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PubMed1993

Effect of glutamate and its analogs on diacylglycerol and monoacylglycerol lipase activities of neuron-enriched cultures.

Neuron-enriched cultures from fetal mouse spinal cord contain diacylglycerol and monoacylglycerol lipases. The treatment of neuron-enriched cultures with glutamate or NMDA resulted in a dose- and time-dependent stimulation in diacylglycerol and monoacylglycerol lipase activities. The elevation in the activities of lipases was blocked by the NMDA receptor antagonists, dextrorphan and MK-801, suggesting that lipase stimulation is a receptor-mediated process. The treatment of neuron-enriched cultures with kainate had no effect on diacylglycerol and monoacylglycerol lipase activities. The stimulation of diacylglycerol and monoacylglycerol lipase activities by glutamate and NMDA suggests that these enzymes may play an important role in processes mediated by the NMDA type of the glutamate receptors.

Animals↗
PubMed1993

Inhibition of nitric oxide formation does not protect murine cortical cell cultures from N-methyl-D-aspartate neurotoxicity.

We examined the role of nitric oxide in N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity in rat and mouse primary cortical cell cultures. In rat and mouse cultures, the NO synthase inhibitor, NG-Nitro-L-arginine, blocked cGMP formation but not neuronal cell death following a 5-10 min exposure to 300-500 microM NMDA. NG-Monomethyl-L-arginine was also unable to prevent neuronal death. In contrast, the non-competitive NMDA receptor antagonist, dextrorphan, prevented both cGMP formation and cell death. While other data suggest that the synthesis of nitric oxide can mediate NMDA receptor-mediated neurotoxicity, present results suggest that such synthesis is not necessarily required.

Animals↗
PubMed1994

Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists.

Our laboratory and others have previously reported that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, interferes with the development of tolerance to the analgesic effects of morphine. The present studies were performed in order to further characterize the role of NMDA receptors in opiate tolerance. The results demonstrate that opiate tolerance is inhibited rapidly, and at low doses, by four different non-competitive NMDA receptor antagonists (MK-801, ketamine, dextrorphan and phencyclidine), suggesting that this inhibition results from blockade of NMDA receptors rather than from the 'side-effect' of a particular drug. The NMDA antagonists were found to inhibit the development but not the expression of opiate tolerance; i.e. they were able to prevent but not reverse tolerance. Finally, the results suggest that NMDA receptor antagonists do not interfere with associative tolerance; instead it appears that these drugs may specifically inhibit non-associative tolerance. It thus appears that NMDA receptors may have a fundamental role in the development of opiate tolerance, and that non-competitive NMDA receptor antagonists may be effective adjuncts to opiates in the treatment of chronic pain.

Adaptation, Psychological↗
PubMed1994

Trolox attenuates cortical neuronal injury induced by iron, ultraviolet light, glucose deprivation, or AMPA.

The vitamin E analog, trolox, protected cultured cortical neurons against damage induced by exposure to either iron ions or ultraviolet (UV) light, consistent with an ability to inhibit free radical-mediated cytotoxicity. Trolox also reduced neuronal death induced by 24 h exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), but not that induced by N-methyl-D-aspartate (NMDA). When combined with the NMDA receptor antagonist dextrorphan, trolox also reduced the neuronal injury induced by glucose deprivation.

Animals↗
PubMed1976

Mechanism of morphine block of electrical activity in ganglia of Auerbach's plexus.

A study was made of the effect of morphine on electrical activity within single ganglia of Auerbach's plexus of guinea pig longitudinal muscle-myenteric plexus as monitored by means of external electrodes. Morphine produces a concentration dependent block of single spike activity. This effect is competitively antagonized by naloxone. The ED50 for morphine effect is about 7 X 10(-7) M. Naloxone and dextrorphan have no effect on electrical activity. Acetylcholine in the concentration range of 10(-7)--10(-5) M augments electrical activity of ganglia. Morphine has little if any effect on the enhanced stimulation produced by acetylcholine thus indicating that the drug does not act directly upon the ganglion. Our results suggest that a specific opiate receptor is present on the preganglionic nerve terminals and that morphine and other opiates block ganglionic transmission by inhibiting the release of preganglionic acetylcholine.

Acetylcholine↗
PubMed1976

Effects of acute and chronic methadone treatment of the uptake of 3H-5-hydroxytryptamine in rat hypothalamus slices.

