Morphine Catalepsy Research Articles

Nicotine potentiation of morphine-induced catalepsy in mice

In the present study, effects of nicotine on catalepsy induced by morphine in mice have been investigated. Morphine but not nicotine induced a dose-dependent catalepsy. The response of morphine was potentiated by nicotine. Intraperitoneal administration of atropine, naloxone, mecamylamine, and hexamethonium to mice reduced catalepsy induced by a combination of morphine with nicotine. Intracerebroventricular injection of atropine, hexamethonium, and naloxone also decreased catalepsy induced by morphine plus nicotine. Intraperitoneal administration of atropine, but not intraperitoneal or intracerebroventricular injection of hexamethonium, decreased the effect of a single dose of morphine. It was concluded that morphine catalepsy can be elicited by opioid and cholinergic receptors, and the potentiation of morphine induced by nicotine may also be mediated through cholinergic receptor mechanisms.

Cholera toxin antagonizes morphine-induced catalepsy through a cyclic AMP-independent mechanism

We studied the effect of intracerebroventricular pretreatment with pertussis toxin and cholera toxin on morphine catalepsy in rats. Pertussis toxin (1 μg/rat, two, three and six days before) did not affect catalepsy evoked by central morphine. Cholera toxin (1 μg/rat) did not affect morphine catalepsy after 24 h,and 48 h, but significantly reduced it (about 60%) after three and five days. Ten days later the morphine response had totally recovered. This effect was selective, since morphine analgesia was not modified. The reduction of catalepsy appeared unrelated to the ability of cholera toxin to raise cAMP levels, as demonstrated by the different time course of changes in striatal cholera toxin-stimulated aadenylate cyclase activity. The effect required an intact cholera toxin molecule and did not occur with a similar dose of cholera toxin-B subunit. These findings demonstrate that catalepsy is an opioid effect not linked to pertussis toxin-sensitive G proteins and suggest that the G s protein might be involved.

The NMDA receptor antagonist MK-801 increases morphine catalepsy and lethality

Interactions between excitatory amino acids and opioids were examined by studying the ability of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to affect morphine catalepsy and lethality. MK-801 (0.3 mg/kg) reduced the ED 50 for morphine-induced catalepsy from approximately 30 mg/kg to less than 10 mg/kg, and reduced the LD 50 for morphine from approximately 100 mg/kg to approximately 10 mg/kg. Lower doses of MK-801 did not affect morphine catalepsy or lethality. MK-801, in the absence of morphine, produced no catalepsy or lethality at doses up to 3.0 mg/kg; at 0.3 mg/kg MK-801 caused weaving, body rolling and ataxia, as previously described, while at 3.0 mg/kg animals appeared to lose muscle tone, becoming limp. These results demonstrate that blockade of NMDA receptors can dramatically potentiate morphine catalepsy and lethality, and suggest a potential dangerous interaction with opioids in the clinical use of NMDA receptor antagonists.

Stress by restraining potentiates morphine catalepsy in rats.

Restraint-induced stress potentiated morphine catalepsy in rats. This potentiation was partially antagonized by pharmacologic treatments decreasing central serotonin, acetylcholine, prostaglandins and by naloxone. Selective increase in central dopamine also inhibited the potentiation.

Thalamus as a relay station for catalepsy and rigidity

The aim of the study was to determine to what extent catalepsy and tonic rigidity of muscles induced by muscimol administration into the ventral thalamic nuclei disturb the motor activity of rats. This study also aimed to test whether the ventromedial thalamic nucleus (Vm) was involved in transmitting effects evoked by the systemic injection of neuroleptics or opioids. For this purpose muscimol and/or picrotoxin was injected into the ventral thalamic nuclei and the behaviour of the animals was assessed in a series of test situations. It was found that muscimol administration to the Vm disturbs not only the initiation and performance of voluntary movements but also the occurrence of avoidance when the animal's life is endangered. Postural reflexes remained, however, undisturbed. Those effects seemed to be GABA- and site-specific to Vm. The haloperidol catalepsy was strongly inhibited by administration of picrotoxin to the Vm while the morphine catalepsy remained unchanged after picrotoxin. The Vm plays a crucial role in the motor behaviour and transmission of cataleptogenic effects of haloperidol, whereas similar effects produced by morphine appear to by-pass the investigated thalamic region.

