Attenuation of epileptogenesis by nonsteroidal anti-inflammatory drugs in the rat.

Subconvulsive doses (25 mg/kg) of pentylenetetrazol were administered at intervals of 4 days for 20 sessions, to induce kindling in conscious, free-moving rats, with chronically-implanted electrodes. This regimen induced an excitation of the CNS, which intensified over the 20 sessions. Periods of motor arrest, concurrent with bursts of electrocortical spike-wave activity, increased to clonic convulsions, concurrent with bursts of spike activity. Separate groups of rats were pretreated over the twenty sessions with nonsteroidal anti-inflammatory drugs (NSAIDs). Pretreatment with paracetamol produced a dose-related reduction in pentylenetetrazol-induced seizure activity. Pretreatment with 20 mg/kg mefenamic acid attenuated, while 60 mg/kg dose potentiated, the pentylenetetrazol-induced excitation. Pretreatment with 10 or 30 mg/kg ibuprofen had no significant effect, while 90 mg/kg was lethal, by itself, in 58% of the group. When all the groups received a single dose of pentylenetetrazol, three weeks after the twenty sessions, there were no significant differences between the groups in level of pentylenetetrazol-induced excitation, when compared to the control (saline-pretreated) group. This suggests that the effective NSAIDs had influenced the manifestation of, but not development of, epileptogenesis over the 20 sessions.

Attenuation of penicillin models of epilepsy by nonsteroidal anti-inflammatory drugs.

Prostaglandin and thromboxane levels increase in mammalian brain during seizures, but whether a metabolite of arachidonic acid has a role in induction, or is merely a by-product, of seizures is still not clear. It has been shown that nonsteroidal anti-inflammatory drugs block arachidonic acid metabolism through inhibition of the enzyme, cyclooxygenase. In the present study, the antiepileptic action of nonsteroidal antiinflammatory drugs was investigated utilizing penicillin-induced focal (250 IU) and primary generalized (2.5 million IU kg-1) models of epilepsy. The effects of the drugs on the electrocortical and motor manifestations of both models were examined. As a group, the nonsteroidal anti-inflammatory drugs significantly affected the central nervous system excitation produced by penicillin. However, individual drugs affected different parameters of the excitation. Paracetamol, the most effective, delayed and/or blocked spikes and seizures in both models. Ibuprofen was more effective against the primary generalized model. Mefenamic acid decreased the number of seizures and indomethacin decreased the voltage output in both models. The present study, together with earlier papers, suggests that an arachidonic acid metabolite plays a role in induction of several animal models of epilepsy.

Differential effect of prostaglandin synthetase inhibitor pretreatment on pentylenetetrazol-induced seizures in rat.

Release of prostaglandins (PGs) from brain tissue increases during experimentally-induced and spontaneous seizures. However, whether PGs or other arachidonic acid metabolites have a role in induction of seizures is still unclear. The effectiveness of pretreatment with PG synthetase inhibitors on pentylenetetrazol (PTZ)-induced models of epilepsy was investigated in free-moving rats with chronically-implanted supracortical electrodes. The effects on the electrocortical and motor manifestations of both a subconvulsive (30 mg.kg-1) and a convulsive (60 mg.kg-1) dose of PTZ were examined. Mefenamic acid (15 or 50 mg.kg-1), meclofenamic acid (15 or 50 mg.kg-1), ibuprofen (30 or 90 mg.kg-1) and paracetamol (300 or 450 mg.kg-1) delayed the onset of PTZ-induced convulsions. But mefenamic acid and meclofenamic acid also potentiated the excitatory effects of both subconvulsive and convulsive doses of PTZ. Indomethacin (3, 10 or 30 mg.kg-1) had no significant effect. The results suggest that the differential effects were produced by actions not related to the cyclo-oxygenase inhibition although the more consistent decrease of convulsive behavior may have resulted from inhibition of PG synthesis.

Differential effects of prostaglandin synthetase inhibitors on EEG in rat.

The effects of five nonsteriodal prostaglandin (PG) synthetase inhibitors on the electrocorticogram were studied in rats with chronically implanted supracortical electrodes. All of PG synthetase inhibitors produced high voltage activity in the electrocorticogram. However, behavior and spectral analysis of the electrocortical activity suggests that these drugs could be divided into two groups. Meclofenamic acid and mefenamic acid produced dose-related increases in excitation (to seizure) while ibuprofen, paracetamol and indomethacin produced dose-related increases in sedation.

Effect of prostaglandin synthetase inhibitors on experimentally induced convulsions in rats.

To investigate the relationship of prostaglandins (PGs) to seizure induction, the effects of six PG synthetase inhibitors on convulsions induced by flurothyl, picrotoxin, pentetrazol (PTZ), electroshock or bicuculline were evaluated. Ibuprofen, sulindac, mefenamic acid, and low dose meclofenamic acid increased the latency-to-onset in the flurothyl and/or PTZ models; the electroshock, picrotoxin and bicuculline models were not significantly affected by any of the pretreatment agents. These results suggest that PGs are involved in the mechanism(s) underlying fluorthyl- and PTZ-induced convulsions, but not picrotoxin-, electroshock-, or bicuculline-induced convulsions.

