Muscular Rigidity In Rats Research Articles

Discrimination of morphine- and haloperidol-induced muscular rigidity and akinesia/catalepsy in simple tests in rats

The present study was conducted to establish a simple method for measuring muscular rigidity in rats, which could be used for screening and is able to discriminate between rigidity and akinesia/catalepsy. Therefore, we treated rats with morphine (30 mg/kg i.p.), since large doses of morphine lead to muscular rigidity and akinesia. We measured muscular rigidity with a new method by determining the resistance of the hindlimb to passive flexion in the ‘balance test’ and also checked haloperidol (3 mg/kg i.p.) treated rats for muscular rigidity. Furthermore, catalepsy was also tested after administration of each of these drugs. Then, the influence of D 1-like and D 2-like dopamine receptor stimulation on muscular rigidity and catalepsy was studied. Therefore, the partial D 1 agonist SKF 38393 (3 and 8 mg/kg s.c.), the D 2/ D 1 agonist pergolide (0.25 and 0.5 mg/kg i.p.) and the dopamine precursor l-DOPA (50 and 100 mg/kg i.p.) were administered up to 30 min before muscular rigidity was measured in morphine-treated rats. The results showed that morphine, but not haloperidol led to muscular rigidity, whereas both drugs led to positive scores in the catalepsy test. The dopaminergic drugs partly antagonized the morphine-induced muscular rigidity in the doses applied, but not the catalepsy. Apparently, rigidity, akinesia/catalepsy produced by morphine can be discriminated from that produced by haloperidol in simple and quick tests.

Involvement of spinal adenosine A 1 and A 2 receptors in fentanyl-induced muscular rigidity in the rat

In the present study, using hydrophilic adenosine antagonists either selective to A 1 or A 2 receptors, we investigated the central and spinal adenosinergic participation in fentanyl-induced muscular rigidity. Adult Sprague–Dawley rats were anesthetized with ketamine and were under mechanical ventilation. Fentanyl (100 μg/kg, i.v.) consistently elicited electromyographic (EMG) activation in the sacrococcygeal dorsalis lateralis muscle. This implied muscular rigidity was not blocked by i.c.v. administration of the adenosine A 1 antagonist, 1-allyl-3,7-dimethyl-8- p-sulfophenyl-xanthine (ADSPX; 20 or 40 nmol/2.5 μl), except at higher dose (80 nmol). Equimolar doses of the adenosine A 2 antagonist, 3,7-dimethyl-1-propargylxanthane (DMPX), did not exert any inhibitory effect on fentanyl-induced rigidity. Intrathecal (i.t.) administration of the same doses of ADSPX (20, 40 or 80 nmol/10 μl) appreciably suppressed the EMG activation. However, the rigidity was only inhibited by 40 or 80 nmol (i.t.) of DMPX, but not by the lowest dose. High-dose (80 nmol, i.t.) adenosine A 1 or A 2 antagonist per se did not induce motor impairment or hindlimb paralysis in conscious animals. These results suggest that adenosine A 1 and A 2 receptors in the spinal cord may play a more crucial role than those in the central nervous system (CNS) in fentanyl-induced muscular rigidity in rats.

Power spectral analysis of electromyographic and systemic arterial pressure signals during fentanyl-induced muscular rigidity in the rat

We have measured electromyographic (EMG) and systemic arterial pressure (SAP) signals during fentanyl-induced muscular rigidity in adult male Sprague-Dawley rats anaesthetized initially with ketamine 120 mg kg-1 i.p. during controlled ventilation. Fentanyl 100 micrograms kg-1 i.v. induced significant increase in EMG activity, recorded from the sacrococcygeus dorsi lateralis muscle. Power spectral analysis revealed that this was produced by an increase in the root mean square and a decrease in the mean power frequency values of the signals, signifying recruitment and synchronous activation of motor units. Together with transient hypotension and bradycardia, power spectral analysis of the SAP signals demonstrated a reduced but maintained power density of the frequency components that represent respiratory, baroreceptor and vasomotor activities. All these effects were only demonstrated unequivocally in rats maintained by i.v. infusion of ketamine until 10 min before the administration of fentanyl. We conclude that analysis of the temporal alterations in the spectral components of the EMG and SAP signals in rats during mechanical ventilation provides a sensitive method of measuring fentanyl-induced muscular rigidity and the accompanying alterations in haemodynamic variables.

