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Biomedical subjects

F C Tortella

Publications and source records attributed to F C Tortella.

At least 91 records · Page 5Linked to original sources
PubMed1984

ICI 154,129, a delta-opioid receptor antagonist raises seizure threshold in rats.

Acute i.c.v. administration of ICI 154,129 (100-600 micrograms), a delta-opioid receptor antagonist, raised the seizure threshold in a dose-related manner in rats exposed to flurothyl, a volatile convulsant. Pretreatment with naloxone or beta-funaltrexamine (beta-FNA) antagonized this effect. Lower doses of ICI 154,129 (12.5-50 micrograms), which did not influence seizure threshold, selectively antagonized the anticonvulsant action of [D-Ala2,D-Leu5]enkephalin (DADLE) in the same procedure. Consequently, it may be inferred that ICI 154,129 at high doses has mu-agonist and at low doses delta-antagonist properties in the rat flurothyl test.

Animals↗
PubMed1984

Studies on the excitatory and inhibitory influence of intracerebroventricularly injected opioids on seizure thresholds in rats.

The influence of centrally administered meperidine, normeperidine and pentazocine on the excitability of brain was studied by measuring the threshold for flurothyl-induced convulsions in rats. All three opioids are reported to lower seizure thresholds when given subcutaneously to rats in this test. Dose-and time-dependent changes in the seizure threshold occurred after intracerebroventricular injection of pentazocine (10-160 micrograms), meperidine (25-150 micrograms) and normeperidine (50-150 micrograms). Rapid increases in the seizure threshold were associated with pentazocine and meperidine, whereas a slowly developing decrease in the threshold was caused by normeperidine. Naloxone (10 mg/kg, s.c.) antagonized the anticonvulsant effect of meperidine (but not that of pentazocine) and enhanced the proconvulsant effect of normeperidine. Thebaine (25-150 micrograms), which had no marked influence on the seizure threshold when given intracerebroventricularly, lowered the threshold after subcutaneous injection of 12.5 and 25 mg/kg. This effect was not altered by injection of naloxone. These results show that centrally administered opioids can act on excitatory or inhibitory systems that regulate seizure mechanisms in the rat brain. Furthermore both naloxone-sensitive and naloxone-insensitive components are involved. Meperidine, pentazocine and thebaine have different actions on the seizure threshold after intracerebroventricular, as opposed to subcutaneous, administration. This work has, therefore, identified the route of administration as a critical variable in the effect of opioids on the seizure threshold in rats.

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PubMed1984

Electroencephalographic assessment of the role of delta receptors in opioid peptide - induced seizures.

DPDPE ([D-Pen2, D-Pen5]-Enkephalin) and DPLPE ([D-Pen2, L-Pen5]-Enkephalin) are conformationally-constrained cyclic analogs of enkephalin with high selectivity for delta opioid receptors. Intracerebroventricular (i.c.v.) administration of each analog acutely produces a complex EEG response in rats characterized by a dose-related increase in spectral power and HVSA (peak frequency of 5.0 Hz) during behavioral stupor, and a theta driving (5.25-8.0 Hz) associated with intense behavioral arousal. These effects were antagonized by high (10 mg/kg), but not low (1.0 mg/kg), doses of naloxone. Both analogs failed to cause EEG or convulsive seizures. In contrast, i.c.v. administration of DADLE ([D-Ala2, D-Leu5]-Enkephalin), an enkephalin analog with activity at both mu and delta binding sites, caused initial nonconvulsive EEG seizures followed by HVSA (3.0 Hz); theta driving was not evident. The incidence of the seizures was dose-related and antagonized by very low doses of naloxone (0.01-1.0 mg/kg). Collectively, the inability of DPDPE and DPLPE to cause seizure activity, and the marked sensitivity of DADLE-induced EEG seizures to naloxone, suggest that delta receptors are not directly responsible for DADLE-induced EEG seizure activity. Furthermore, these data implicate mu opioid receptors as the primary sites responsible for enkephalin-induced seizures.

Animals↗
PubMed1983

A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold.