Lesions of ventral tegmental dopamine neurons delay the development of tolerance to morphine catalepsy

Selective lesions of the dopamine (DA) neurons of the ventral tegmental area (VTA) were found to substantially delay the development of tolerance to morphine-induced catalepsy, in comparison with sham-operated controls receiving morphine. Lesioned subjects receiving vehicle injections showed no catalepsy. The data suggest that tolerance to morphine catalepsy requires intact VTA DA neurons. Furthermore, since the acute cataleptic response was intact in lesioned animals, the data suggest that the mechanisms involved in the cataleptic response to morphine are dissociable from those which bring about tolerance to that response.

Morphine catalepsy as an adaptive reflex state in rats.

Morphine catalepsy as an adaptive reflex state in rats.

Morphine catalepsy as an adaptive reflex state in rats.

These experiments demonstrate that morphine-induced catalepsy consists of two complementary, but opposite, behavioral extremes (rigid immobility and sudden locomotor bursts), each of which can be controlled by distinct classes of external stimuli. When stimuli that involve pain and/or nonnociceptive skin pressure are tonic (continuous), morphine-induced electroencephalographic (EEG) deactivation and behavioral immobility are potentiated, even to the extent that a stimulation-bound reversible coma results. In contrast, phasic (discrete) stimulation produces behavioral and/or EEG activation. EEG and behavioral rebound effects are observed following stressful (intense, prolonged) stimuli. On the basis of the observed stimulus controls, sensorimotor characteristics, and EEG reactions, it is suggested that similarities may exist between morphine-induced catalepsy and defensive reactions of immobility and escape in drug-free animals (i.e., the adaptive death- feigning reflex).

Morphine catalepsy in the rat: Involvement of μ1 (high affinity) opioid binding sites

Since the proposal of multiple classes of opiate receptors, much effort has been devoted to understanding the subtypes mediating specific opioid actions. Using the irreversible antagonist naloxozone, we have established a role for the high affinity ( μ 1) sites in analgesia. These sites also appear important in opiate catalepsy. Control rats showed dramatic catalepsy following a high dose of morphine sulfate (100 mg/kg, s.c.). Rats whose high affinity ( μ 1) sites had been blocked with naloxazone 24 h earlier, on the other hand, showed no evidence of catalepsy ( P < 0.01). Accordingly, catalepsy appears to involve the same receptors as analgesia, the higher affinity ( μ 1) sites.

Involvement of caudate nucleus, amygdala or reticular formation in neuroleptic and narcotic catalepsy

Local injection of haloperidol into the caudate nucleus produced catalepsy in contrast to the weak effects of morphine injected at the same site. Injection of either haloperidol or morphine into the amygdala did not have any cataleptogenic effect. Both haloperidol and morphine produced catalepsy when injected into the reticular formation. Naloxone injected into the reticular formation completely reversed the catalepsy following intraperitoneal morphine but not haloperidol. Pretreatment with α-methyl-p-tyrosine potentiated the effect of haloperidol injected into either the reticular formation or caudate nucleus. Phentolamine but not lignocaine or metergoline, injected into the reticular formation also caused a cataleptic response. The results confirm the caudate nucleus as a site for haloperidol catalepsy and in addition, suggest the reticular formation as a primary site for morphine catalepsy and a secondary site for haloperidol catalepsy; additionally a noradrenergic modulation of catalepsy may occur within this brainstem region.

The influence of 5-HT receptor blocking agents on the behavioral effects of analgesics in rats.

