Cyclobenzaprine: A novel centrally acting skeletal muscle relaxant

N~sropi~urn~acolog~, 1975. 14. 615

684. Pergamon

Press. Punted m Gt Bntain.

CYCLOBENZAPRINE: ACTING SKELETAL N. N. SHARE

A NOVEL CENTRALLY MUSCLE RELAXANT* and C. S. MCFARLANE

Department of Pharmacology. Merck Frosst Research Laboratories, Kirkland, Quebec, Canada H9R 4P8 (Accepted 25 February

1975)

Summary-The muscle relaxant activity of cyclobenzaprine relative to chlorpromazine and diazepam in several animal models manifesting hypertonic skeletal muscle activity is described. In mice subjected to electrical and chemical induced tonic-extensor seizures, only cyclobenzaprine achieved a protective index greater than unity in all preparations. Cyclobenzaprine also appeared to be highly potent and selective in abolishing local tetanus in rabbits. Relative to the other compounds, cyclobenzaprine was consistently active in y- and cc-decerebrate as well as in ischemic spinal cord rigid cat preparations, at doses which produced no signs of motorincoordination (ataxia) or behavioural depression. Consequently, only cyclobenzaprine exhibited high protective indices and those of greater than unity for all three cat preparations. Furthermore, in contrast with chlorpromazine and diazepam. repeated administration of cyclobenzaprine to ischemic spinal cord rigid cats failed to induce tachyphylaxis. Cyclobenzaprine was also well absorbed orally in mice and cats. These observations suggest that cyclobenzaprine may be useful in the treatment of human pathological conditions manifested by excessive tonic skeletal muscle activity. The potential usefulness of cyclobenzaprine as a pharmacological tool for further studies involving somatic motor systems is also suggested.

Interest in compounds with skeletal muscle relaxant activity is concerned primarily with discovering better means of inhibiting unwanted or excessive muscle activity. Of perhaps equal importance is that compounds with specific mechanisms of action may provide useful pharmacologic “tools” for further neurophysiologic and pathophysiologic function studies of somatic motor systems (SMITH, 1965). The following report describes some of the skeletal muscle relaxant properties of cyclobenzaprine compared with chlorpromazine and diazepam. It will be seen that cyclobenzaprine is most consistent and highly selective in reducing or abolishing excessive tonic skeletal muscle activity in several animal models. Its pharmacological profile therefore suggests its potential utility in the clinical treatment of tonic spasms and perhaps also as a tool for further studies involving somatic motor systems.

,CH3

CHCH&H,N\

.H.CL CH3

Cyclobenzaprine hydrochloride: N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-As~-propylamine hydrochloride, Lisseril@, Merck Sharp & Dohme, Rahway, New Jersey 07065.

METHODS

Male albino CF 1 mice (18-22 g), New Zealand male albino rabbits (25-3 kg) and cats of either sex (2-4 kg) were employed in the present study. Mice were allowed free access to food and water except during testing procedures. For oral studies in mice, and experiments involving rabbits and cats, food was withheld overnight. * Presented in part at the Fall Meeting of the American Society for Pharmacology Therapeutics 23-27 August 1970, at Stanford, California. 675

and Experimental

676

N.

Anticorzvulsarlr activity

N.

SHARE

and C. S.

MCFAKLANE

in mice

Anticonvulsant activity was determined in 3 tests using a 30 min drug pretreatment period. Maximal electroshock seizures were evoked through cornea1 electrodes (50 mA a.c. at 60 Hz for 0.2 set) as described by SWINYARD,BROWN and GCXDMAN(1952) and chemical seizures were induced by pentylenetetrazol (125 mg/kg, i.p.) or strychnine (3 mg/kg, i.p.) as described by BERGER(1954). The potency of a drug (ED,,) was based upon its ability to prevent the hindlimb tonic-extensor component of the various seizures. Determination of ED,, and confidence limits was based upon a minimum of 3 doses with 10 mice/level according to the method of LITCHFIELDand WILCOXON(1949). Araxia and protective

index in mice

Drug-induced ataxia was evaluated according to the method of DUNHAMand MIYA (1957). Briefly, animals were placed on a rotating (lO/min) knurled brass rod (2 cm dia), and separated from one another by brass discs. Mice were evaluated 30 min following drug treatment and considered ataxic only if they fell twice during a 2 min test period. Subsequently, the protective index for each drug was determined as the ratio of its intraperitoneal ED,, for ataxia to that of its intraperitoneal ED,, for prevention of maximal electroshock, pentylenetetrazol and strychnine-induced tonic-extensor seizures. Local