Automated method for the measurement of fentanyl-induced muscular rigidity

An automated method is described that can accurately and reliably measure weight displacement resulting from hindlimb extension due to muscular rigidity following opioid administration in rats. IV administration of fentanyl (0.035 mg/kg) immediately induced rigidity. Rigidity was dose dependently reversed by the α 2-agonist clonidine with an ED 50 value equal to 0.011 mg/kg IV. Second, rigidity was restored following administration of the α 2-antagonist idazoxan (0.3 mg/kg, IV) thereby confirming an α 2-mediated mechanism of action. Previously, reversal of fentanyl-induced muscular rigidity was measured by subjective rating criteria not suitable for quantitative potency comparisons. The new automated rigidity model provides a simple yet precise measurement of the ability of α 2-agonist to attenuate opioid-induced muscular rigidity in rats.

Involvement of coerulospinal noradrenergic pathway in fentanyl-induced muscular rigidity in rats

Unilateral, site-specific microinjection of fentanyl ( 2.5 μ g 50 nl ) into the locus coeruleus (LC) in Sprague-Dawley rats anesthetized with ketamine evoked a significant increase in the electromyographic activity recorded from both caudal lateral extensor and gastrocnemius muscles. This correlate of opiate-induced muscular rigidity was appreciably antagonized by a pretreatment with the specific α 1-adrenoceptor blocker, prazosin (250 μg/kg, i.v.). On the other hand, an equimolar dose (0.65 μmol/kg) of the specific α 2-adrenoceptor blocker, yohimbine (0.23 mg/kg, i.v.) failed to prevent the occurrence of fentanyl-induced EMG activation. We suggest that the coerulospinal noradrenergic pathway may be directly involved in the elicitation of muscular rigidity by fentanyl, possibly via α 1-adrenoceptors in the spinal cord.

Differential effects of prazosin and yohimbine on fentanyl-induced muscular rigidity in rats

Whereas muscular rigidity is a well-known phenomenon that is related to anesthesia induced by large doses of narcotic drugs, the precise underlying mechanism(s) remain to be fully elucidated. This study investigated the possible role of noradrenergic neurotransmission and the participation of α-adrenoceptors in this phenomenon. Male Sprague-Dawley rats, under ketamine-induced anesthesia (120 mg/kg, i.p.) and with proper control of respiration, body temperature and end-tidal CO 2 were used. Intravenous administration of fentanyl (lOO g/kg) consistently caused a significant increase in the electromyographic (EMG) activity, recorded from both gastrocnemius and abdominal reetus muscles. This implied muscular rigidity was markedly antagonized by pretreatment with the specific α 1-adrenoceptor blocker, prazosin (50 or 250μg/kg, i.V.). This antagonism occurred in spite of a high level of fentanyl in the plasma, as determined by radioimmunoassay. The specific α 2-adrenoceptor blocker, yohimbine (1.15 or 2.3 mg/kg, i.V.), on the other hand, not only failed to prevent fentanyl-induced activation of the EMG, but actually potentiated the response. It is concluded that noradrenergic neurotransmission, possibly originating from the locus coeruleus, may participate in the elicitation of muscular rigidity by fentanyl. Furthermore, this process may involve an excitatory action through α 1-, and an inhibitory action through α 2-adrenoceptors, in the spinal cord.

The nucleus accumbens and forelimb muscular rigidity in rats.

The present set of experiments were performed to evaluate the role of the nucleus accumbens in the regulation of forelimb muscle tone. Rats were chronically implanted with cannulae aimed at the nucleus accumbens or the neostriatum and with EMG electrodes in the triceps or the gastrocnemius soleus muscle. The experiments were all performed in non-anaesthetised freely moving animals. The results show that haloperidol induced an increase in triceps muscle tone when injected into the nucleus accumbens but not when injected into the neostriatum. Likewise it was found that haloperidol induced an increase in gastrocnemius soleus muscle tone when injected into the neostriatum but not when injected into the nucleus accumbens. The increase in triceps muscle tone seen after intra-accumbens haloperidol was only briefly attenuated by apomorphine, whereas phenylephrine produced a more long lasting antagonism. The present data show that in addition to the cortex, subcortical structures also appear to possess a certain topography, with forelimb rigidity being mediated, at least in part, by the nucleus accumbens, and hindlimb rigidity, at least in part by the neostriatum. In addition it appears that the effects of haloperidol in the nucleus accumbens on triceps muscle tone are primarily mediated by alpha 1 adrenergic receptors, although a minor role of dopamine D2 receptors cannot be fully excluded.

