations have resulted in the present conception that activation of the
GABAA recognition site initiates the opening of the
chloride channel and that BZDs facilitate the process.
When diazepam acts on the spinal cord, presynaptic
inhibition (and other inhibitions dependent upon
GABA f113f) is augmented. It is believed-but not
proved-that increasing presynaptic inhibition in the
spinal cords of patients with spasticity should reduce
the release of excitatory transmitters from afferent
fibers and thereby reduce the gain of the stretch reflex
and flexor reflex. The muscle relaxant properties of
diazepam are postulated to result from this action.
Since diazepam has been shown to act effectively in
patients with complete spinal cord transections 1241,
we can assume that the compound works directly on
the spinal cord. in addition, low doses of diazepam
intensify presynaptic inhibition equally in animals both
with intact and transected spinal cords f127, 129, 138).
Hence, it is not known with certainty whether supraspinal actions contribute at all to the ability of
diazepam to enhance presynaptic inhibition.
While amplification of presynaptic inhibition seems
to be the most prominent and specific action of the
BZDs on the spinal cord, effects not attributable to
presynaptic mechanisms have also been reported. For
example, diazepam reduces electrically evoked monosynaptic and polysynaptic reflexes 125, 67, 127-129,
1441; it is not certain, however, if polysynaptic reflexes
are more susceptible to the actions of diazepam than
are monosynaptic ones (cf. 125, 127, 129, 1441). Why
monosynaptic patellar reflexes appear to be resistant to
diazepam 125, 67, 1001, while monosynaptic reflexes
produced by electrical stimulation of afferent fibers are
depressed, is unclear (cf. {6?, 114, 1291). Higher doses
of diazepam are needed to suppress polysynaptic
reflexes in animals with spinal transections than in animals in which the brainstem is contiguous with the
spinal cord (cf. f67, 100, 127, 127, 138, 1441), implying that the effects on reflexes probably require an
intact brainstem reticular formation. This latter finding
110 Annals of Neurology
Vol 17 N o 2
February 1985
has been interpreted as showing that the BZDs exert
their effects on polysynaptic reflexes by inhibiting a
descending facilitatory system { 1001.
Baclofen
Baclofen {Lioresal, P-(4-chlorophenyl)GABA] was
originally thought to function as a GABA agonist,
since it is a lipophilic derivative of GABA that can
penetrate the blood-brain barrier to enter the CNS.
Although baclofen depresses monosynaptic and polysynaptic excitation of motoneurons and interneurons
in a manner expected of a GABA-mimetic drug 135,
49, 110, 1111, its electrophysiological and pharmacological profile is quite different from that of
GABA 127, 28, 35, 49, 77). In particular, it is devoid
of electrophysiological action at, and does not bind
strongly or specifically to, classic GABAA receptors
{lo, 13, 27, 377. Baclofen reduces the symptoms of
spasticity as effectively in patients with complete spinal
transections as in patients with incomplete lesions f6,
1071, indicating, on clinical grounds at least, that its
major site of action is in the spinal cord. This concept
is supported by animal studies: its actions on spinal
reflexes are the same in intact, decerebrate, and spinaltransected cats 131.
Monosynaptic excitation of motoneurons by lowthreshold muscle afferents is more sensitive to baclofen than is polysynaptic excitation by higher-threshold
afferents {28}. The reduction in reflex activity in response to the compound reflects a decrease in the amplitude of EPSPs in motoneurons {35, 49, 1101. This
can be produced by presynaptic and/or postsynaptic
effects, and both have been described. However, only
high concentrations of baclofen consistently depress
the excitability of postsynaptic neurons or significantly
alter the responses of neurons to any of the putative
excitatory transmitters {27, 36, 37, 471. In contrast,
presynaptic effects of baclofen can be demonstrated
with concentrations that are in the therapeutic range.
For example, chemical studies show that baclofen reduces the electrically evoked release of the putative
excitatory transmitters glutamate and aspartate from
brain slices and synaptosomes {?4, 1151. Physiological investigations in cultured spinal neurons indicate
that baclofen reduces monosynaptic EPSPs between
neurons by reducing the number of quanta released by
action potentials, a clear indication of a presynaptic
action 1119).
13HJBaclofen binds to GABAB sites on brain and
spinal membranes [lo, 131. Chemical characterizations of C3HJbaclofen binding sites show they possess
the same structural requirements that physiologically
defined baclofen sites demonstrate. In particular, the
binding is stereospecific, the ( -)isomer being much
more active than the (+)isomer. This parallels the
physiological effects. Thus ( - )badofen is responsible
for almost all of the reflex-depressant properties of the
racemic mixture that is used clinically 128, 1041. Currently it is thought that activation of GABAB receptors
by ( - )baclofen restricts calcium influx into presynaptic
terminals 141, 421 and that it is this restriction that
reduces evoked transmitter release. In turn, the reduction of excitatory transmitter release by afferent fibers
(and presumably by interneurons) is responsible for
the diminished reflex activity.
