U. Havemann

Opioid receptors in the caudate nucleus can mediate EMG-recorded rigidity in rats

SummarySystemic administrations of opioids are known to induce “catatonia” or “lead pipe rigidity” in rats. The relevance of the caudate nucleus in inducing rigidity was tested. For this purpose, several opioids (or saline) were injected into the head of the caudate nucleus (“intrastriatal” injection) through an implanted cannula, and the electromyographical activity (EMG) was recorded in the gastrocnemius-soleus muscle (GS). Morphine (7.5–30 μg), injected unilaterally, induced a continuous EMG activity in the ipsilateral GS muscle. This effect could be antagonized by systemic administration of naloxone (1 or 2 mg/kg i.p.). D-ala2-met5-enkephalinamide (3 μg) and levorphanol (22.5 μg) induced an EMG activity, too, whereas an equimolar dose of dextrorphan was ineffective, indicating that this effect was stereospecific and mediated via opioid receptors in the caudate nucleus. The EMG activity observed after systemic morphine administration (15 mg/kg i.p.) was antagonized by intrastriatal injection of naloxone (5 μg). From our results, it can be concluded that the striatum — at least the head of the caudate nucleus — plays an important role in mediating the rigidity observed after systemic administration of morphine and other opioids.

GABAergic mechanisms in mediating muscular rigidity, catalepsy and postural asymmetry in rats: Differences between dorsal and ventral striatum

In rats, the GABAergic agonist muscimol was injected unilaterally either into the mid ventroposterior striatum (ventral striatum) or into the mid dorsoposterior striatum (dorsal striatum), and the following parameters were estimated: (1) a tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus (GS) muscle, which appears to reflect a muscular rigidity; (2) catalepsy, and (3) asymmetries in posture. Injection of muscimol (25 or 50 ng) into the ventral striatum produced tonic EMG activity, catalepsy and ipsiversive posture; these signs were much less pronounced or not observed after injections into the dorsal striatum. Co-administration of bicuculline (500 ng) into the ventral striatum, or simultaneous injection of muscimol (25 ng) into the substantia nigra pars reticulata (SNR), antagonized both the tonic EMG activity and the catalepsy produced by injection of 50 ng muscimol into the ventral striatum. These results seem to support the assumption that all 3 symptoms mentioned can be produced by an inhibition of striatonigral GABAergic neurones. These symptoms are probably due to a disinhibition of nigrofugal neurones, originating in the SNR.

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

SummaryIn 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 gastrocnemiussoleus 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 μ-type agonist, in the dose of 40 nmol induced a pronounced EMG activity, while 10 or 40 nmol of [D-Ala2, D-Leu5] enkephalin, a δ-type agonist, led to no or little effect, respectively. β-Endorphin, which reacts with the ε-type of receptors, was completely ineffective in doses of 3 or 15 nmol. The benzomorphan compound Mr 2033-Cl, which is a ν-type agonist, induced a moderate activity in the dose of 15 nmol; 3 nmol were ineffective. β-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 μ-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 primay mechanism inducing the rigidity. β-LPH62–67 and β-LPH66–77 (15 nmol) intrastritally] were also completely inactive.

Role of opioid receptors in the substantia nigra in morphine-induced muscular rigidity.

Uni- or bilateral injection of morphine (MO) (3-13 nmoles) into the substantia nigra pars reticulata (SNR) produced tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus (GS) muscle of non-anesthesized rats. This activity was antagonized by naloxone (NAL) (10 nmoles) coadministered with MO into the SNR. Bilateral lesion of the caudate nucleus (CN) with kainic acid did not prevent the tonic EMG activity occurring after the injection of MO into the SNR. Unilateral injection of MO (40 nmoles) into the CN also induced tonic EMG activity in the GS-muscle, which was antagonized by NAL (10 nmoles) administered into the SNR ipsilaterally and simultaneously to the intrastriatal injection of MO. The results suggest that enkephalinergic mechanisms in the SNR seem to play a crucial role in the function of striatal efferent pathways relayed in the SNR.

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

SummaryThe 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 μg of morphine induced a decrease of locomotor activity and weak catalepsy; 15 μg 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 μg) 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.

The role of the substantia nigra in motility of the rat. Muscular rigidity, body asymmetry and catalepsy after injection of morphine into the nigra.

