Influence of morphine and cyclazocine on the cortical epileptic foci in rabbits

The effects of morphine, cyclazocine and naloxone on penicillin- and strychnine-induced epileptic foci were studied in rabbits. The intracortical injection of penicillin (75, 150 and 300 units) elicited isolated spikes followed by repeated ictal events. The application of strychnine (0.062 and 0.125%) over the cortical surface of one side induced appearance of ipsilateral spiking spreading to the contralateral cortex.

Administration of morphine (0.25–0.75 mg/kg i.v.) or cyclazocine (0.05–3.0 mg/kg i.v.) inhibited the occurrence or the duration of the EEG and motor manifestations induced by penicillin (75 and 150 units) and strychnine (0.062 and 0.125%), while it did not influence the effect of 300 units of penicillin. High doses of morphine (up to 10 mg/kg i.v.) failed to affect the epileptic responses to penicillin and strychnine and at the same time significantly reduced the pO₂ in arterial blood.

Naloxone per se potentiated the effects of the lower doses of penicillin and strychnine. Only at very high doses (20 mg/kg i.v.) displayed a weak antagonism towards the anticonvulsant effect of the two opiates. A full antagonism is only observed towards the effect of cyclazocine (2 mg/kg i.v.) administered after penicillin.

Present data provide additional evidence of the heterogeneity of regulations by opioids of convulsive phenomena. One can hypothesize that the anticonvulsant effect of the two opiate agonists is mediated by naloxone-insensitive opiate receptors, while the proconvulsant-convulsant effect of naloxone might be related to an inhibition of GABA and glycine-mediated transmission.     

Effects of pain, morphine and naloxone on the duration of animal hypnosis

Previous research has shown that animal hypnosis (tonic immobility) in the rabbit may be elicited in a condition of prolonged nociceptive stimulation. These experiments show that long-lasting irritative pain, produced within 15 min of formalin injection, potentiates the duration of hypnosis. Morphine, in the absence of painful stimuli, also potentiates hypnosis duration and this effect is antagonized by naloxone. Naloxone reduces hypnosis duration, but only at high doses (15 mg/kg). In a condition of irritative pain, the potentiation of hypnosis duration is abolished by naloxone (5 mg/kg). Hypnosis response is abolished in 6 out of 7 morphine-tolerant rabbits, but prolonged pain restores the response. The hypothesis that an opioid mechanism may be activated during animal hypnosis is discussed.     

Effects of morphine and naloxone on the K-stimulated release of methionine-enkephalin from slices of rat corpus striatum

Methionine-enkephalin (ME) released from superfused slices of rat corpus striatum was estimated by radioimmunoassay (RIA). The basal release of2.5 ± 0.2pmol/g/min (0.15% of content per min) was increased approximately 3-fold upon exposure of tissue to 30 mM K⁺ for 5 min. This increase in release was not observed in the absence of Ca²⁺. Both morphine (10⁻⁵ M) and (−)-naloxone (10−⁵ and 10−⁶ M) significantly depressed the release of ME evoked by 30 mM K⁺ but did not alter basal release. The +-isomer of naloxone, which lacks opiate antagonist activity, did not affect basal or evoked release. A consistent depression of release was not observed when 47 mM K⁺ was used to evoke the release of ME. The issue of whether a feedback mechanism controls the release of ME from the striatum cannot be resolved until it is known whether the effect of morphine and naloxone on ME release are mediated by opiate or non-opiate mechanisms.     

Actions of iontophoretically applied morphine on hypothalamic thermosensitive units