Effects of in vitro methadone and several other narcotics were investigated on 3H-5-HT uptake in rat hypothalamus slices. The results indicated that d, l-methadone and levorphanol had slightly greater inhibitory action on the uptake than the isomers, d-methadone and dextrorphan, respectively. Morphine, diacetylmorphine and the narcotic antagonist naloxone produced a considerably weaker inhibitory effect. After an acute injection of methadone, but not morphine, the uptake of 5-HT by hypothalamic slices of treated animals was inhibited. The chronic treatment of rats with methadone for 18 days had no significant effect on the uptake, but following the withdrawal of this treatment for 2 weeks the 5-HT uptake was significantly elevated. The inhibitory effects of in vitro methadone in the hypothalamus slices were not modified by the chronic drug treatment.

Animals↗
PubMed1985

Increased sensitivity to dopamine agonists following a single dose of morphine or levorphanol in mice.

Acute administration of an opiate has been suggested to result in the development of supersensitive dopamine receptors. This hypothesis was tested in mice by determining the effect of a single administration of morphine or levorphanol on dopamine agonist-induced stereotypic behaviors and [3H]spiroperidol binding. Administration of morphine (1.0 mg/kg s.c.), which itself had no significant effect on spontaneous locomotor activity 3 h following administration, significantly potentiated locomotor activity induced by 1.5 or 4.5 mg/kg of apomorphine (i.p.) administered 3 h later. Morphine (10 mg/kg, s.c.) or levorphanol (0.2 and 2.0 mg/kg, s.c.), but not dextrorphan (up to 20 mg/kg, s.c.), enhanced climbing behavior induced by apomorphine (i.p.) or (-)-N-n-propylnorapomorphine (i.p.; NPA) administered 3 h later. An increase in whole brain and striatal [3H]spiroperidol binding sites was found 3 h after administration of 10 mg/kg of morphine. Concurrent administration of 5 mEq/kg of LiCl (i.p.) or 5 mg/kg of naloxone (i.p.; administered twice) attenuated both the potentiation of the climbing behavior induced by the two dopamine agonists and the increase in [3H]spiroperidol binding sites. These results suggest that a single administration of an opiate can induce the development of supersensitive dopamine receptors that is mediated by an interaction at opioid receptors.

Animals↗
PubMed1985

Comparison of the ability of opioid analgesics to increase endogenous opioid-like activity in the cerebrospinal fluid of rabbits.

We have previously demonstrated that the acute administration of morphine increases the level of endogenous substances, which have antinociceptive activity, in cerebrospinal fluid (CSF). The present study was conducted to determine whether other opioid analgesics exert a similar effect. CSF was withdrawn from the cisterna magna of anesthetized rabbits before and after s.c. injections of meperidine, pentazocine, levorphanol and methadone, and was bioassayed for opioid-like activity in the mouse tail-flick and phenylquinone writhing tests. The opioid-like activity of CSF taken 60 min after meperidine (50 mg/kg) was significantly increased in both bioassays, and the CSF level of meperidine was insufficient to account for this effect. Pentazocine (25-75 mg/kg) also significantly increased opioid-like activity in rabbit CSF, but the effects of methadone (5-10 mg/kg) and levorphanol (20 mg/kg) were less marked. Dextrorphan (20 mg/kg), diazepam (10 mg/kg) and pentobarbital (20 mg/kg) administration did not significantly increase opioid-like activity in CSF. It is concluded that the antinociceptive action of some opioid analgesics in rabbits may be mediated in part by the release of endogenous antinociceptive substances.

Animals↗
PubMed1986

Preference conditioning produced by opioid active and inactive isomers of levorphanol and morphine in rat.

Using taste and place preference conditioning, the present study examined the motivational properties produced in adult rats by systemic administration of (-) and (+) morphine, levorphanol, and dextrorphan. Conditioned place preference was stereospecific; it was only produced by the opioid receptor active isomers, levorphanol and (-) morphine. Similarly, a conditioned taste preference produced by a low dose of morphine was only seen with the active isomer. Conditioned taste aversion, however, was produced in a comparable dose range by both the active and the inactive isomers. In addition injections of inactive isomers also produced tolerance to the taste aversion produced by (-) morphine. Therefore, administration of both opioid active and inactive isomers of opioid agonists are unconditioned stimuli for the production of preference behaviors. In addition, it was concluded that the appetitive reinforcing properties of these drugs, seen as taste and place preferences, appear to require activation of specific opioid receptors, whereas the aversive effects, seen as taste aversion may also involve other mechanisms.