The influence of methergoline, methysergide, mianserine, cyproheptadine, and pizotifen on catalepsy induced by morphine, codeine, and fentanyl, and antinociception induced by these three drugs and by pentazocine was studied in rats. Methergoline dose-dependently reduced catalepsy induced by these three drugs. Methysergide abolished only morphine catalepsy, while mianserine significantly reduced the effect of morphine and codeine. Cyprohepatide and pizotifen did not modify the cataleptic effect of the three analgesics used. Antinociceptive action of morphine, codeine, fentanyl, and pentazocine, measured by the hot plate method, was not influenced or changed differentially by any serotonin receptor blocking compounds. One may conclude that catalepsy induced by morphine is, in general, antagonized by serotonin receptor blockade, but this does not concern all narcotic analgesics. In the antinociceptive effects of drugs used, the serotonergic influence seems to play a less important role than in catalepsy.

The induction of catalepsy and hyperactivity by morphine administered directly into the nucleus accumbens of rats

The injection of morphine (1–100 μg) into the nucleus accumbens of the rat caused dose-dependent changes in motor function. An initial cataleptic phase was followed by hyperactivity which was associated with a weak and periodic biting behaviour. Injection of morphine (1–50 μg) into associated brain areas (anterior and posterior regions of the olfactory tubercle, anterior caudate putamen, area preoptica, globus pallidus and ventricular system) failed to induce catalepsy or induce a catalepsy of comparable intensity to that observed after intra-accumbens morphine. The catalepsy induced by 12.5 or 50 μg intra-accumbens morphine was antagonised by nalorphine when administered s.c. (2.5–10 mg/kg) and by nalorphine (2.5–10 μg)_and naloxone (0.25–1.0 μg) when injected into the nucleus accumbens, by low doses of cyproheptadine (1.25–5 mg/kg i.p.) and by large and probably non-specific doses of atropine (10 mg/kg i.p.) and piperoxan (20 mg/kg i.p.). In relatively large doses haloperidol (0.25–1.0 mg/kg i.p.) potentiated morphine (3.125 μg) catalepsy whereas α-methylparatyrosine reduced or failed to modify the morphine (1–50 μg) response. It is considered that the catalepsy induced by intra-accumbens morphine is due to a significant action within that nucleus which directly or indirectly involves an enhanced serotonergic activity. The subsequent hyperactivity phase induced by intra-accumbens morphine was markedly reduced by α-methyl-p-tyrosine pretreatment (250 mg/kg i.p.) and the biting component was abolished. The hyperactivity was more sensitive to the antagonistic action of α-adrenoceptor blocking agents piperoxan (10–40 mg/kg i.p.), aceperone (1.25–20 mg/kg i.p.), piperoxan (6.25–25 μg intra-accumbens) and phentolamine (1.25– 10 μg intra-accumbens) than fluphenazine (1.25–2.5 mg/kg i.p.), whilst the biting was inhibited by both the α-adrenoceptor blocking agents and fluphenazine. These data suggest that whereas the hyperactivity induced by intra-accumbens morphine primarily involves an enhanced noradrenergic action, the biting effect involves both noradrenaline and dopamine. However, it is uncertain as to whether mechanisms within the nucleus accumbens or associated areas are primarily or jointly involved as substrates for this effect, for whilst injections of morphine (1–50 μg)_into the anterior alfactory tubercle failed to induce hyperactivity, injections into the anterior caudata putamen and globus pallidus evoked a weak response, and injections into the posterior olfactory tubercle and area preoptica induced marked hyperactivity associated with weak biting. An assessment of the diffusion of (N-methyl- 14C)-morphine on intra-accumbens injection, and particularly at the time when the hyperactivity phase was apparent indicated an ability to reach and more speculatively influence other than brain areas. This would emphasise that an extra-accumbens site of action for the mediation of the hyperactivity/biting effects cannot be excluded. The results indicate a differential involvement of forebrain structures with the biphasic motor behaviour induced by intracerebral injections of morphine and a usefulness of this agent to investigate the mechanisms involved in motor control.

Noradrenergic influences on catalepsy.