The effects of iontophoretically applied morphine and naloxone were examined on 62 neurons in the preoptic/anterior hypothalamus (POAH) of urethane-anesthetized Sprague-Dawley rats. Thirty-four temperature-insensitive cells responded variably to morphine application. Four cells were excited, 19 inhibited and 11 remained unaffected. Morphine increased the firing rate 12 of 20 warm-sensitive cells. The other 8 were unaffected. None were inhibited. The spontaneous activity of 7 cold-sensitive cells was decreased by morphine application. One cell was unaffected and none were excited. Naloxone (≤ 15 nA) antagonized morphine's excitatoory effects on warm-sensitive cells and its inhibitory effects on cold-sensitive cells. Naloxone failed to antagonize any of morphine's actions on temperature-insensitive cells.Our results demonstrate that morphine excited warm-sensitive cells, which are assumed to mediate heat-dissipation responses, and inhibited cold-sensitive cells, which are assumed to mediate heat-gain responses. These actions parallel morphine's hypothermic action in the intact animal and, therefore, suggest that morphine lowers body temperature by exerting a coherent action on POAH warm- and cold-sensitive neurons. Since these effects were antagonized by naloxone, the action of morphine on warm- and cold-sensitive cells seems to be mediated by an opiate receptor.     

Alteration of morphine withdrawal to naloxone by interferon

The opiate abstinence syndrome represents a fundamental feature of the addictive process. The present study demonstrated that: 1) recombinant leukocyte A Interferon (alpha-IFN) injection prior to chronic morphine treatment reduces addiction liability; and 2) alpha-IFN and not human gamma-IFN injection to morphine dependent rats significantly modifies the naloxone-induced abstinence syndrome in a characteristic dose response manner. Two hypotheses concerning IFN's action were discussed.     

Spinal vs supraspinal actions of morphine on cat spinal cord multireceptive neurons

To examine whether morphine elicits a supraspinal mediated spinal inhibition of nociceptive transmission, several investigators have compared the effects of morphine on nociceptive transmission in animals with the spinal cord intact vs transected or cold-blocked. The results have been conflicting, possibly due to different methods of analysis. For example, some investigators have found i.v. administered morphine produces a greater percentage decrease in nociceptive transmission when the spinal cord is intact compared to the transected state. Therefore, they concluded that morphine elicits a supraspinal-mediated inhibition. Conversely, others have reported that the increase in noxious stimulus-evoked responses of dorsal horn neurons upon cold blocking the spinal cord was reduced by i.v. morphine. They therefore concluded that morphine decreases descending inhibition. We tested the effects of i.v. morphine on spinal cord multireceptive neurons in the presence and absence of descending inhibition. Using the above methods of analysis, our results were found to be consistent with their findings which indicate that the method of analysis used is critical to the interpretation reached. To determine how these calculations would be affected by a depressant effect on the spinal cord neurons only, we performed similar experiments iontophoresing gamma-aminobutyric acid (GABA) onto these dorsal horn neurons. The similarity between the morphine and GABA data suggests that the effects of systemically administered morphine on multireceptive dorsal horn neurons can be adequately explained by a spinal cord site of action.     

Opiate and non-opiate aspects of morphine induced seizures

The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.     

Intrathecal high dose morphine produces hyperalgesia in the rat

Intrathecal microinjections of high doses of morphine in the rat produce algesia, hyperalgesia and hypersthesia as opposed to the analgesia found at lower doses. This hyperalgesia is not naloxone reversible and is only partially stereospecific. Morphine-3-glucuronide produces the hyperalgesia at low doses. This morphine-hyperalgesia may be mediated by a class of receptors similar to that which produces opiate-induced central excitation.     

Effects of morphine and naloxone on cerebral blood flow and metabolism in experimental subarachnoid hemorrhage

Objective - Naloxone is reported to improve the clinical condition of patients with subarachnoid hemorrhage (SAH). If this effect is vascular determined is unknown, wherefore the influence of morphine and naloxone on cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO_z) after SAH was evaluated. Material and methods - Two groups of 8 rats each with SAH and 2 corresponding groups of controls were investigated. CBF was calculated by the intracarotid ¹³³Xenon method and CMRO₂ as the product of CBF and the difference between systemic arterial and cerebral venous oxygen content. Results - In controls morphine, 1 mg/kg administered intravenously, decreased CBF by 25% ( P < 0.001) without changing the CBF/CMRO₂ ratio. In animals with SAH CBF was decreased by 32% ( P < 0.001) and CBF/CMRO₂ ratio by 38% ( P < 0.01). Naloxone, 40ug/kg administered intravenously neither influenced CBF nor the CBF/CMRO₂ ratio in the 2 groups. Conclusion - The reported clinical effect of naloxone after SAH can, according to our results, not be explained by changing the relationship between CBF and metabolism.     