Animals↗
PubMed1996

Inhibition by noncompetitive NMDA receptor antagonists of apomorphine-induced climbing behavior in mice.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is an important mediator of several forms of neural and behavioral plasticity. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptor by determining the effects of NMDA antagonists on apomorphine-induced climbing behavior in mice. The noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan, and dextromethorphan attenuated the apomorphine-induced climbing behavior at does well below those that produce untoward side effects. These results suggest that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptors that mediate the apomorphine-induced climbing behavior in mice.

Animals↗
PubMed1982

Prostaglandin hyperalgesia, V: a peripheral analgesic receptor for opiates.

Prostaglandin E2 injected in the rat paw causes hyperalgesia which is antagonized by local injections of opiate and opiate antagonists. In the present investigation in rats it is shown that naloxone has an analgesic effect at doses as low as 2 micrograms/site, injected into the rat hind paw. At a dose that has no analgesic effect (1 microgram/site) naloxone antagonized the analgesia produced by either local or systemic administration of morphine. Local administration of levorphanol (50 micrograms/site) caused a 50% reduction in the intensity of the hyperalgesia induced by prostaglandin E2. A dose four times greater of its isomer, dextrorphan, had little analgesic effect. The present results support the suggestion that this peripheral analgesia is the result of an action of opiates in receptors located at the nociceptors.

Analgesia↗
PubMed1981

Stereoselective effects of opiate agonists and antagonists on ingestive behavior in rats.

In male Sprague Dawley rats, the (-)-isomer of the opiate antagonist GPA 1843 (beta-9-methyl-5-phenyl-2-allyl-2'-hydroxy-6, 7-benzomorphan) produced dose-related decreases in nocturnal feeding and of hyperphagias induced by 2-deoxy-D-glucose (2-DG; 400 mg/kg) and 24 hr food deprivation (FD). The hyperphagia induced by insulin (10 U/kg) was not significantly decreased by GPA 1843. In contrast, comparable doses of the (+)-stereoisomer, GPA 1847, had no effect on nocturnal, 2-DG or FD hyperphagia. In addition, hyperphagia and hyperdipsia were observed following administration of the opiate agonist levorphanol, but not its stereoisomer, dextrorphan. Thus, the effects of these agents on consummatory behavior are mediated by a stereospecific interaction with opiate receptors, which further indicates that endogenous opiate peptides are involved in the expression of these opiate-related hyperphagias.

Animals↗
PubMed1982

Concerning the specificity of the hypothalamic opiate receptor responsible for food intake in the rat.

Direct application of small quantities of morphine (a mu-opiate receptor agonist) to the ventromedial hypothalamus (VMH) of rats can induce a stimulated food intake. Because this effect is only partly reduced by the opiate antagonist naloxone, given into the VMH, various other studies were undertaken to examine characteristics of the receptors at this site. The opiate agonist levorphanol but not its stereoisomer dextrorphan effectively increased feeding. Codeine, a weak opiate ligand, was also ineffective as were the kappa-opioid agonist ketocyclazocine and the sigma-opioid agonist phencyclidine. the hyperthermia which accompanies peripheral and central injections of morphine was not observed after hypothalamic application of a quantity of levorphanol sufficient to stimulate feeding. This leads us to propose that the opioid receptors in the VMH are: (1) stereoselective; (2) responsive to mu-, but not kappa- or sigma-agonists: and (3) different from the receptors that elicit hyperthermia.

Animals↗
PubMed1991

Effects of NMDA and calcium channel antagonists on regional cerebral blood flow.

N-Methyl-D-aspartate (NMDA) antagonists and voltage-dependent calcium channel antagonists were tested to determine potential effects on regional cerebral blood flow in the normal rabbit brain. Ketamine had no effects on cortical or hippocampal blood flow, but was found to significantly decrease blood flow in the inferior colliculus. MK-801 decreased blood flow in almost all regions of the brain tested. On the other hand, nimodipine significantly increased flow in the cortex, hippocampus, and tegmentum. Dextromethorphan and dextrorphan, which have been shown to act at the NMDA receptor as well as the dihydropyridine calcium channel, decreased blood flow in the inferior colliculus, but showed no effects in the cortex or hippocampus. These results suggest that the neuroprotective NMDA antagonists do not increase blood flow primarily in the normal brain.

Animals↗
PubMed1992

Protection by N-methyl-D-aspartate receptor antagonists against impairment of working memory in rats following transient cerebral ischemia.