Widespread depletion of forebrain noradrenaline, produced by the intracerebral injection of 4 microgram of 6-hydroxydopamine into the fibres of the dorsal noradrenergic bundle, potentiated the catalepsy induced by 20 mg/kg of morphine and severely attenuated the catalepsy induced by two separate cholinergic agonists, arecoline and pilocarpine. It did not, however, affect haloperidol catalepsy at any of the four doses tested. These results suggest that cholinergic catalepsy may be critically dependent on an intact noradrenergic substrate, perhaps through cholinergic receptors located either presynaptically on noradrenergic terminals or on the cell bodies of origin in the locus coeruleus. Noradrenaline appears to play a modulatory role in morphine catalepsy, although other sites of action must also be involved. Ascending noradrenergic systems do not appear to influence haloperidol catalepsy.

Effects of furosemide and spironolactone on the behavior of morphine-tolerant rats.

In morphine-tolerant rats, a reappearance of morphine catalepsy and a disappearance of the turning behavior characteristic of brain-lesioned tolerant animals were observed under the influence of furosemide and spironolactone. The administration of spironolactone together with daily morphine treatment resulted first in an intensification of the morphine symptoms as measured by catalepsy and a retarded appearance of tolerance, typically characterized by a shift from catalepsy to turning movements in animals with single-sided brain lesions. Nontoxic doses of spironolactone raised the sensitivity of morphine-tolerant rats so that previously tolarated morphine doses become lethal.

Morphine catalepsy in relation to striatal and extrastriatal dopamine

1. 1. When morphine (20 mg/kg i.p.) was administered to rats 30 min. after treatment with an inhibitor of dopamine biosynthesis (α-methyl-paratyro-sine), it induced strong catalepsy. 2. 2. No effect on the decline of dopamine was observed in the striatum under these conditions. If morphine catalepsy is caused at the level of the striatum only dopamine receptor blockade is compatible with these results. 3. 3. Under this experimental condition, morphine does increase the decline of dopamine in the frontal cortex. 4. 4. The results suggest, that mesolimbic dopaminergic systems might be involved in the generation of morphine catalepsy.

Effect of muscarinic cholinergic drugs on morphine-induced catalepsy, antinociception and changes in brain dopamine metabolism

The effects of drugs acting on muscarinic cholinergic receptors on the catalepsy, antinociception and changes in rectal temperature and in brain dopamine metabolism induced by morphine were studied in Wistar rats. Scopolamine (0.3 - 30 mg/kg) was about three times as potent as atropine (1 - 30 mg/kg) in potentiating the cataleptic effect of morphine. Methylscopolamine and methylatropine did not alter the cataleptic effect of morphine. Pilocarpine (100 mg/kg) and arecoline (10 mg/kg) slightly but significantly and RS86 (20 - 40 mg/kg) clearly antagonized the morphine-catalepsy. RS86 antagonized the atropine-induced potentiation of morphine catalepsy. The antinociceptive effect of pilocarpine was additive and that of RS86 less than additive with morphine. The antimuscarinic compounds did not alter the antinociceptive effect of morphine. Antimuscarinic compounds enhanced the hypothermic effect of morphine, but none of the compounds studied altered the hyperthermic effect of morphine. The antimuscarinic drugs reduced the concentration of striatal homovanillic acid (HVA) in about same proportion in control and morphine-treated rats. Both the muscarinic compounds and morphine increased the concentration of striatal HVA, but when combined their effects were not significantly different from those of morphine alone. Scopolamine antagonized and pilocarpine accelerated the morphine-induced increase in the rate of depletion of cerebral dopamine content. The present results show that the effects of muscarinic aand antimuscarinic cholinergic drugs on the cataleptic effect of morphine were opposite to their effects on the catalepsy induced by neuroleptic compounds.

Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with morphine

Apomorphine in a very small non-stimulant dose 0.05 mg/kg s.c. antagonized the locomotor stimulant effect of morphine (50 mg/kg) in mice. Apomorphine (0.05 mg/kg) antagonized also the locomotor stimulant effect of a single low dose of morphine (2 mg/kg) in the rat as well as “the late stimulatory effect” seen after a higher dose of morphine (10 or 20 mg/kg). The pretreatment with morphine in increasing doses induced an increasing degree of potentiation of stereotyped behavior induced by high doses of apomorphine (0.5 and 2 mg/kg s.c.) in the rat. The apomorphine stereotyped biting/gnawing activity was found strongly increased by morphine (10–50 mg/kg) during the time interval where morphine given alone induced catalepsy. Our results indicate that the acute treatment with morphine may induce an increase of apomorphine sensitive dopaminergic mechanisms. The inhibitory effect by a very small dose of apomorphine (0.05 mg/kg) of morphine stimulation may be due to a presynaptic dopamine receptor stimulant effect of apomorphine. The antagonism by the serotonin antagonist methergoline of morphine catalepsy and the increase by this drug of “the late morphine excitation” indicate in addition a role of a serotonergic mechanism.