Effect of prostaglandin synthetase inhibitors on non-analgesic actions of morphine.

The present study investigates the results of pretreatment with five prostaglandin (PG) synthetase inhibitors on effects of morphine on body temperature, pupillary diameter, body movement and production of exophthalmos in rat. Hyperthermia, induced by a low dose of morphine, was inhibited in animals pretreated with any of the PG synthetase inhibitors. However, PG synthetase inhibitors had no clear effect on hypothermia induced by higher doses of morphine. The duration of morphine-induced catalepsy was attenuated by pretreatment with the PG synthetase inhibitors in a dose-related manner. The exophthalmos induced by all doses of morphine was either shortened in duration or inhibited by sulindac, paracetamol or ibuprofen. Morphine-induced mydriasis was either attenuated or inhibited by paracetamol, ibuprofen or meclofenamic acid. The results suggest that endogenous PGs play a role in morphine-induced hyperthermia, catalepsy, exophthalmos and mydriasis whereas a physiological role for PGs in morphine-induced hypothermia was not indicated.

Role of adrenal medulla in morphine-induced hyperthermia through central action.

The role of the adrenal glands, in morphine-induced hyperthermia was studied in normal, chemically-sympathectomized, adrenalectomized, adrenal-demedullated or splanchnicotomized rats. 2. In restrained female rats, 5 mg/kg morphine produced hyperthermia whereas 20 mg/kg and 40 mg/kg produced hyperthermia. 3. After adrenalectomy, 5 mg/kg morphine did not produce hyperthermia. 4. After adrenal-demedullation or adrenal-denervation (splanchnicotomy), 5 mg/kg morphine did not produce hyperthermia. 5. The results suggest that, in the rat, the adrenal medulla plays an important role in morphine-induced hyperthermia, and that morphine acts centrally to stimulate the medulla.

Bole of adrenals in morphine-induced hyperthermia in restrained rats.

Bole of adrenals in morphine-induced hyperthermia was studied in normal, neurotransmitter antagonist-pretreated, chemical-sympathectomized, adrenalectomized or adrenal-demedullated rats. In restrained female rats, 5 mg/kg morphine produced hyperthermia whereas 20 mg/kg and 40 mg/kg produced hypothermia. Pretreatment with either phenoxybenzamine, propranolol, pentolinium or scopolamine inhibited the hyperthermia. After adrenalectomy, neither 5 mg/kg nor chronic administration of 20 mg/kg morphine produced previously demonstrated hyperthermia. After adrenal-demedullation, a dose of 5 mg/kg morphine also did not produce hyperthermia. In contrast to female rats, restrained male rats showed no significant effect on body temperature after 5 mg/kg morphine, requiring 20 mg/kg and 40 mg/kg morphine to produce hyperthermia. In adrenalectomized male rats, 20 mg/kg morphine did not produce the usual hyperthermia. The results suggest that male rats are more resistant to the hyperthermic effects of morphine than female rats and that in the rat, the adrenals, likely the medulla, play an important role in morphine-induced hyperthermia.

Role of sympathetic system in morphine-induced mydriasis in rat.

The effects of three doses (5, 30, and 60 mg/kg) of morphine on pupillary diameter (PD) were studied in rats that were either normal, neurotransmitter antagonist pretreated, guanethidine pretreated, cervical sympathectomized, or adrenalectomized. Morphine produced a dose-dependent increase in PD and exophthalmos. In addition, the PD concurrently underwent fluctuations. alpha-Adrenergic antagonists blocked both mydriasis and exophthalmos, whereas a beta-adrenergic antagonist had no significant effect. This suggested a role for the sympathetic nervous system. However, cervical sympathectomy or guanethidine pretreatment only partially blocked the increase in PD or exophthalmos. Adrenalectomy also partially blocked the mydriasis and exophthalmos. Adrenalectomy combined with guanethidine pretreatment completely blocked morphine-induced mydriasis but no exophthalmos. Thus, the results suggest that both direct sympathetic innervation and hormonal action from the adrenals are involved in morphine-induced mydriasis in the rat.

Biphasic effects of morphine on cardiovascular system of the cat.

Morphine has been reported to both lower blood pressure (BP) and cause excitation in some species. These are seemingly contradictory effects. In this series of experiments, the actions of morphine on BP, heart rate (HR) and pupillary diameter were re-examined in sedated, paralyzed cats under 2 ranges of dosage and 3 types of sedative. Small doses (1--2 mg/kg) lowered BP and HR while larger doses (8--12 mg/kg) increased both BP and HR. The effect of morphine on pupillary diameter, however, was not biphasic in that increasing doses proportionally increased pupillary diameter. In adrenalectomized cats smaller doses of morphine decreased, but larger doses no longer increased, BP and HR as it has in the non-adrenalectomized animals. Morphine also no longer produced mydriasis in the adrenalectomized cats. The results suggest that, in the cat, morphine can have a biphasic effect and that the adrenals may play a role in the excitatory phase.