tetarlus in rabbits

Local tetanus was induced by the injection of tetanus toxin (1200 mouse minimum lethal dose units) into a gastrocnemius muscle (LAURENCEand WEBSTER,1958). Approximately 72 hr later, animals were suspended in a canvas sling so that their hindlimbs just touched the bench. Electromyographic (EMG) activity of the developed tetanus was recorded with intramuscular platinum electrodes (Grass E-2) implanted approximately 1 cm apart. The EMG activity of the uninjected contralateral gastrocnemius muscle was recorded as a non-tetanic control. The recorded potentials were amplified and displayed on a Beckman Type R Dynograph at a sensitivity of 100 ,uV/cm. The frequency of the muscle potentials per unit of time was recorded concurrently by coupling the amplified output to a Hewlett-Packard 5201L Scaler Timer and 562A Digital Recorder. Since spontaneous local tetanus was variable, an electrically driven hammer was arranged to strike the frame supporting the animal in its sling at 1 min intervals. With this standard afferent stimulus, it was possible to achieve a more steady state of muscle hyperactivity for drug evaluation. In all rabbits, steady state frequencies obtained from the tetanic gastrocnemius muscle averaged 5s-133 Hz. After a minimal 15 min stabilization period, a dose of 0.031 mg/kg for each test substance was injected intravenously. Additional doses were given subsequently at 15 min intervals until all EMG activity was virtually abolished. The results are expressed in terms of the amount of drug required to nearly completely abolish EMG activity (ED,,_ 1oa) during a 5 min recording period. Decerehrate

rigidity in cats

Animals were anaesthetized with ether and a tracheal cannula was inserted to facilitate respiration. For y-decerebrate rigidity, the carotid arteries were clamped and the midbrain sectioned between the colliculi. The forebrain was removed by suction, the basilar artery clamped, and Oxycel applied to the pituitary fossa. Ether was then discontinued and the carotid clamps were removed. Recordings did not begin until at least 2 hr after decerebration. The animal was placed on one side and the left femur was held in a vertical position by a steel pin in its lower end, the lower leg being allowed to hang freely from the knee (KEARY and MAXWELL, 1967). The EMG recordings were obtained from the quadriceps muscle before and after gently extending the lower leg to its full length, and then lowering it gently until it was held by the tone of the

Cyclobenzaprine

677

quadriceps muscle. These extensions were carried out at 5 to 7 min intervals and the resultant tonic EMG activity was amplified and displayed on a Beckman Type R Dynograph at a sensitivity of 100 yV/cm. Between leg extensions, the knee-jerk was elicited by tapping the patella tendon with a solenoid hammer (3/min) and the resultant EMG of the quadriceps was recorded through the same electrodes on a different channel of the polygraph at a lower sensitivity (1 mV/cm). For anaemic r-decerebrate rigidity, the method of POLLOCK and DAVIS (1930) was employed. Briefly, this consisted of clamping the carotid arteries and immediately thereafter clamping the basilar artery between the tympanic bullae. Ether anaesthesia was then discontinued. At least 2 hr later, tonic EMG recordings were obtained at 5 to 7 min intervals as for the y-decerebrate preparations. Beginning with 0.5 mg/kg of each compound, additional doses were injected intravenously at 10 to 15 min intervals. The accumulated dose which completely abolished tonic EMG activity (ED,,,) was determined. Drug injections were then stopped, and the activity was followed for an additional 2 hr. Rigidity qf’ spinal origin (ischic