In an effort to identify delta-receptor-specific properties for opioid modulation of seizure activity, studies were conducted with ICI 154,129, a putative delta-receptor antagonist, in the rat flurothyl test. Rats were pretreated i.c.v. with ICI 154,129 (50 micrograms) which, at this dose, does not alter normal seizure thresholds. Mean seizure thresholds for control groups (i.c.v. saline) ranged between 323-349 sec. In this test, D-Ala2-D-Leu5 enkephalin (20 micrograms, i.c.v.), metkephamid (40 mg/kg, s.c.), and etorphine (20 micrograms/kg, s.c.) raised seizure thresholds by 117, 128, and 140% of control, respectively. Meperidine (25 mg/kg, s.c.) lowered seizure thresholds by 14% less than control. Pretreatment with ICI 154,129 failed to antagonize the proconvulsant action of meperidine or the anticonvulsant and behavioral depressant actions of etorphine. The increases in seizure threshold produced by DADL and metkephamid (two delta-directed ligands) were significantly attenuated by ICI 154,129. However, the DADL-induced wet-shakes, rigid immobility, and behavioral depression were insensitive to ICI 154,129. These data indicate that ICI 154,129 possesses delta-receptor antagonistic properties in this in vivo model of seizure activity. Furthermore, since only the changes in seizure threshold were antagonized, it may be inferred that opioid-induced behavioral depression and DADLE wet-shakes are not a function of delta-receptor activity.

Animals↗
PubMed1982

EEG, EMG and behavioral evidence for the involvement of endorphin systems in postictal events after electroconvulsive shock in rats.

We studied the effects of transauricular electroshock (ECS) on EEG and EMG patterns, and overt behaviors (wet-dog shaking and excessive grooming), caused by RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2', 8',14 codeinone) in rats. Male, Sprague Dawley rats were prepared with cerebrocortical EEG and temporalis muscle EMG electrodes. In sham-shocked rats, RX 336-M (6 mg/kg, i.p.) induced behavioral activation, rapid forepaw movements, wet-dog shaking and excessive grooming; this syndrome was associated with EEG activation and EMG spiking. ECS alone produced a generalized seizure followed by postictal EEG slowing and behavioral depression. ECS suppressed the RX 336-M-induced behavioral syndrome and associated EEG and EMG responses. This attenuating action of ECS, presumed to involve the release of endogenous opioids, was antagonized when the rats were pretreated with naloxone (10 mg/kg, s.c.). Our results provide further evidence for the view that endogenous opioids are involved in the pathophysiology of certain postictal phenomena.

Animals↗
PubMed1982

A quantitative analysis of the shaking behavior induced in rats by beta-endorphin and [D-Ala2, Met5]enkephalinamide.

beta-Endorphin (5-80 microgram) or [D-Ala2,Met5]enkephalinamide (DALA) (5-40 microgram) was administered intracerebroventricularly to rats. With both opioid peptides, there was no direct relationship between log dose and mean number of wet-dog shakes (WDS) that occurred during the following 15 min. When the results were analyzed quantitatively, the dose of DALA that caused 50% of the rats to shake at least twice was 8.6 microgram (4.9-15 microgram). beta-Endorphin had such poor efficacy that an ED 50 could not be obtained. Morphine (1 and 5 mg/kg, s.c.) antagonized shaking caused by the optimal dose of DALA (20 microgram). Naloxone (0.1-10 mg/kg, s.c.) attenuated both DALA- and beta-endorphin-induced WDS in a dose-related manner. This latter result differentiates shaking associated with opioid peptides from that caused by thyrotropin releasing hormone (TRH), another endogenous stimulant of WDS in rats. There was no cross-tolerance between RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone), a novel shake inducing agent, and beta-endorphin. This finding again differentiates beta-endorphin-induced shaking from that caused by TRH and also from that associated with several exogenous stimulants of WDS.

Animals↗
PubMed1981

Opiate-like electroencephalographic and behavioral effects of electroconvulsive shock in rats.

Rats were studied (a) after a single transauricular electroshock (acute ECS) and (b) following 10 consecutive once-daily shocks (chronic ECS). ECS produced a generalized convulsion marked by a polyspike EEG seizure. The seizure was followed by a period of postictal depression (PID) characterized by EEG high-voltage synchrony, EMG quietening, and an associated stuporous behavior in the rat. Acute ECS produced a maximal of 33 +/- 8 (S.E.) percent above control in the EEG voltage output during postictus, with the PID lasting 2680 +/- 658 sec. Chronic ECS resulted in a significant enhancement of these acute responses. Pretreating rats with naloxone (0.3-10 mg/kg s.c.) antagonized the postictal effects of acute ECS, but not of chronic ECS. These naloxone-sensitive postictal EEG and behavioral changes appear to reflect a release of endogenous opioid peptides during ictus, a finding consistent with the hypothesis that electroshock activates opioid systems.