Reversal of opioid-induced muscular rigidity in rats: Evidence for alpha-2 adrenergic involvement

Compounds from several different pharmacological classes were tested for their ability to reverse the muscular rigidity induced by an intravenous dose of fentanyl that also caused loss of the righting reflex (LOR). Opioid antagonists reversed the entire syndrome—LOR and rigidity but, generally, rigidity could be reversed nonspecifically by doses of compounds that caused LOR by themselves (e.g., CNS depressants). Muscle relaxants and agonists of histamine, which appeared to be acting peripherally, were also effective. On the other hand, serotonergic drugs and dopamine agonists were not. However, dopaminergic antagonists with adrenolytic activity (i.e., chlorpromazine, haloperidol) reversed rigidity, whereas sulpiride did not. Moreover, rigidity reversed by neuroleptics could be restored by piperoxane, an alpha-2 adrenergic antagonist. In addition, clonidine and other alpha-2 agonists selectively reversed only rigidity following systemic or central administration at doses several orders of magnitude lower than other compounds tested. It is proposed that opioid-induced rigidity is reversed by inhibition of sympathoadrenal outflow which can be accomplished selectively, centrally, by alpha-2 agonists.

Role of muscarinic cholinergic mechanisms in the substantia nigra pars reticulata in mediating muscular rigidity in rats.

Bethanechol chloride (5-25 micrograms), when injected into the substantia nigra pars reticulata (SNR) of rats, produced muscular rigidity in a dose-dependent way, and in addition, catalepsy and ipsilateral posture. The effects of bethanechol in the dose of 25 micrograms were prevented by co-administration of 10 micrograms scopolamine hydrochloride. Injections of 25 micrograms bethanechol or 10 micrograms scopolamine into the reticulata only slightly affected the muscular rigidity produced by 15 mg/kg i.p. morphine hydrochloride. The results suggest that muscarinic cholinergic mechanisms in the substantia nigra pars reticulata, although effective by themselves, affect by expression of at least one striatal functional alteration, the muscular rigidity, in a less effective way than GABAergic or endogenous opioid mechanisms do.

Reversal of the muscle relaxant effect of diazepam by the specific benzodiazepine antagonist Ro 15-1788: An electromyographic study in morphine model of muscular rigidity in rats

The effects of the benzodiazepines diazepam and midazolam on the rigidity produced by systemic administration of morphine (15 mg/kg i.p.) were studied in rats. The rigidity was recorded as a tonic activity from the gastrocnemius-soleus muscle of non-anesthetized rats in the electromyogram. Both diazepam (1–5 mg/kg i.p.) and midazolam (2.5 and 5 mg/kg i.p.), when administered 45 min after morphine, temporarily antagonized the muscular rigidity. When the competitive antagonist Ro 15-1788 (ethyl-8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5a]-[1, 4] benzodiazepine-3-carboxylate) (5 mg/kg i.p.) was administered together with diazepam (5 mg/kg i.p.), it prevented the effect of diazepam, although by itself it did not affect the morphine-induced muscular rigidity. Our results suggest that diazepam, by acting on benzodiazepine receptors, can antagonize the morphine-induced muscular rigidity. The latter phenomenon might serve as a model for some types of muscular rigidity observed in humans.

Role of GABAergic mechanisms in the substantia nigra pars reticulata in modulating morphine-induced muscular rigidity in rats

Systemic administration of morphine (15 mg/kg i.p.) induced a muscular rigidity in rats, which was recorded from the gastrocnemius-soleus muscle as tonic activity in the electromyogram (EMG). Administration of muscimol (12.5 or 25 ng) into the substantia nigra pars reticulata (SNR) antagonized the rigidity in a dose-dependent manner, whereas bicuculline enhanced it. It was concluded that GABAergic mechanisms in the SNR play an important role in mediating or modulating the expression of the morphine-induced rigidity, which is known to be due to an alteration of striatal function via opioid receptors located in this brain area.

Evidence for functional interactions of morphine in substantia nigra and striatum in relation to muscular rigidity in rats

Systemic administration of morphine (15 mg/kg i.p.) induced muscular rigidity in rats, which was recorded from the gastrocnemius-soleus muscle as tonic activity in the electromyogram. Administration of morphine (5 or 10 μg) into the pars compacta of the substantia nigra antagonized the rigidity in a dose-dependent manner, whereas administration of morphine at a dose of 5 μg into the pars reticulata of the substantia nigra enhanced the tonic EMG activity. When morphine and naloxone were co-administered intranigrally, the tonic EMG activity was not affected.