Unilateral injection of morphine (1.0, 2.5 or 5.0 micrograms/0.5 microliter) into the substantia nigra pars reticulata produced, in a dose-dependent way, tonic activity in the electromyogram (EMG) recorded from the ipsilateral gastrocnemius-soleus muscle of unanaesthetized rats. The effect produced by 5 micrograms of morphine was antagonized by co-administration of 5 micrograms of naloxone. Bilateral injection of morphine (5 micrograms each side) also produced a tonic activity in the EMG and catalepsy, but no asymmetry of posture. Unilateral injection of morphine (5 micrograms) into the substantia nigra pars compacta produced contralateral turning and/or stereotypy, but no tonic activity in the EMG. Naloxone (5 micrograms), when injected into the substantia nigra failed to produce any tonic activity in the EMG or any catalepsy. Larger doses of naloxone (10 or 20 micrograms) produced slight to moderate tonic activity in the EMG when injected into the pars reticulata. Injections of saline (0.5 microliter) into either the reticulata or compacta were ineffective. Bilateral lesions of the caudate nucleus with kainic acid (1 microgram each side) did not prevent the development either of the tonic activity in the EMG or of the catalepsy, which were both produced by unilateral injection of morphine (5 micrograms) into the pars reticulata. These results suggest that opioid mechanisms in the nigra might play a role in the regulation of posture and muscle tone and participate in the expression of motor functions controlled by the striatum (and probably also by the nucleus accumbens).

Locomotor activity of rats after injection of various opiods into the nucleus accumbens and the septum mediale

SummaryThe possible role of the nucleus accumbens (ACB) and, in some experiments, the septum mediale (SM) in mediating alterations in locomotor activity, produced by various opioids, was evaluated in the rat, the drug being injected either into the left central part of the ACB or into the left SM. Morphine, predominantly acting at the mu-type receptors, given in larger doses (13 or 40 nmol into the ACB) produced depression of locomotor activity and catalepsy, whereas 2.5 nmol were ineffective. Co-administration of naloxone into the ACB suppressed the effects of morphine.d-ala2,d-leu5-enkephalin (DADL), a preferential delta-type receptor agonist, produced a biphasic effect on locomotor activity, namely an inhibition of it and a catalepsy, followed by a locomotor activation. This effect was observed after 4 or 13 nmol; 1 nmol produced a delayed locomotor activation without any previous inhibition, whereas 0.4 or 0.1 nmol were ineffective. Equimolar doses of naloxone, when coadministered with DADL, only partially antagonized these effects of DADL. In contrast, co-administration of a small dose of DADL and an excess dose of naloxone into the ACB produced an immediate increase in locomotor activity. Injections of a predominant kappa type receptor agonist, MR 2033-Cl, were ineffective.Injection of DADL, either alone or combined with naloxone into the SM (1 nmol) produced an immediate stimulation of locomotor activity.The results suggest that locomotor depression and catalepsy may be mediated by opioid receptors of the mutype in the ACB, whereas locomotor stimulation is due to an action on delta type receptors, an effect which may be masked by simultaneous stimulation of mu-type receptors under certain conditions. Kappa-type receptors apparently are not involved in any of these effects. In addition, a diffusion of DADL to the adjacent SM may contribute to locomotor stimulation.

Nigral gabaergic mechanisms and EMG activity in rats: Differences between pars reticulata and pars compacta

The effects of GABAergic drugs, injected unilaterally either into the substantia nigra pars compacta (SNC) or pars reticulata (SNR) of rats, on motility (tonic activity in the gastrocnemius-soleus muscle, turning behaviour, catalepsy) were studied. Administration of the GABAergic antagonist bicuculline (12.5-50 ng) into the SNR produced tonic activity in the EMG, catalepsy and an ipsiversive posture. The tonic EMG activity was prevented by co-administration of muscimol (25 ng), but not by bilateral lesions of the striatum with kainic acid. Tonic activity in the EMG was also produced by injections of muscimol (25 ng) into the SNC, whereas injections into the SNR led to contraversive circling and no tonic activity in the EMG. Because a new parameter was used--the tonic activity in the EMG--our results support the assumption that GABAergic mechanisms in both parts of the substantia nigra play a different role in regulating and mediating striatal function.

Effects of striatal lesions with kainic acid on morphine-induced “catatonia” and increase of striatal dopamine turnover

SummaryThe influence of striatal lesions (head of the caudate nucleus) with kainic acid on “catatonia” and on the increase of the dopamine metabolite DOPAC in the striatum after systemic morphine administration was measured in rats. These lesions strongly prevented the morphine-induced muscular rigidity, measured as activity in the electromyogram (EMG) of the gastrocnemius-soleus muscle of non-anesthesized animals. On the other hand, the decrease of locomotion (akinesia) measured using an Animex Activity Meter and an acitivity wheel, was not prevented or reduced. The lesions did not influence the inhibitory effect of morphine on the activation of flexor α-motoneurones, either. These results suggest that the head of the caudate nucleus plays an important role in mediating morphine rigidity, but not akinesia or inhibition of the activation of flexor α-motoneurones. Opioid-induced “catatonia” ought to be regarded as a mixture both of rigidity and of akinesia.Morphine led to a rapid decrease, followed by a slow increase of striatal DOPAC concentration. Lesions induced by kainic acid slightly inhibited the decrease and markedly enhanced the increase of DOPAC. Accordingly, an intact nigro-striato-nigral loop is not necessary for the increase of striatal dopamine turnover, observed after morphine administration. The different sites of action, which are likely to mediate all these effects of morphine, are discussed.

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

Abstract 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.