Mechanism of morphine-induced mydriasis in the cat.

Neurons that increased their firing rate in response to light stimulation were recorded from the pretectal region and the anterior oculomotor nucleus of sedated immobilized cats while morphine (2 mg/kg iv) was administered. The dose produced mydriasis and an increase in spontaneous firing rate of all light-sensitive neurons recorded from the anterior oculomotor nucleus. This suggested that morphine did not produce mydriasis through inhibition of the third nerve. Phenoxybenzamine, iv or topically, antagonized the mydriasis, indicating a peripheral source of sympathetic input as the basis for morphine-induced mydriasis. Morphine (2 mg/kg iv), administered 1 h after adrenalectomy, produced miosis and increased the spontaneous firing rate of light-sensitive neurons recorded from the oculomotor nucleus. These observations suggest that, in the cat, although morphine activates the oculomotor neurons to produce miosis, the effect is masked by the morphine-induced release of catecholamines, mainly from the adrenal glands, which produced mydriasis.

Prostaglandin E1-induced latent epileptogenic foci.

Suprafusion of 125 microliter 6% KCl solution over the visual cortex of rabbits 2-24 h after they suffered a prostaglandin (PG) E1-induced epileptic seizure was found to cause a recurrence of seizure activity. The initial seizure was induced by the cortical suprafusion of PGE1 over the left visual cortex of PG transport inhibitor-pretreated rabbits. Control animals that were not pretreated with PG transport inhibitors (bromcresol green or probenecid), or received suprafusion of saline or PGF2 alpha rather than PGE1, did not show initial seizure activity. In these animals, and in animals that had PG-induced seizures 72 h before KCl administration, the KCl solution caused only inhibition of the visually evoked response but no seizure activity. The results are interpreted to indicate that under appropriate conditions PGE1 can create a latent epileptogenic focus which can be reactivated by KCl. It is suggested that since PGE1 is produced by the brain normally, and in increased amounts as the result of overstimulation, irritation or trauma, this potent autacoid may play a role in the spontaneous development of latent epileptogenic foci or the recurrence of epileptic seizures.

The effects of intravitreally injected prostaglandin E1 on retinal function and their enhancement by a prostaglandin-transporter inhibitor.

The effects of intravitreally injected prostaglandins (PG's) E1 and F2alpha were studied on conscious, bromcresol green (BrCG)-pretreated and control rabbits. The electroretinogram (ERG) of both the PG-injected and the contralateral control eyes was recorded with contact lens electrodes; and electrocorticogram and the visually evoked response (VER) were recorded from both hemispheres with previously implanted supradural electrodes. In normal rabbits, intravitreal injection of 0.70 mg of PGE1 resulted in a small reduction in the amplitude of the ERG b-wave and of the slow negative wave (SNW) of the contralateral VER. In BrCG-pretreated rabbits, intravitreal injection of 0.70 mg of PGE1 caused a statistically significant decrease in the amplitude of the ERG b-wave and the SNW. Intravitreal injection of 0.7 mg of PGE1 also caused a significantly prolonged inhibition of the ERG in BrCG-pretreated, but not in normal rabbits, following exposure of the eye to a bright light flash. A smaller dose of PGE1 (0.35 mg/eye) caused more moderate effects on some of these parameters. These effects could not be explained by the PG-induced miosis. PGF2alpha (0.7 mg/eye) caused no significant changes in any of the parameters studied. These results indicate that exogenous PG's can have adverse effects on retinal function and that these effects are enhanced by BrCG, a PG-transport inhibitor. Presumably, this inhibitor blocks the PG-removal mechanisms across the blood-retinal barriers and hence allows the accumulation of PG's in the extracellular fluids of the retina.

Temperature response to morphine in paralyzed cats.

Cats, sedated and paralyzed, showed a significant increase in body temperature after intravenous injection of morphine while animals with additional spinal blockade (C3) from injection of 2% lidocaine solution, did not. The results suggest that motor activity is not necessary for morphine-induced hyperthermia in the cat, as had been suggested in the literature.

Studies on the potency of various antitussive agents.

Several antitussive agents were assessed for their cough-suppressant activity. Cough responses were obtained by electrically stimulating the lower brainstem, in cats lightly anesthetized with sodium pentobarbital or in unanesthetized midcollicular decerebrate preparations. Cough sounds were recorded with the aid of a microphone. The cough reactive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The potency of these antitussive agents (dextromethorphan, RO 21-4790-001, codeine, clonazepam, diazepam and caramiphen) were determined by studying their effect on the centrally induced cough responses. Each of these agents was administered in graded doses intravenously to determine the minimal effective doses for suppressing the cough responses. They are 0.57, 2.55, 1.71, 0.048, 0.28 and 3.18 mg/kg for the above listed drugs. The results indicate that clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is six times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.