Animals↗
PubMed1981

A comparison of the anticonvulsant effects of two systemically active enkephalin analogues in rats.

FK-33,824 (Tyr-D-Ala-Gly-MePhe-Met(O)-ol) and metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-CONH2; LY 127623) are two parenterally active synthetic analogues of the endogenous morphinomimetic pentapeptide, [Met5]-enkephalin. Acute s.c. administration of each analogue raised the seizure threshold in a dose-related manner in rats challenged with flurothyl, a volatile convulsant. The anticonvulsant action was antagonized by a low dose of naloxone (0.10 mg/kg s.c.). FK-33,824 and metkephamid can therefore be classified with typical mu-receptor agonists such as morphine and etorphine in this procedure.

Animals↗
PubMed1980

D-ala2-methionine-enkephalinamide self-administration in the morphine-dependent rat.

The self-administration of D-enkephalin was studied in the dependent rat self-administering morphine. The rats were prepared with chronic IV and bilateral intraventricular (IVT) injection cannulae. They were made physically dependent on morphine and trained to lever press for IV morphine self-injections (inj) (10 mg/kg) on a fixed ratio (20) (FR20) schedule of reinforcement. Substitution of D-enkephalin either IVT (40 microgram/inj) or IV (10 mg/kg/inj) in the morphine-dependent rat maintained consistent lever pressing and self-administration behavior similar to morphine self-administration. No signs of abstinence were observed during the D-enkephalin substitution. However, saline substitution (0.05 ml/inj IV) for morphine in the self-administering rat produced an abstinence syndrome characterized by extinction of responding, wet-dog shakes, writhes, and diarrhea, which were reversed for 1 h by a single IVT injection of D-enkephalin (40 or 80 microgram). These results indicate that D-enkephalin will serve as a reinforcer to maintain opiate-seeking behavior and support physical dependence in the rat.

Animals↗
PubMed1980

Pupillary effects of leucine and methionine enkephalin in rats after intraperitoneal administration.

Changes in pupil size after peripheral administration of met-enkephalin, leu-enkephalin, or morphine were studied in the rat. With a simple pupillographic technique, the pupil diameter of male, S.D. rats (250--300 g) was measured by a series of photographs taken every 60 sec for at least 45 min after the last drug injection. Morphine (8 mg/kg, SC) caused mydriasis characterized by rapid and marked fluctuations of pupil size. Mydriasis also occurred after leu-enkephalin (5 and 10 mg/kg, IP) and met-enkephalin (20 mg/kg, IP) Both peptides induced morphine-like fluctuations. When given 15 min after morphine, leu-enkephalin (5 and 10 mg/kg) increased the mydriatic effect of morphine from 172 percent of control to 224 and 272 percent, respectively. Met-enkephalin (20 mg/kg, but not 10 mg/kg) also enhanced the mydriatic response of morphine, to 244 percent of control. These interactions appear to represent simple addition rather than potentiation. The effects of both peptides were reversed by naloxone (1 mg/kg, SC), suggesting an opiate receptor interaction for the pupillary effect of the enkephalins. The rat pupil thus provides one of the few in vivo models permitting quantification of enkephalin action after parenteral administration.

Animals↗
PubMed1979

Electroencephalographic and behavioral tolerance to and cross-tolerance between D-Ala2-methionine-enkephalinamide and morphine in the rat.

Rats were given repeated intraventricular (i.vt.) injections of D-enkephalin (20 microgram/4 hr) or morphine (20 microgram/4 hr) for 72 to 96 hr during electroencephalograman(EEG) recording. Initial epileptiform EEG and associated wet-dog shakes occurred following D-enkephalin but not morphine. The epileptoid EEG progressed to a continous high-voltage EEG synchrony similar to morphine and was associated with behavioral stupor. Rapid eye movement sleep was also suppressed. Repeated administration of D-enkephalin or morphine produced tolerance to their effects. When challenged with i.vt. morphine, D-enkephalin-tolerant rats were cross-tolerant to morphine. Likewise, morphine-tolerant rats were cross-tolerant to D-enkephalin. While the morphine-tolerant rats demonstrated a marked abstinence syndrome when challenged with naloxone (10 mg/kg i.p.), no abstinence signs were observed in the D-enkephalin-tolerant rats. The demonstration of tolerance and cross-tolerance between morphine and D-enkephalin suggests a similar mechanism of action, but the differential development of physical dependence may entail different mechanisms or receptor sensitivities for this effect. These findings of similarities and differences in the acute and chronic effects of D-enkephalin and morphine support the contention that heterogenous opiate receptors may mediate their pharmacologic actions.