Topical application of morphine to the rat somatosensory cortex produces analgesia to tonic pain

Topical application of 0.01 or 0.1% morphine solution to the somatosensory SI area of the rat cerebral cortex significantly decreased the pain intensity rating in the formalin test without producing motor side effects or sensory deficits. Naloxone partially antagonizes this effect. Topical application of morphine to the striate cortex did not induce analgesia. It is suggested that the primary somatosensory SI area of the cerebral cortex plays a role in opiate pain control.     

Dose effects of morphine on the spontaneous unit activity recorded from the thalamus,hypothalamus, septum,hippocampus, reticular formation,central gray,and caudate nucleus

Spontaneous activity was recorded from 652 units in 8 subcortical structures of unanesthetized rats. Recordings were obtained in central gray, mesencephalic reticular formation, parafasciculus thalami, caudate nucleus, anterior and ventro- medial hypothalamus, lateral septum, and dorsal hippocampus. Eighty recordings were obtained from untreated animals and 80 from saline-injected controls, none of which showed any significant changes of unit activity during the 4- 5-hr observation period. The effect of morphine, given in 5 incremental doses from 0.5 to 30.0 mg/kg ip, was followed in 492 units. Morphine enhanced or depressed spontaneous discharge rates, or caused biphasic effects, ie enhancement alternating with depression and vice versa. Naloxone induced increase in firing after either effect of morphine, or reduced spontaneous activity after morphineinduced increases. However, when morphine reduced neuronal discharges, naloxone never caused further depression. In 86 units, morphine at any dosage failed to alter neuronal activity, but in 54 of these units naloxone nevertheless induced alterations in firing rates. The pattern of responses to morphine differed between all 8 brain regions examined and was characteristic for each individual structure. This is the first systematic study describing the dose-response characteristics of morphine in 8 brain sites recorded simultaneously. Furthermore, it utilized freely behaving animals without the interference of anesthetics, which are themselves known to interact with opiates. The variety of response patterns seen supports the neuro pharmacological evidence for multiple opiate receptors or multiple sites of opiate action.     

Effect of gene transfer of GLT-1, a glutamate transporter, into the locus coeruleus by recombinant adenoviruses on morphine physical dependence in rats

There is a body of evidence implying the involvement of the central glutamatergic system in morphine dependence. We previously reported changes in the mRNA expression of a glial glutamate transporter GLT-1 in some brain regions of morphine-dependent and naloxone-precipitated withdrawal rats, and inhibition of morphine physical dependence by a glutamate transporter activator in mice. These findings support the possibility that glutamate transporters such as GLT-1 are involved in morphine dependence. In this study, we examined the effects of gene transfer of GLT-1 into the locus coeruleus (LC) by recombinant adenoviruses on morphine physical dependence in rats. We constructed recombinant adenoviruses that successfully delivered the GLT-1 gene in vitro and in vivo. Local overexpression of GLT-1 within the bilateral LC by the recombinant adenoviruses before implantation of the morphine pellet significantly inhibited various somatic signs of naloxone-precipitated morphine withdrawal, compared with the control. These results suggest that GLT-1 within the LC plays an inhibitory role in morphine physical dependence.     

Neurotransmitter, receptor and biochemical changes in monkey cortical epileptic foci

Epileptic and normal Macaca mulatta monkey cortex was investigated using ligand binding techniques. Subpial injections of aluminum hydroxide gel into the left sensorimotor cortex produced stable seizure frequencies over a two year period and resulted in specific biochemical and receptor abnormalities. Pair matched CSF samples comparing epileptic and non-epileptic hemispheres showed a significant decreased GABA concentration over the epileptic side. The epileptic cortex demonstrated markedly reduced GABA receptor binding and diminished tissue GABA concentration and GAD activity. Two patterns of receptor loss were observed: nonspecific local cellular drop out involving multiple neurotransmitter receptors; and distal receptor loss which was specific for the neurotransmitter intervention pattern of the cortex. GABAergic receptor loss was more marked than receptor losses for the other neurotransmitter and was more widespread. Scatchard plot analysis demonstrated that the diminished GABAergic receptors within the focus were due to receptor loss and not affinity changes. Spearman rank correlations showed a significant correlation only between the degree of GABAergic receptor loss or decrease in GAD activity and the seizure frequency. Epilepsy appears to be a multifactoral disorder with multiple neuroreceptor abnormalities, the most notable of which are the destruction of GABAergic neurons and GABA receptors.     

