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PubMed1986

Response decrement patterns after neuroleptic and non-neuroleptic drugs.

Previous work has shown that administration of pimozide and other neuroleptic drugs can produce within-session response decrement patterns of appetitively-reinforced behaviour. This phenomenon has been described as an extinction-like pattern of responding and used as evidence for the hypothesis that these drugs attenuate the rewarding properties of food, water and electrical stimulation of the brain. The present study was carried out to investigate within-session patterns of responding maintained by food presentation or shock avoidance after administration of a variety of neuroleptic and non-neuroleptic drugs. Haloperidol, metoclopramide, pimozide and butaclamol produced within-session response decrements of both food-reinforced lever pressing and one-way shock avoidance. The atypical antipsychotic drug clozapine did not consistently produce similar effects nor did the alpha-adrenoceptor agonist clonidine, the opiate agonist morphine, the benzodiazepine anxiolytic chlordiazepoxide and the muscle relaxant methocarbamol, although all these drugs were tested up to doses which markedly disrupted responding. Thus, within-session response decrement patterns are a characteristic effect of dopamine-blocking neuroleptic drugs. However, because of the generally similar effects of these drugs on appetitively- and aversively-motivated behaviour, these effects are probably best interpreted as actions on motor, rather than motivational, mechanisms.

Animals↗
PubMed1987

A comparison of diazepam stimuli in aged and adult rats.

Young adult rats (5 months) were compared with aged (28 months) rats in their ability to learn and perform in a diazepam drug discrimination. Both groups of rats were drug naive at the onset of the experiment. Adult and aged animals learned to discriminate diazepam. In general, the response rates under both drug and vehicle conditions were significantly lower for the aged group. The diazepam stimuli were dose-dependent in each group. Similar dose-dependent generalization with chlordiazepoxide, pentobarbital, and methocarbamol was also noted in both the aged and adult animals. These data suggest that aged animals, who have experienced anxiolytic compounds over a period of time (in this case, repeated administration of diazepam in the discrimination procedure), respond in a similar fashion to drug treatment as do young adult animals, verifying the reliability and validity of results obtained in aging rats who are repeatedly exposed to drug treatment.

Aging↗
PubMed1986

2-Amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam.

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).

2-Amino-5-phosphonovalerate↗
PubMed1986

The curve-shift paradigm in self-stimulation.

Eleven rats were trained to press a lever in an operant chamber in order to earn rewarding trains of cathodal rectangular pulses of fixed intensity and variable frequency. The rate-frequency functions were examined under administration of two neuroleptics (pimozide and chlorpromazine) and three manipulations that interfered with bar pressing (muscular relaxation with methocarbamol, increased lever weight, and limitation of maximum response rates by an F1 reinforcement schedule). Chlorpromazine, and pimozide at low dosages produced a near parallel shift of the rate-frequency functions on the logarithmic axis of pulses, suggesting that these drugs decreased the reinforcing efficacy of the stimulation. The three conditions that interfered with bar-pressing decreased the asymptotic rates and produced small or moderate lateral shifts. Changes in the reinforcing efficacy of the stimulation following the above manipulations were inferred from the shift in the number of pulses required at zero and half-maximal performance (theta 0 and M50 indices, respectively). In the cases of the manipulations that interfered with bar-pressing, M50 indicated a larger artifactual change in the efficacy of the stimulation, compared to theta 0. This phenomenon was mainly due to the fact that the asymptote of the altered functions was shifted towards higher pulse numbers.

Animals↗
PubMed1977

Drug discrimination and generalization in pigeons.

In a three-key operant conditioning situation six pigeons were trained to select the response key which was associated with each of three drug treatment conditions: d-amphetamine (2 mg/kg), pentobarbital (5 mg/kg), and saline. Thus, the drug state served as a discriminative stimulus for food reinforcement. After 20 sessions of discrimination training in each of the three conditions, more than 90% of the responses were correctly emitted in the presence of the appropriate drug or saline stimulus. Acquisition of the discrimination progressed at approximately equal rates for the three treatments. Subsequent to discrimination training, generalization gradients were obtained for several doses of the training drugs and for dose ranges of cocaine, morphine, and methocarbamol. The pigeons responded to morphine by choosing the key paired with pentobarbital during training; further, cocaine administration resulted in choice of the amphetamine key. However, metocarbamol, over the doses used, produced responding more characteristic of saline than of the other training drugs. The data suggest that a three-key operant discrimination procedure using pigeons provides a sensitive method for investigating the stimulus properties of relatively low doses of behaviorally relevant drugs.