Animals↗
PubMed1978

Electroencephalographic and behavioral effects of D-ala2-methionine-enkephalinamide and morphine in the rat.

Rats were prepared with chronic cortical and temporalis muscle electrodes and bilateral intraventricular (i.vt.) cannulae. The direct and voltage integrated electroencephalogram (EEG) and integrated electromyogram as well as gross behavior were monitored after the i.vt. injection of D-enkephalin (10--240 microgram), morphine (2.5--40 microgram), naloxone (25--50 microgram) or sterile water (10 microliter). EEG high-amplitude slow-frequency waves (EEG slow bursts) occurred after i.vt. morphine or D-enkephalin and were associated with behavioral stupor. The behavioral depressant effect was followed by behavioral arousal and EEG activation. The EEG voltage output during morphine or D-enkephalin-induced EEG slow-wave activity was dose-dependent and was correlated with the behavioral state of the rat. D-Enkephalin was less potent and shorter-acting than morphine but produced a greater maximal response with respect to increasing the EEG voltage output. The effects of D-enkephalin and morphine were antagonized by pretreatment with naloxone (10 mg/kg s.c.). On the other hand, the i.vt. injection of naloxone alone or sterile water had no disruptive effect of the EEG or behavior of the rat. The results of this study established a dose-response relationship for the i.vt. administration of morphine and D-enkephalin using the direct and voltage integrated EEG. The demonstrated difference in maximal EEG response between morphine and D-enkephalin supports the contention that heterogenous opiate receptors in the brain may mediate their effects.

Animals↗
PubMedDate not supplied

Dodecylglycerol provides partial protection against glutamate toxicity in neuronal cultures derived from different regions of embryonic rat brain.

Primary cultures enriched in neurons dissociated from embryonic rat cerebral cortex, cerebellum, or hippocampus were treated in a chemically defined serum-free media with either vehicle, dodecylglycerol (DDG, 3 microM), or glutamate (75 microM), or preincubated with DDG for 4 or 24 h, and further incubated with glutamate. Their morphological and biochemical assessments (lactate dehydrogenase [LDH] release in the culture media, neuronal viability and intracellular Ca2+ mobilization) were made. Neurotoxic effects of glutamate and glutamate-mediated increases in intracellular Ca2+ were maximal in neurons from cerebellum and minimal in neurons from cortex. Cotreatment of cells with DDG and glutamate failed to provide significant neuronal protection against glutamate in the three brain regions. Pretreatment of cells with DDG for 4 or 24 h prior to glutamate treatment provided significant neuroprotection as judged by morphological changes and a decrease in LDH activity. Neuroprotection of approximately 15-35% was observed following 4 h of DDG pretreatment, increasing to 60-85% protection after 24 h of DDG pretreatment. Although the mechanism of DDG's neuroprotective action remains to be elucidated, these results demonstrate that both glutamate and DDG have differential specificity for anatomical regions of the brain.

Animals↗
PubMedDate not supplied

Studies on opioid peptides as endogenous anticonvulsants.

In both normal and hypophysectomized rats, electroconvulsive shock (ECS) produced a significant postictal rise in seizure threshold (S.T.) to flurothyl, a volatile convulsant. This ECS-induced increase in S.T. was markedly attenuated by naloxone (10 mg/kg s.c.), which itself did not alter basal S.T. A dose of bicuculline (0.1 mg/kg i.p.) which was slightly proconvulsant in the flurothyl test did not significantly alter the postictal rise in S.T. produced by ECS. With hypophysectomized rats, there was a 24% increase in basal S.T. to flurothyl challenge. Hypophysectomy had no influence on the postictal rise in S.T. produced by ECS, nor on the attenuation that occurs with naloxone. We propose that the postictal rise in S.T. reflects a change occurring centrally which prevents a static convulsive state, possibly through brain opioid peptides acting as endogenous anticonvulsants.

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