cord rigidity) in cats

The method for producing hind limb rigidity in cats by occlusion of the spinal cord blood supply has been described in detail by MURAYAMA and SMITH (1965). Animals were anaesthetized with 25 mg/kg of pentobarbital sodium administered intravenously under aseptic conditions. Thoracotomy was accomplished in the left 4th intercostal space, after which artificial respiration was instituted through a previously inserted endotracheal cannula. The internal mammary and aortic arteries were then dissected free and occluded above the origin of the intercostal arteries. Occlusion was maintained for 40 min, the chest was closed by standard surgical procedures, and the animal was permitted to breathe spontaneously. Several days to weeks after surgery, the animals were suspended in a canvas sling, and the quadriceps EMG activity was recorded on a Beckman Type R Dynograph. The amplified output was also coupled to a HewlettPackard 5201L Scaler Timer and 562A Digital Recorder. In this preparation. predrug control quadriceps muscle frequencies averaged 200 Hz. The intravenous dosage regimen was similar to that employed in the decerebrate cat. In some experiments, cumulative doses of cyclobenzaprine were also administered orally (beginning with 4 mg/kg) at 60 min intervals. The dose which reduced the frequency of muscle potentials to less than 10 Hz (equivalent to visual abolition of EMG activity) was determined (ED,,,). In other experiments, the accumulative EDloo for intravenously administered cyclobenzaprine was first determined in intact ischemic spinal cord preparations. One week later, the same animals were subjected to spinal cord (C2) section under ether anaesthesia. Two or more hr later, the accumulative EDloo for cyclobenzaprine was again determined. Atasia

arid protrctiw

irldex in cats

All observations were carried out “blind” using 4 animals for each compound tested. Intravenous doses of each substance, beginning with 0.5 mg/kg cyclobenzaprine, 0.125 mg/kg chlorpromazine and 0.063 mg/kg diazepam, were administered at 15 min intervals. Between drug injections, animals were permitted free movement and continuously observed especially for the presence or absence of ataxia (first noticeable sign of staggering or wobbly gait). The protective indices for each drug was determined by calculation of the ratio: average accumulative intravenous dose for induction of ataxia to average accumulate intravenous ED, o,, for abolition of EMG activity in the intercollicular yand r-decerebrate as well as ischemic spinal cord rigid preparations. Acute tachyphylaxis

in cats

The ischemic cord rigid cat preparation was used and quadriceps EMG frequencies were continuously recorded and averaged at 5 min intervals. Test substances were

678

N. N. SHARE and C. S. MCFARLANE

administered intravenously and repeated whenever EMG activity returned to 60% or greater than the predrug control value (t&. In the absence of tachyphylaxis, subsequent drug injections should re-establish blockade, whereas in the development of tachyphylaxis, repeated drug administration should induce a weaker and/or shorter duration of activity. Drugs

Cyclobenzaprine hydrochloride is a product of Merck Sharp & Dohme Research Laboratories (West Point, Pa.). Diazepam and chlorpromazine hydrochloride were gifts from Dr. J. Gareau (Hoffman La-Roche, Montreal, Quebec) and Mr. C. Bellof (Poulenc, Lt&e, Montreal, Quebec) respectively. Also used were pentylenetetrazol (Knoll Pharmaceutical Co., Cooksville, Ontario), strychnine sulphate (May & Baker Ltd., Dagenham, U.K.) and tetanus toxin (Connaught Medical Research Laboratories, Toronto, Ontario). All drugs were used as solutions in normal saline except for diazepam which was suspended in 1% Methocel 65 HG-400 cps (Dow Chemicals, Midland, Michigan). Drug doses were calculated as base.

RESULTS

Anticomxhant

activity and protective

index in mice

As shown in Table I, cyclobenzaprine prevented the electrical and chemical induced hind limb tonic-extensor seizures in mice, with EDScYsranging from 6 to 12.5 mg/kg for the intraperitoneal route. The compound was less active than diazepam (1.4 to 5.1 mg/kg, i.p.) but considerably more active than chlorpromazine (32 to 64 mg/kg, i.p.). Cyclobenzaprine was also shown to be well absorbed orally in this species, the ED,, for prevention of electroshock seizures being 22.8 mg/kg orally and 12.5 mg/kg intraperitoneally. All test compounds induced ataxia as measured in the rotating rod assay (Table 1). Least active was cyclobenzaprine followed by chlorpromazine and diazepam, with intraperitoneal ED,V, of 17, 2 and 1.8 mg/kg respectively. Consequently, only with cyclobenzaprine could a protective index of greater than 1.0 be demonstrated for all tonicextensor seizures in mice. A protective index of greater than unity was not achieved in any assay for chlorpromazine. and achieved only in the pentylenetetrazol assay for diazepam. Table

I. Effect of cyclobenzaprine

Test Maximal

upon electroshock, pentylenetetrazol seizures in mice*

Route electroshock

i.p. p.0.

Pentylenetetrazol

i.p.

Strychnine

i.p.

Ataxia

i.p.