Animals↗
PubMed1981

Differential effects of drug treatments on nose-poke and bar-press self-stimulation.

To assess the possibility of dissociating drug-induced gross performance deficits from effects on brain stimulation reward, the nose-poke and bar-press operants were systematically compared. Pentobarbital and methocarbamol (a muscle relaxant) reduced bar-pressing more strongly than nose-poking. In contrast, clonidine and haloperidol, which disrupt noradrenergic and dopaminergic neurotransmission respectively, had no differential effect on these operants. The nose-poke operant appears less vulnerable to drug-induced gross motor impairment and may be more suitable for pharmacological studies of self-stimulation.

Animals↗
PubMed1982

Self-stimulation response decrement patterns differentiate clonidine, baclofen and dopamine antagonists from drugs causing performance deficit.

Fouriezos and co-workers have reported that rats treated with the neuroleptics, pimozide or d-butaclamol, barpress at baseline rates at the start of an intracranial self-stimulation (ICSS) session, but cease responding within a few minutes. They suggested that this response decrement pattern (RDP) resembles natural extinction, indicating attenuation of reward by neuroleptic treatment. In the present experiments, the RDPs produced by several different drug classes were systematically compared. Two dopamine receptor antagonists, haloperidol and metoclopramide, produced an extinctionlike RDP. In contrast, the alpha-1 adrenoceptor blocker, prazosin, and the muscle relaxant, methocarbamol, caused uniformly low response rates that did not decrease further as the session progressed. Clonidine, an alpha-2 adrenoceptor agonist, and baclofen, a novel GABAB receptor agonist, were associated with RDPs that resembled those of the dopamine antagonists tested. Analysis of drug-induced RDPs is characterized as a valuable tool for exploring the nature of drug effects on ICSS responding.

Animals↗
PubMed1982

Effects of various catecholamine receptor antagonists, muscle relaxation and physical hindrance on shuttlebox self-stimulation.

Certain drugs, particularly clozapine and clonidine, have been reported to increase selectively the latency to initiate brain stimulation (the ON latency) in a shuttlebox test of self-stimulation, suggesting a preferential attenuation of the "reward" component. The pharmacological selectivity of this reported effect was systematically evaluated. At doses that blocked bar-pressing self-stimulation, metoclopramide (3 mg/kg), prazosin (3 mg/kg) clonidine (0.1mg/kg), clozapine (3 mg/kg)and haloperidol (0.3 mg/kg), all elevated the ON latency to a greater extent than the OFF latency. Methocarbamol (200 mg/kg), and a muscle relaxant, also elevated the ON latency preferentially but the magnitude of this preferential effect was smaller than that produced by the other drugs. A hurdle in the center of the shuttlebox increased the ON and OFF latencies nonselectively. The shuttlebox procedure does not clearly discriminate among various substances that interfere with noradrenergic or dopaminergic neurotransmission, but the common profile produced by the these substances is distinguishable to some degree from simple motor disruption.

Adrenergic alpha-Antagonists↗
PubMed1974

Tetanus: conservative management made easier by combination of muscle relaxants.

Conservative management of 11 consecutive cases of tetanus with diazepam in heavy doses and methocarbamol is described. All drugs were administered intravenously through a cut-down. Patients were nursed near the nurses' station for the first 3 to 5 days when fatal complications and very severe spasms are most likely to occur. There was minimal interference with the patients and a reasonable reduction in the duration of significant spasms, and complications were minimized. No neonates were included. Severity of tetanus cannot be determined only by consideration of onset of symptoms before admission. It is suggested that a combination of muscle relaxants without heavy sedation may produce an improvement in the results of conservative management of clinical tetanus.

Adolescent↗
PubMed1995

Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.

Animals↗
PubMed1986

Peripheral dystonia.