One of the interesting properties of (-)baclofen is
its ability to decrease the response to noxious stimuli
(analgesia) in experimental animals 130, 82, 122, 1491.
Baclofen has also been reported to alleviate pain in
patients with spasticity 159, 1121. Because analgesia
occurs following either restricted administration of the
drug into the spinal subarachnoid space 11491 or microinjection into discrete sites in the brainstem {82),
it may be that baclofen produces analgesia by acting
at both spinal and supraspinal sites. This baclofeninduced analgesia, however, does not result from activation of opiate receptors or GABAA receptors, since
it is not antagonized by naloxone or bicuculline 1126,
1491.
In the spinal cord, baclofen has a prolonged depressant effect on the excitation of neurons of the dorsal
horn by noxious peripheral stimuli [61,62, 111). Presumably the depression of responsiveness of nociceptive neurons is the mechanism of action in the spinal
cord causing the analgesia. Antagonism of the effects
of substance P would explain the analgesia, and it has
been reported that baclofen antagonizes the postsynaptic actions of the excitatory peptide 11061. Despite the
attractiveness of the idea, however, the evidence for
specific interaction between baclofen and substance P
receptors is not persuasive {48, 57, 1091. In contrast,
activation by baclofen of GABAB receptors on nociceptive afferent fibers is suggested by the observation
that the drug affects calcium permeability in the cell
bodies of slow-conducting unmyelinated and myelinated fibers that are thought to subserve nociception
141; cf. 1251.
A variety of other effects have been ascribed to baclofen (eg., augmentation of Renshaw cell activity {lo;
cf. 361 and depression of fusimotor activity 147, 58,
1413, but their importance in the therapeutic manifestations of the drug is currently unknown.
Progabide
Preliminary reports have shown that the experimental drug progabide, {a-(chloro-4’-phenyl)fluoro-5-hydroxy-2-benzylidene-amino}-4-butyramide;
SL 76 002,
a systemically active GABA agonist {8, 841, can
ameliorate some symptoms of spasticity {94, 951. Part
of the GABA-mimetic activity of progabide is owed to
the metabolic products GABA, GABA amide, and SL
75 102 183. Interestingly, progabide and SL 75 102,
another GABA agonist, have activity at both GABAA
and GABAB receptors C12, 40, 831; presumably, progabide’s ability to activate these receptors on afferent
terminals and interneurons is the explanation for its
reported effects on spinal reflexes in patients with
spasticity. More clinical and laboratory data are required before this drug’s potential and exact mode of
action can be evaluated.
Glycine
Preliminary investigations have shown that oral administration of the simple amino acid glycine alleviates the
symptoms of spasticity in patients 17, 137) and reduces
experimentally induced hypertonia in animals { 136,
1391. Glycine is one of the few pharmacologically active amino acids that readily pass through the bloodbrain barrier 11401. It acts at specific glycine receptors
that are present in large numbers on motoneurons and
interneurons in the spinal cord and brainstem {lSO}.
Activation of glycine receptors hyperpolarizes the
membranes of these neurons by increasing their conductance to chloride ions. As a result, cell firing is
decreased and reflex excitability damped. The clinical
value of glycine awaits further investigation.
Phenotbiazines and Adrenergic Blockers
Clinical interest in the effect of phenothiazines on
spasticity stems from the observation that small doses
of chlorpromazine and other phenothiazines reduce
the discharge of fusimotor fibers {60, 91, 1141 and
abolish the hypertonia of cats decerebrated by intercollicular section [GO, 751. On the (probably mistaken)
assumption that decerebrate rigidity is a model of spasticity, clinical trials of phenothiazines have been undertaken, but only limited efficacy has been reported 119,
90; d.221. Because the depression of motor function
by phenothiazines is thought to be exerted primarily
upon the brainstem reticular formation, it might have
been predicted that these compounds would have little
effect on spinal spasticity. Segmental reflexes are very
resistant to these drugs in spinal-transected animals
{60, 1161.
The phenothiazines most effective in reducing
decerebrate rigidity have the most potent alphaadrenoceptor blocking activity; the actions of these
compounds on rigidity and on fusimotor activity have
been ascribed to their alpha-adrenoceptor blocking
properties C911. Without doubt, there is a correlation
between fusimotor activity and rigidity in animals with
intercollicular section: both phenomena can be depressed by those phenothiazines that antagonize adrenoceptors. Interpretations of this correlation, however, have been based for the most part on the
hypothetical framework that hypertonia results entirely from fusimotor hyperactivity, and have ignored
pertinent data showing that the characteristics of interNeurological Progress: DavidoE Antispasticity Drugs
111
collicularly decerebrated cats reflect not only increased
fusimotor discharges but also other abnormalities of
reflex activity capable of influencing muscle tone (871.