Cyclobenzaprine ED,, mg/kg 12.5 (lOGl5.6) 22.8 (18.8-27~5) 6.0 (4&7,5) 12.5 (11~1~14~0) 17.0 (114-25~1)

and strychnine-induced

Chlorpromazine PI

ED,,

mg/kg

1.4

64.0

2.8

32.0 (22.3-45.7) 49.0 (36.5-65.6) 2.0 (1.772.3)

1.4

tonic-extensor

Diazepam PI <@I

0.1 <@l

ED,,

mg/kg

PI

5.0 (3.1-75)

0.4

1.4 (1~1~1.8) 5.1 (4.1-6.3) I.8 (1.7-2.5)

1.3 0.4

* Groups of 10 mice were pretreated with a minimum of 3 dose levels of the drugs and 30 min later were subjected to maximal electroshock (50 mA a.c. at 60 Hz of 0.2 set) or injected with 125 mg/kg pentylentetrazol or 3 mg/kg strychnine sulphate i.p. For ataxia, their ability to remain upon a rotating (1Ojmin) knurled brass rod (2 cm diameter) was determined. ED,, and confidence limits (in brackets) were calculated according to LITTHFIELII and WILCOXAN (1949). The protective index (PI) of a drug for each test was determined by the ratio: ED,, ataxia to ED,, (test).

Cyclobcnzaprine Table

2. Effect

619

of cyclobenzaprine upon rabbits*

local

tetanus

in intact

Reduction of local tetanus Average accumulative ED,, rO,, mg/kg

Drug Cyclobenzaprine Chlorpromazine Diazepam

0.72 044 0.29

(0.22. (0.09, (0.09,

0.47, 0.22, 0.22,

0.47. 0.47, @22.

@47, 0.47, 0.47,

1.97) 0.97) 0.47)

* EMG recordings were obtained from the gastrocnemeus muscle in which local tetanus had been induced by the injection of tetanus toxin (1200 MLD units) 72 hr earlier. Doubling accumulative doses (beginning with WO31 mg/kg, iv.) were administered at 15 min intervals, the ED,,_, 00 being that amount which virtually abolished EMG activity for a 5 min recording period. Five animals were used for each drug, numbers in brackets refer to individual experimental values.

Local

tetanus in rabbits

Activity of the three compounds in the rabbit local tetanus preparation is shown in Table 2. Following removal of the rabbits from the restraining apparatus after effective EMG reduction with cyclobenzaprine (ED,,_,,, = 0.72 mg,kg, i.v.), all animals appeared behaviourally indistinguishable from predrug injection observations. While chlorpromazine and diazepam were more active in this assay (respective ED,,_,,, of 0.44 and 0.29 mg/kg, i.v.), all animals appeared depressed and ataxic following their removal from the restraining apparatus. Decerebrate

rigidity in cats

With all three substances, regularization of the knee-jerk appeared to be directly proportional to reduction of rigidity aration. An example of this effect with cyclobenzaprine is Figure 1. All test compounds were approximately equipotent 3) with a duration of activity greater than 2 hr.

CONTROL

0.5 mg/kg

I

CBZ

ix

4++t+ l.Omg/kg

(patellar) EMG response in the y-decerebrate prepshown on the left side of in this preparation (Table

CBZ

:I^------

ix

I

Fig. 1. Effect of cyclobenzaprine (CBZ) upon intercollicular (y) decerebrate rigidity in the cat. EMG recordings obtained from quadriceps muscle. At S, lower leg fully extended and gently released. Tracings on the left from the patellar reflex (3/min). Note different recording speeds and sensitivities at the upper right and left hand corners, respectively. Cyclobenzaprine administered at 15 min intervals, and recordings taken 5-7 min after each indicated dose. Final tracing shows partial recovery 120 min after accumulative dose of 1.5 mg/kg. Note also that raising the lower leg at S completely abolished EMG activity which then markedly increased as the leg was lowered, presumably due to increased muscle spindle activation.