We studied four patients with distal, action-induced involuntary postures of the hand that could be considered focal dystonia. All four patients had electrophysiologic findings consistent with peripheral nervous system lesions (pronator teres syndrome, radial nerve palsy, lower brachial plexus lesion, or median nerve lesion). With varying success, patients were treated with carbamazepine, trihexyphenidyl, methocarbamol, and wrist splinting. We wish to emphasize that peripheral entrapment and brachial plexopathy should be added to the causes of secondary dystonias.

Adult↗
PubMed1993

Quantitative grip strength assessment as a means of evaluating muscle relaxation in mice.

The effects of various centrally acting drugs and some peripherally acting agents on the forelimb grip strength of CD-1 mice were explored. Forelimb grip strength was assessed by use of a strain gauge to measure the lateral pull force, in grams, exerted by mice as an index of muscle relaxation. The muscle relaxants, diazepam, midazolam, baclofen, methocarbamol, dantrolene sodium and the neuromuscular blocking agents, succinylcholine and pancuronium bromide, dose-dependently reduced forelimb grip strength. 2-Amino-7-phosphonoheptanoic acid (AP7), which has also been shown to have muscle relaxant effects, also reduced grip strength. Pentobarbital, ethanol, phencyclidine, ketamine and chlorpromazine reduced grip strength at doses which produced behavioral impairments. Lithium chloride, a toxic compound used to induce taste aversions, and clonidine, at doses which affect blood pressure, body temperature and locomotor activity, did not affect grip strength. In addition, stimulant doses of amphetamine and caffeine, but not of morphine, increased grip strength in a dose-dependent manner. These results extend previous findings and suggest that this forelimb grip strength procedure may be a useful screening test for the identification of the potential muscle relaxant properties of drugs.

Animals↗
PubMed1975

Etonitazine-induced rigidity and its antagonism by centrally acting muscle relaxants.

Some narcotic drugs have been reported to produce increases in muscle tone in rats. In our laboratory we have found that etonitazine produces a 'lead-pipe' rigidity of the trunk and limb musculature. The reported studies were conducted to characterize etonitazine-induced rigidity more fully, to compare the degree of rigidity with that produced by morphine, codeine and methadone, and to assess the sensitivity of this rigidity to centrally acting muscle relaxants. Of the 4 narcotics tested, etonitazine was far more potent than methadone or morphine for producing rigidity; codeine did not produce peak rigidity comparable to the other 3 narcotics. Etonitazine-induced rigidity occurs at a supraspinal level since the effect was prevented by spinal transsection. Etonitazine-induced rigidity was prevented by the narcotic antagonists cyclazocine, pentazocine and naloxone but not by the serotonin depletor, p-chlorophenylalanine. Etonitazine-induced rigidity was antagonized by centrally acting muscle relaxants, including diazepam, methocarbamol, carisoprodol and zoxazolamine; in agreement with their relative clinical muscle relaxant potencies, diazepam is the most potent antagonist of etonitazine-induced rigidity.

Analgesics, Opioid↗
PubMed1984

Evidence for heterogeneous rotational responsiveness to apomorphine, 3-PPP and SKF 38393 in 6-hydroxydopamine-denervated rats.

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Review of oral skeletal muscle relaxants for the craniomandibular disorder (CMD) practitioner.

The presence of acute or chronic muscle pain and muscle spasm is a common finding in the treatment of craniomandibular disorders. A review of the literature on the centrally acting oral skeletal muscle relaxants is presented to assist the practitioner in treating CMD. The pharmacology, pharmacokinetics, metabolism, adverse reactions and available dosage forms of the skeletal muscle relaxants are discussed. The agents reviewed are carisoprodol, methocarbamol, chlorphenesin carbamate, metaxalone, chloroxazone, orphenadrine citrate, diazepam, and cyclobenzaprine. Their mechanisms are not well defined. Most act via selective inhibition of polysynaptic pathways in the central nervous system. Most evidence for their efficacy is based on subjective responses and there is question as to the adequacy of the clinical studies to date. Based on the data all of the relaxants (possibly excepting diazepam) are better than placebo based on subjective analyses. Although combinations with analgesics provide better symptom relief, no superiority over analgesics exists. No skeletal relaxant has been shown to be superior over any other oral relaxant. Based on recent clinical suspicions, further study of multiple pharmacologic effects of newer agents is indicated.

Humans↗
PubMed2004

Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants for back pain in the United States.