Unilateral injection of morphine into the nucleus accumbens induces akinesia and catalepsy, but no spontaneous muscular rigidity in rats

The role of the nucleus accumbens in the generation of the signs of morphine-induced "catatonia" namely akinesia, catalepsy and muscular rigidity, was studied in rats. Morphine was injected into the nucleus accumbens and either spontaneous locomotor activity or catalepsy or activity in the electromyogram of the gastrocnemius-soleus muscle, signalling the appearance of rigidity, were recorded. Unilateral injections of 5 micrograms of morphine induced a decrease of locomotor activity and weak catalepsy; 15 micrograms of morphine completely abolished locomotor activity (akinesia) and produced a very pronounced catalepsy. All these effects were antagonized by naloxone (2 mg/kg i.p.). Injections of morphine into the nucleus accumbens did not induce muscular rigidity. In contrast, injection of morphine (15 micrograms) into the head of the caudate nucleus, which induced a pronounced muscular rigidity, did not noticeably alter the locomotor activity nor did it produce catalepsy. Our results suggest that 1) the nucleus accumbens is relevant for systemically administered morphine to produce akinesia and catalepsy, but is not noticeably involved in the development of muscular rigidity; 2) they provide evidence that morphine-induced catalepsy is largely due to a strong akinesia, and that muscular rigidity, observed after morphine administration, does not contribute to positive scores in the catalepsy test.

Further characterization of opioid receptors in the striatum mediating muscular rigidity in rats.

In previous studies, we had found that opioid receptors in the striatum can mediate muscular rigidity which can be recorded as a tonic EMG activity in the gastrocnemius-soleus muscle of rats. We have now tried to evaluate the type of opioid receptors mediating the EMG activity. For this purpose, opioids regarded to be selective agonists at one type of opioid receptors were injected into the striatum of unanesthesized rats. Morphine, a micro-type agonist, in the dose of 40 nmol induced a pronounced EMG activity, while 10 to 40 nmol of [D-Ala2, D-Leu5] enkephalin, a delta-type agonist, led to no or little effect, respectively. beta-Endorphin, which reacts with the epsilon -type of receptors, was completely ineffective in doses of 3 or 15 nmol. The benzomorphan compound Mr 2033-Cl, which is a kappa-type agonist, induced a moderate activity in the dose of 15 nmol; 3 nmol were ineffective. beta-Casomorphin-4 was the most potent of the drugs studied in our system, since 9 nmol induced a pronounced rigidity, which was naloxone-reversible (2 mg/kg i.p.). The doses of these opioids effective in comparison with their known in vitro potencies suggest that the rigidity is mediated by a group of striatal opioid receptors, which has some similarity to the micro-type, but also shows some differences. In contrast, haloperidol, injected either into the striatum (30 nmol) or systemically (2 mg/kg i.p.), did not induce any EMG activity, suggesting that a decrease in dopaminergic neurotransmission is not the primary mechanism inducing the rigidity. beta-LPH62-77 and beta-LPH66-77 (15 nmol) intrastritally] were also completely inactive.

Depression of reserpine-induced muscular rigidity in rats after administration of lisuride into the spinal subarachnoid space.

Muscular rigidity was induced by reserpine (10 mg/kg) in rats and the tonic activity of the gastrocnemius muscle was recorded in the electromyogram. Systemic administration of lisuride, an ergoline, resulted in a dose-dependent depression of rigidity. To examine the spinal cord as a site of action for lisuride to depress reserpine-induced rigidity, a method for the chronic catheterization of the lumbar spinal subarachnoid space was used, which allowed the administration of drugs to reserpinized, intact rats without anaesthesia. Lisuride injected into the lumbar spinal subarachnoid space resulted in a longlasting depression of rigidity. These results suggest that the spinal cord is an important site of action of lisuride.

Morphine-induced muscular rigidity in rats

Morphine in doses of 7.5 to 17.5 mg/kg, i.p. induced dose-dependent, electromyographically recorded muscular activity (rigidity), which could be inhibited by the morphine antagonist, naloxone and by drugs increasing central dopaminergic activity, L-DOPA and apomorphine. The results suggest that the rigidity was morphine specific and was due to a functional dopamine deficiency in the striata. There was a good parallelism between catalepsy and rigidity. Since both effects were easily reversed by L-DOPA, it is suggested that in our system studied the primary action of morphine was a presynaptic effect in the nigrostriatal neurons and not blockade of striatal dopamine receptors. The results could be explained by ‘diversion’ of newly synthetized dopamine from storage sites to sites of catabolism resulting in a lack of dopamine at striatal receptor sites which might lead to a subsequent compensatory increase of dopamine utilization.