Moreover, catecholamines exert potent effects on
reflex discharges affecting muscle, other than the
monosynaptic stretch reflex which is dependent upon
fusimotor activity {72). Furthermore, phenothiazines
antagonize the postsynaptic actions of dopamine and
affect excitable membranes in a variety of ways 11301
in addition to their adrenoceptor blocking actions. Attempts to clarify the role of adrenergic blockade have
made use of thymoxamine, an alpha-adrenergic antagonist, and propranolol, a beta blocker {86, 1471. Thymoxamine, but not propranolol, decreases stretch and
tendon reflexes in spastic patients, but both drugs tend
to increase the flexor reflex. The use of adrenoceptor
blockers for spasticity may be of potential value, but
further work is needed using more specific adrenoceptor antagonists.
Anticonvuhants
The anticonvulsants phenytoin and carbamazepine
have recently aroused interest because in decerebrate
cats they have been found to suppress the spontaneous
and stretch-evoked discharges of afferent fibers originating in muscle spindles ( 3 , 651 and the extensor hypertonus (4, 641. These effects are found only when
high doses of the anticonvulsants are administered
1641. The compounds must work directly on the receptor mechanism in the spindle since the depression
of afferent spindle activity is present in de-efferented
spindles. However, phenytoin also affects fusimotor
firing although carbamazepine does not 163, 641. It is
not known what role these various effects play in the
actions phenytoin is reported to exert on the symptoms of patients with spasticity {22}.
Although effects on spindle activity have been postulated to be responsible for the clinical actions on
hypertonia demonstrated for phenytoin (especially
when used in conjunction with chlorpromazine [22}),
anticonvulsants have other effects on the spinal cord.
For example, they affect the function of presynaptic
terminals of afferent fibers by reducing post-tetanic
potentiation of monosynaptic reflexes 146, 1431 and by
increasing presynaptic inhibition ( 311. In addition,
high doses of phenytoin and carbamazepine reduce
polysynaptic reflexes (46, 64, 1281, although monosynaptic reflexes are usually unaffected. It is obvious
that these actions may significantly affect spinal cord
function.
Dantrolene
Dantrolene is unique among clinically used antispasticity agents in that its therapeutic efficacy is produced by
peripheral actions. The evidence indicates that dantrolene has little or no effect either on neuromuscular
112
Annals of Neurology
Vol 1 7 No 2
February 1985
transmission (451 or on the electrical properties of the
skeletal muscle membrane {44}. Its action is exerted
on muscle fibers where it is thought to inhibit the
release of calcium ions from the sarcoplasmic reticulum, thereby preventing activation of the contractile apparatus and diminishing the mechanical force of
contraction (44, 45, 56, 1201. The block of calcium
release is not complete and contraction is never abolished (14,44, 561.
Such depressant effects are more pronounced in
fast-contracting than in slow-contracting muscle fibers
(14, 7 1, SO}. In addition, dantrolene-induced changes
in the contractile response are dependent upon the
frequency of nerve stimulation (14, 45, SO}. Singletwitch contractions are more affected than maximal
fully fused tetanic contractions (14, 45, 1201, but each
muscle type is depressed maximally at a specific frequency. This means that the clinical effects of the drug
wili depend upon a balance between the frequency of
motor unit firing in a given muscle and the type of
muscle fiber firing in that muscle. Dantrolene also
curbs intrafusal muscle fiber contraction in muscle
spindles and reduces the increment in afferent fiber
discharge produced by stimulation of fusimotor fibers
(81, 1081. It has been suggested that this effect would
reduce the excitation of alpha motoneurons through
the muscle spindle, but its contribution to the therapeutic actions of the drug is not known.
Comment
Study of the many ways that antispasticity drugs can
influence the excitability of the spinal cord (and supraspinal structures) has resulted in fundamental new
knowledge about the workings of the CNS. The results of investigations of the effects of baclofen have
thus led to the discovery of a new type of GABA
receptor. The intriguing actions of diazepam and the
other BZDs have spurred efforts that have led to an
understanding of the supramolecular organization of
the classic GABA receptor. Nevertheless, no currently available pharmacological agent is completely
adequate to alleviate the symptoms of spasticity (15 ,
17, 1511. O n the other hand, these basic discoveries
may eventually lead to the development of drugs more
useful in countering the effects of chronic upper motor
neuron lesions.
Supported in part by US Public Health Service Grant NS 17577 and
Veterans Administration Medical Center Funds (MRIS 1769).
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Notice Regarding Manuscript Submission
As of December 15, 1984, manuscripts submitted for
publication in Annals of Neurology should be sent to
Arthur K. Asbury, MD, Editor, Annals of Neurology,
Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
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