STUDY DESIGN: Secondary analysis of the 2000 Medical Expenditure Panel Survey (MEPS). OBJECTIVE.: To examine national prescription patterns of nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants among individuals with back pain in the United States. SUMMARY OF BACKGROUND DATA: There is a lack of information on national prescription patterns of NSAIDs and muscle relaxants among individuals with back pain in the United States. METHODS: Traditional NSAIDs, cyclooxygenase-2-specific (COX-2) inhibitors, and muscle relaxants were investigated. Individuals with back pain were stratified by socio-demographic characteristics and geographic regions. For each medication category, overall prescribing frequency was compared across different strata and individual drug prescription was analyzed. RESULTS: Traditional NSAIDs, COX-2 inhibitors, and muscle relaxants, respectively, accounted for 16.3%, 10%, and 18.5% of total prescriptions for back pain in 2000. Among individual drugs, ibuprofen and naproxen accounted for most of the prescriptions for traditional NSAIDs (60%), whereas two thirds of the prescriptions for muscle relaxants were attributable to cyclobenzaprine, carisoprodol, and methocarbamol. Prescription of COX-2 inhibitors or muscle relaxants demonstrated wide variations across different regions. Several individual characteristics including age, race, and educational level were associated with the prescription of some of the medications. CONCLUSIONS: Neither traditional NSAIDs, nor COX-2 inhibitors, nor muscle relaxants dominated prescriptions for back pain. However, a small number of individual drugs were attributable to most of the prescriptions for traditional NSAIDs or muscle relaxants. The prescription of some of the medications demonstrated wide variations across different regions or different racial and educational groups. More studies are needed to understand the source of the variations and what constitutes optimal prescribing.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Tremorgenic mycotoxicosis in four dogs from a single household.

Mycotoxins are fungal metabolites that induce undesirable effects. The effects of these mycotoxins vary depending on the chemical structure of the toxin and degree of toxicity. Mycotoxins that induce muscle tremors, ataxia, and convulsions are termed tremorgenic mycotoxins. Our report documents the clinical course of 4 dogs from a single household that were simultaneously affected by tremorgenic mycotoxins. Diagnosis of tremorgenic mycotoxicosis was confirmed by stomach content analysis from 1 of the dogs. The mycotoxins identified were penitrem A and roquefortine, which are both produced by Penicillium spp. Treatment goals following tremorgenic mycotoxin ingestion include minimizing absorption, controlling tremors and seizures with methocarbamol and pentobarbital sodium administration, and providing supportive care. Two of the affected dogs required ventilatory support. With early aggressive treatment, prognosis is good and recovery is complete without sequelae. It is helpful for the clinician to be familiar with the typical clinical signs at the time of admission, treatment, and clinical course of dogs with tremorgenic mycotoxicosis.

Animals↗
PubMed2005

Diagnosis and treatment of hind limb muscle strain injuries in 22 dogs.

The anamnesis was obtained from the medical records of 22 dogs diagnosed with hind limb muscle strain injury over a four-year period. The signalment, history, diagnostic imaging and clinical findings, treatment and outcome are described. The affected dogs were primarily from large breeds. Although only a few clients reported a specific injury, 11 dogs were admitted for an acute onset of lameness of unknown origin. The hip adductor muscles were affected in 21 dogs, and 11 dogs had previously undergone orthopaedic surgery of the affected limb. The dogs were primarily diagnosed by physical examination, although the diagnosis was confirmed with ultrasound imaging in the two most recent cases. Neither concurrent orthopoedic nor neurological disease was found during the study period in four of 22 dogs, and another three dogs had only mild radiographic coxofemoral osteoarthritis that did not cause any clinical signs during the study period. All of the dogs were treated medically with some combination of rest, physical therapy, methocarbamol, and a non-steroidol anti-inflammatory drug (NSAID). The injury-associated lameness improved, or completely resolved, with conservative, non-surgical therapy in most dogs. Of the 15 dogs available for follow-up (mean 577 days), eight had complete resolution of their clinical signs, two showed significant improvement, and one showed some improvement. Muscle strain injury may be an under-diagnosed cause or contributor to acute hind limb lameness in large breed dogs, either alone or following orthopoedic surgery.

Animals↗