N. N. SHARE and C. S. MCFARLANE

680 Table

3. Effect of cyclobenzaprine

Drug

n

Cyclobenzaprine

9

upon

intercollicular (y) decerebrate, spinal cord rigidity in the cat*

y-Decerebrate rigidity mg/kg, iv. ED,,,

I

0551.5 3.5 15.5

4 1

0.5-1.5 7.5

I

Diazepam

5 2

.

and

4 3

0.5- 1.5 3.5

3.5

(2.1)

(3.5)

2 2 2

0,5- I.5 3.5 7.5 15.5 > 15.5 (>5.9)

0.5 1.5 7.5 > 15.5

0.5-I ,5 15.5

2

(W

2

I

P551.5 15.5 115.5 (>9.5)

i.v

II

ischemic

Ischcmic spinal cord rigidity ED,,,,, mg/kg. i.v

n

I 1

(2.5)

(a) decerebratc

r-Decerebrate rigidity ED,oo mg/kg,

(2.6) Chlorpromazine

anaemic

( > X4)) 2 1 3

I3 15.5 > 15.5

(> IO+)

* In all preparations, EMG recordings were obtained from the quadriceps muscle at 5 min intervals. In acute y- and cc-decerebrate animals, drug administration did not begin until at least 2 hr after cessation of ether anaesthesia. Chronic ischemic spinal cord preparations were used 3-665 days (average 52 days) after surgery. Accumulative doses of each compound were administered (beginning with 0.5 mg/kg. i.v.) at I@15 min intervals. The ED,oo was that amount which virtually abolished the EMG response to extension and lowering of the hindlimb in y- and r-decerebrate preparations, or the tonic EMG activity in ischemic spinal cord preparations. Average accumulative ED,,, in brackets. n = number of experimental animals.

Cyclobenzaprine also appeared to be similarly active in dity (Table 3). Whereas all compounds at effective blocking of greater than 120 min, doses required for abolition of preparation appeared highly variable with chlorpromazine lobenzaprine.

10 min

after

0.5

10 min

after

1.0 mg/kg,i.v.

10 min

after

2.0 mg/kg,i.v.

abolishing x-decerebrate rigidoses were active for periods rigidity in the y-decerebrate and diazepam than with cyc-

mg/kg,i.v

-w.

120

min

after

2.0

mg/kg,i.v.

Fig. 2. Effect of cyclobenzaprine upon rigidity of spinal origin (ischemic cord rigidity) in the unanaesthetized cat. EMG recordings from quadriceps muscle. Cyclobenzaprine administered at l&l5 min intervals. Abolition of EMG activity occurred within 5 min after accumulative dose of 3.5 mg/kg and partial recovery was seen after 120 min. Cats 3.2 kg. 40 days after spinal cord ischemia.

681

Cyclobenzaprine Table 4. Comparative

effects of cyclobenzaprine

upon rigidity cats*

Accumulative

Day interval 95 95 42 35 19 Mean values

of spinal origin in intact

and spinal C2 sectioned

Spinal C2 section Post c2 control EMG (Hz)

Accumulative ED,,, mg/kg, iv.

Control EMG (Hz)

ED,,” mg/kg, iv.

Pre C2 control EMG (Hz)

213 201 187 185 193

3.5 3.5 3.5 3.5 3.5

213 201 180 187 149

171 201 167 187 149

7.5 3.5 1.5 3.5 0.5

195.8

3.5

186

155

3.3

* Methods and preparations for intact animals as in Table 5. Accumulative EDtows were first determined in intact animals. One week later, the same animals were subjected to spinal cord (C2) section and accumulative EDrows again determined.

Ischemic

spinal cord rigidity in cats

As can be seen from the example in Figure 2 and Table 3, cyclobenzaprine consistently depressed the high quadriceps EMG activity of ischemic spinal cord rigid cat preparations. Behavioural depression was never observed at effective blocking doses in these animals. In fact, some excitation and “anticholinergic-like” (drying of the mouth and mydriasis) activity was generally observed. Cyclobenzaprine was also extremely well absorbed in cats, comparative accumulative EDloo doses being 3.5 mg/kg and 4-12 mg/kg, for the intravenous route and oral route respectively. Chlorpromazine and diazepam were less consistent in reducing the frequency and amplitude of rigid muscle potentials (Table 3) being apparently more active in those animals used more than 30 days after surgery. In preparations where activity could be demonstrated, their duration of action was also considerably shorter (averaging 60 -80 min) than that of cyclobenzaprine (> 120 min). Furthermore, both chlorpromazine and diazepam exhibited behavioural depression at effective blocking doses. In five additional experiments involving some of the above animals, cyclobenzaprine again consistently abolished EMG activity at accumulative intravenous doses of 3.5 mg/kg (Table 4). Control quadriceps EMG frequency averages (195.8 Hz) did not differ significantly from those obtained one week later in the same intact animals (186 Hz). Two or more hr following spinal cord (C2) section, average predrug control frequencies (155 Hz) decreased by only 16.7%. In these spinal preparations, accumulative ED,,?, for cyclobenzaprine administered intravenously were more variable than in intact preparations, but still averaged 3.3 mg/kg. Table