青霉素脑皮质局部浸润制作癫大鼠模型的研究

目的研究采用脑皮质局部应用青霉素浸润方法制作癫大鼠模型的可行性。方法取49只大鼠,氯胺酮腹腔注射麻醉后,双侧钻孔暴露顶叶脑皮质;制作青霉素G钠盐生理盐水(青霉素浓度40MU/L),再将棉片浸泡后贴敷在暴露的脑表面。同时在左右两侧钻开的颅骨里放置银制电极,记录皮质脑电图;在大鼠左后肢股四头肌插入肌电记录电极,记录肢体抽搐引起的肌电活动。结果模型制作成功44只(成功率89.7%),脑电图记录到逐渐增多的高波幅慢波,以及阵发性肌电活动的肌电图。结论应用青霉素局部浸润顶叶皮质的方法,可以成功制作癫大鼠模型。     

Acute stimulation of feeding with repeated injections of morphine sulphate to non-obese and fatty Zucker rats

1. 1. Food intake studies with genetically obese rodents show that these hyperphagic animals, which have increased central and peripheral levels of endogenous opioid peptides (E.O.P.), have an increased sensitivity to the suppressive feeding effects of narcotic antagonists compared to lean controls. Feeding experiments were conducted to determine if genetically obese rats, with enhanced E.O.P., have a reduced sensitivity toward the narcotic agonist property of stimulated feeding seen in non-obese rats.

2. 2. Food intake was monitored continuously over each experimental day in groups of female Sprague-Dawley (S.D.,), fatty Zucker (fa/fa) and their lean heterozygote littermates (Fa/ fa) following subcutaneous a.m. injections of sterile saline, morphine sulphate (5 or 10 mg/kg) or naloxone HCl (10 mg/kg) and during recovery.

3. 3. Acute 4-h post-injection feeding was reduced in all groups with the first 10 mg/kg injection of morphine sulphate. With repeated morphine administration, a phase of stimulated feeding occurred in both obese and non-obese groups.

4. 4. Due to the post-injection phase of vigorous feeding with repeated morphine injections, the circadian pattern of day/night food intake of all groups was altered such that daytime feeding increased from saline control levels.

5. 5. Naloxone HCl abolished the post-injection phase of stimulated feeding seen with chronic morphine injections and reduced 4-h post-injection food intakes.

6. 6. Plasma glucose and serum insulin levels were decreased in non-obese rats from saline controls of blood samples taken 2-h following the 7th daily M.S. injection. These levels increased again by the end of the recovery period. No blood glucose or insulin changes were seen in the obese Zucker rats with morphine administration.

7. 7. The results show that daily morphine injections can cause acute stimulated feeding in obese, fatty Zucker rats as well as in non-obese rats.

Behavioural responses to novelty in two inbred mouse strains after intrahippocampal naloxone and morphine

Male C57BL/6 and DBA/2 mice were injected intrahippocampally with either naloxone (0.5 μg) or morphine (1.0 μg), or saline vehicle alone and, after 15 min, some 12 behavioural components carried out in a novel environment were recorded for 20 min. Naloxone reduced exploratory rearing responses, wall-leaning and object-sniffing in strain C57BL/6 and augmented these behaviours in strain DBA/2, while morphine depressed the scores in both. In conjunction with previously obtained evidence that the mouse hippocampus contains a genotype-dependent cholinergic mechanism which regulates responses to novelty, these findings support the hypothesis that hippocampal opioid peptides modulate the cholinergic control of exploration in mice, possibly indirectly through GABAergic pathways. In contrast, locomotor activity, defaecation and tail elevation remained practically unaffected by the two drugs, and grooming showed another kind of genotype-treatment interaction, that is to say, after morphine.