Catalepsy induced by morphine or haloperidol: effects of apomorphine and anticholinergic drugs.

To investigate the extent of cholinergic involvement in opiate-induced catalepsy, the effects of three anticholinergic drugs were studied on morphine-induced catalepsy. Haloperidol-induced catalepsy was also examined. Maximum catalepsy in rats was obtained with 30 mg/kg morphine or 3 mg/kg haloperidol. The anticholinergic drugs atropine, benztropine, and scopolamine were unable to antagonize morphine-induced catalepsy, yet readily antagonized haloperidol-induced catalepsy. Low doses of apomorphine (7.5 mg/kg), on the other hand, readily antagonized morphine catalepsy, but 13-fold higher doses of apomorphine were needed to block haloperidol-induced catalepsy. The results are compatible with the idea that catalepsy can be mediated via the striatum or the amygdala; morphine-dopamine antagonism may occur in the amygdala, whereas morphine-dopamine-cholinergic interactions occur in the striatum.

Effect of sensory stimulation on the potency of cataleptogens

Pressures of up to 100 mm Hg applied to the mouse tail caused marked enhancement of the cataleptogenic potency of morphine, haloperidol and arecoline. Visual and auditory stimuli of moderate intensity also enhanced morphine catalepsy. Thus potentiation of cataleptogens by alteration of sensory input appears to be a fairly general phenomenon. The significance of these findings is discussed.

Changes in dopamine agonist and antagonist activity following temporary inactivation of the neostraitum.

Changes in drug-induced catalepsy and stereotyped behaviour were investigated in the rat following the intrastriatal application of 1 μl 25% w/v KCl which was shown to reduce striatal electrical activity. The unilateral or bilateral application of KCl to normal animals caused contralateral circling or stereotyped biting and gnawing respectively. These effects were differentiated from injection artifact. The cataleptic actions of haloperidol, fluphenazine, loxapine, oxypertine or metaclopramide were modified biphasically by bilateral intrastriatal KCl: catalepsy was initially reversed and stereotypy developed but, subsequently, catalepsy was intensified. Unilateral injections of KCl also reversed catalepsy and marked contralateral circling activity developed. These actions of intrastriatal KCl, both in normal and cataleptic animals, were abolished by lesions of the substantia nigra. RS 86 catalepsy was potentiated both by uni-and bilateral intrastriatal injections of KCl whilst similar injections failed to modify the depressant effects of IB 503, chloral hydrate, diazepam, clozapine or a combination of reserpine/α-methyl-ptyrosine. Morphine catalepsy was modified by intrastriatal KCl more in the manner of the stereotypic agents (D-and L-amphetamine, apomorphine, methylphenidate, ET 495), this being the production of ipsilateral circling following unilateral KCl or the induction of a state of immobility following bilateral injections (concomitant with antagonism of stereotypy or enhancement of morphine catalepsy). The mild stereotypic and tremorogenic activities of amantadine and NBT I were unmodified by intrastriatal KCl. Similarly, bilateral KCl failed to modify the abnormal motor movements observed after an L-Dopa/nialamide pretreatment, although a contralateral asymmetry was recorded following unilateral injections. The actions of intrastriatal KCl upon D-amphetamine stereotypy were mimicked by the cortical application of KCl at times prior to passage of the ‘spreading depression’ to the striatal area. However, at similar times, the effects of intrastriatal KCl on normal animal behaviour or upon haloperidol catalepsy were not reproduced by KCl applied to the cortex.