5. Ataxia

and protective

index in cats* Protective

Drug Cyclobenzaprine Chlorpromazine Diazepam

Ataxia mg/kg, i.v. 13.5 (8.5155) 0.5 (0~38~0%) 0.15 (0.06+ 19)

y-Decerebrdte rigidity

index

x-Decerebrate rigidity

Ischemic spinal cord-rigidity

5.19

6.43

3.86

0.20


< 0.06

0.03

< 0.02

to.01

* All observations for determining drug-induced ataxia (staggering or wobbly gait) were carried out “blind” using 4 animals for each drug tested. Accumulative intravenous doses (beginning with 0.5 mg/kg cyclobenzaprine, 0.125 mg/kg chlorpromazine, and 0,063 mg/kg diazepam) were administered at 15 min intervals. Between drug injections, animals were permitted free movement. The average accumulative dose for induction of ataxia was determined and values in brackets indicate accumulative dose range. The protective indices for each drug was determined by the ratio: average accumulative i.v. dose for ataxia to average accumulative for abolition of EMC activity in the various preparations. ED,,,

682

N. N. SHARE and C. S. MCFARLANE Table 6. Acute tachyphylaxis

in ischemic

Drug

interval

% reduction

cord rigid cats*

2nd Injection

1st Injection

Dayt

spinal

t,o min

0, 10 reduction

the min

3rd Injection “I,, /0 t,, reduction min

Cyclobenzaprine

140 180 330

100 99 100

65 75 75

94 100 100

210 >300 125

Chlorpromazine

150 170 320

loo 100 100

40 80 65

41 59 29

25 25 15

14 37

607 627 1108

97 100 100

40 30 90

48 88 72

15 40 45

41 44 46

Diazepam

99

> 220 _

100

>I80

I 15 15 15

* Preparation as for Table 5. EMG frequencies were continuously recorded and averaged at 5 min intervals. Single drug doses of 3.5 mg/kg, iv. were administered and repeated whenever EMG activity returned to 60% or greater than the predrug control value (th,,). t Number of days after spinal cord ischemia.

Atuxiu and protective

index in cats

As shown in Table 5, average accumulative intravenous doses required to induce minimal signs of ataxia (staggering or wobbly gait) were 13.5 mg/kg for cyclobenzaprine, 0.5 mg/kg for chlorpromazine, and @I5 mg/kg for diazepam. Mild clonic convulsions lasting 20 set occurred in all animals after 7.9 mg/kg chlorpromazine, and apparent disorientation was seen after 0.19 mg/kg diazepam. Protective indices for cyclobenzaprine calculated for all three rigid cat preparations were clearly superior than corresponding values for the other test substances (Table 5). Values for cyclobenzaprine were consistently greater than unity, being 5.19, 6.43 and 3.86 for the y- and a-decerebrate and ischemic cord rigid cat preparations, respectively. In contrast, both chlorpromazine and diazepam had values of less than unity for all three rigid cat preparations. Acute tachyphylaxis

in cats

Comparative results with cyclobenzaprine, chlorpromazine and diazepam using the ischemic spinal cord rigid preparation are shown in Table 6. For this study, only preparations found sensitive to 3.5 mg/kg of intravenously administered chlorpromazine and diazepam were used. As can be seen, the first injection of all three compounds abolished EMG activity in these animals. However, following recovery of EMG frequencies to 60% (&,) of predrug control values, EMG blockade was re-established and prolonged only with a second, and later a third injection of cyclobenzaprine. In contrast, subsequent doses of either chlorpromazine or diazepam were repeatedly less effective in reducing EMG amplitude and frequency, and recovery to t,, values was more rapid in all preparations. DISCUSSION

In the above study, the skeletal muscle relaxant properties of cyclobenzaprine were compared with chlorpromazine and diazepam in various animal models exhibiting excessive tonic muscle activity. In experiments involving electrically and chemically induced tonic-extensor seizures in mice, diazepam was most active while chlorpromazine required extremely high doses for effect. However, protective indices consistently greater than unity could only be demonstrated for cyclobenzaprine. This suggests that in contrast with chlorpromazine and diazepam, cyclobenzaprine selectively acts upon excessive tonic skeletal muscle activity in mice. Cyclobenzaprine also appeared to be highly specific in its ability to abolish tonic skeletal muscle hyperactivity induced by local injection of tetanus toxin in the rabbit.