A 5-min period of cerebral ischemia increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) assessed by the working memory procedure applied in a three-panel runway task. The selective and competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGS 19755 (3.2 and 10 mg/kg), administered i.p. immediately after blood flow reperfusion, significantly reduced the increase in errors expected to occur 24 h after 5 min of ischemia. CGS 19755 10 mg/kg had no effect on the increase in errors when injected 6 h after ischemia. The i.p. administration of the non-competitive NMDA antagonists dextrorphan 10 and 32 mg/kg and MK-801 1.0 mg/kg immediately after reperfusion decreased the increase of errors in the ischemic rats. The protective effects of NMDA antagonists suggest that the mechanism mediated by NMDA receptors during the early reperfusion phase plays a pivotal role in the postischemic impairment of working memory.

Animals↗
PubMed1990

Opiates suppress carrageenan-induced edema and hyperthermia at doses that inhibit hyperalgesia.

This study determined whether opiates alter vascular components of inflammation (hyperthermia, edema and plasma extravasation) in addition to the suppression of hyperalgesia. Rats were administered carrageenan into one hind paw and saline into the other hind paw, followed by i.p. injection of morphine (0.2-5.0 mg/kg) or saline at 60 min, and testing at 90 min after hind paw injections. Morphine produced a dose-dependent reduction in carrageenan-induced hyperalgesia (17-53%), hyperthermia (39-53%) and edema (24-36%). Morphine treatment did not alter the temperatures of the contralateral saline-injected paws, indicating that opiate suppression of hyperthermia was not confounded by alterations in systemic body temperature or blood flow. The opiate effects on inflammation were stereospecific since levorphanol (1 mg/kg), but not dextrorphan (1 mg/kg), suppressed carrageenan-evoked hyperalgesia, hyperthermia and edema. Pre-treatment with naltrexone (1.5 mg/kg) blocked the effects of a 5 mg/kg dose of morphine sulfate on hyperalgesia, hyperthermia and edema. In a separate study, i.v. injection of morphine sulfate (2 mg/kg) reduced plasma extravasation by 41% (P less than 0.01). Morphine administration resulted in significantly greater increases in paw withdrawal latencies in the inflamed (38-139%) than the contralateral, saline-treated paws (4-19%). The results indicate that opiates exert a moderate, though significant, reduction in the vascular signs of inflammation in addition to their reduction of hyperalgesia. The mechanisms for this vascular effect involve inhibition of both vasodilation (as indicated by a decrease in hyperthermia) and inhibition of vascular permeability. In addition, opiates exhibit enhanced antinociceptive effects in inflamed paws, even when compared to uninjured paws in the same animal.

Analgesics↗
PubMed1991

Diversified electrophysiological properties of morphinan drugs in rats.

1. In in vivo and in vitro studies in rats, the effects of dextromethorphan (DM), dextrorphan (DX), and levorphanol (LV) were compared with those induced by kappa and sigma opiate agonists. 2. In rat hippocampal slices all the morphinans were able to pertubate the CAI hippocampal synaptic transmission, while only DX and LV affected the N-methyl-D-aspartate excitability through a possible interaction at sigma opiate receptors. 3. On the other hand EEG studies show that only DX appears to act as a full agonist at sigma opiate receptors. 4. Present data demonstrate diversified electrophysiological properties of morphinans both in in vitro and in vivo studies.

Animals↗
PubMed1991

Glutamate neurotoxicity in spinal cord cell culture.

The neurotoxicity of glutamate was investigated quantitatively in mixed neuronal and glial spinal cord cell cultures from fetal mice at 12-13 days of gestation. Five-minute exposure to 10-1000 microM glutamate produced widespread acute neuronal swelling, followed by neuronal degeneration over the next 24 h (EC50 for death about 100-200 microM); glia were not injured. Glutamate was neurotoxic in cultures as young as four days in vitro, although greater death was produced in older cultures. By 14-20 days in vitro, 80-90% of the neuronal population was destroyed by a 5-min exposure to 500 microM glutamate. Acute neuronal swelling following glutamate exposure was prevented by replacement of extracellular sodium with equimolar choline, with minimal reduction in late cell death. Removal of extracellular calcium enhanced acute neuronal swelling but attenuated late neuronal death. Both acute neuronal swelling and late degeneration were effectively blocked by the noncompetitive N-methyl-D-aspartate receptor antagonist dextrorphan and by the novel competitive antagonist CGP 37849. Ten micromolar 7-chlorokynurenate also inhibited glutamate neurotoxicity; protection was reversed by the addition of 1 mM glycine to the bathing medium. These observations suggest that glutamate is a potent and rapidly acting neurotoxin on cultured spinal cord neurons, and support involvement of excitotoxicity in acute spinal cord injury. Similar to telencephalic neurons, spinal neurons exposed briefly to glutamate degenerate in a manner dependent on extracellular Ca2+ and the activation of N-methyl-D-aspartate receptors.

Animals↗