Cyclobenzaprine

683

While more potent in this assay, both chlorpromazine and diazepam caused ataxia at effective doses. Unlike experiments involving mice and rabbits, all three substances were approximately equipotent in intercollicular y-decerebrate preparations. However, in contrast with the consistent activity of cyclobenzaprine, doses required for reduction of cA-decerebrate rigidity were markedly variable with chlorpromazine and diazepam. Similar results were obtained for the latter two compounds by MAXWELL and READ (1972). Differences in the skeletal muscle relaxant properties of the three compounds were most evident in the ischemic spinal cord rigid cat. That this preparation is not dependent upon supraspinal drive of motoneurones (GELFAN and TARLOV, 1959; MURAYAMA and SMITH, 1965) was confirmed in the present study, which showed minimal loss of quadriceps EMG activity after spinal C2 section. Fusimotor (]I-motoneurone) activity is probably not essential, since dorsal root section does not permanently abolish tonic motoneurone activity (GELFAN and TARLOV, 1959). Thus, tonic x-motoneurone activity is most likely responsible for the observed hind limb rigidity. In this preparation, cyclobenzaprine consistently reduced the frequency and amplitude of quadriceps muscle potentials in contrast with the variable effects of chlorpromazine and diazepam. The duration of action of cyclobenzaprine was also considerably longer than that of the other two compounds. The ability of cyclobenzaprine to selectively reduce excessive tonic skeletal muscle activity was further suggested by observations in intact cats. In these animals, at or below effective doses in rigid preparations, cyclobenzaprine did not produce any signs of ataxia while this phenomenon was obvious in all animals after both chlorpromazine and diazepam. Thus, highest protective indices and those of greater than unity for all three rigid preparations were obtained only for cyclobenzaprine. In addition, acute tachyphylaxis or tolerance to drug action has been demonstrated for chlorpromazine in the local tetanus rabbit (LAURENCEand WEBSTER,1961) and diazepam in the anaesthetized cat and in man (BARNETTand FIORE, 1971; PARSONAGEand NORRIS,1967; WILSON, 1970). The development of acute tachyphylaxis to chlorpromazine and diazepam were also demonstrated in the present study using the ischemic spinal cord rigid cat. However, in this preparation, repeated doses of cyclobenzaprine not only failed to induce tachyphylaxis but rather reinstated and prolonged the duration of blockade. Finally, it may be noted that cyclobenzaprine appears generally more potent in yrelative to a-decerebrate rigid cats. This would suggest that the major site of action of cyclobenzaprine is supraspinal, reducing descending tonic discharges primarily upon y- but also upon r-motoneurones. However, its activity in intact as well as spinal C2 sectioned ischemic cord rigid preparations at slightly higher doses indicates that an action upon spinal motoneurons contributes to its overall efficacy as a skeletal muscle relaxant. In conclusion, the activity of cyclobenzaprine appeared to be highly consistent in several animal models exhibiting tonic skeletal muscle hyperactivity at dose levels which had no observable ataxic or behavioural depressant effects. The compound was also effective upon oral administration in mice and cats and acute tachyphylaxis to drug action could not be demonstrated. These observations suggest a potential utility for cyclobenzaprine in human pathological conditions manifested by excessive tonic skeletal muscle activity. Preliminary studies in man have tended to confirm the activity of cyclobenzaprine in hypertonic (MOLINA-NEGRO and ILLINGWORTH, 1971; LANCE and ANTHONY,1972) as opposed to hyperphasic disorders (ASHBY,BURKE, SUDHAKARand JONES, 1972). Furthermore, its rather selective action upon hypertonic skeletal muscle activity also suggests its potential utility as a pharmacological “tool” for further somatic motor function studies. Acknowledgernerlts-The A. RACKHAM for

Miss

authors are indebted to Miss L. their skilful technical

assistance.

BUSBY,

Mrs. S.

CHAKLESOF~,Mr. N. MCKEEL and

684

N. N. SHAREand C. S. MCFARLANE REFERENCES

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