Experimental convulsions in rats induced by intraventricular administration of kynurenine and structurally related compounds.

Administration of L-kynurenine and some analogous molecules into the right lateral ventricle caused convulsive attacks in rats. These convulsions are tonic-clonic. Various modifications of the structure of L-kynurenine affected the production of convulsions. In particular, methylation of the carboxyl group increased the potency. Methylation of the carboxyl function and hydroxylation of the benzene ring greatly increased the latency and the duration of the convulsions. Removal of the carboxyl function or its reduction resulted in the loss of the epileptogenic effect. Masking of the amino function with formyl or acetyl residues also produced inactive compounds. The results of structural modification of the kynurenine carbon skeleton clearly show that the structure essential for stimulation of convulsive activity includes a free amino group and a free or masked carboxyl function. The molecular structure able to induce convulsive effects appears to be the laevo -isomer of kynurenine, since the dextro-form has been proved to be inactive. The convulsant activity, evaluated as the ED50, for L-kynurenine, is between that of bicuculline and pentamethylenetetrazole . The convulsant mechanism of kynurenine is unknown, but might very possibly involve interference with the activity of certain inhibitory neurotransmitters.

Involvement of periaqueductal gray matter in intestinal effect of centrally administered morphine.

Microinjections of morphine in the rat periaqueductal gray matter (PAG) inhibited intestinal transit in linear relation to the log of the dose administered (in the range from 5 to 20 micrograms/rat). This linear regression was parallel with that obtained on intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration of morphine and the intracerebral (i.c.) route was calculated to be 4 times more potent than the i.c.v. route and 189 times more potent than the i.p. route. Monolateral electrolytic lesions into the PAG abolished the intestinal effect of i.c.v. morphine to a large extent. The relevance of other brain areas and the type of opiate receptors involved in this central effect of morphine are discussed.

Central and peripheral components of dermorphin's effect on rat intestinal propulsion in comparison to morphine.

Dermorphin, injected intracerebroventricularly (ICV) to rats, provokes, like to morphine, an inhibition of intestinal propulsion linearly related to the log of the administered doses (in the range from 0.06 to 0.56 micrograms/rat), but it is 143 times more active than morphine. Naloxone, ICV or IP, antagonizes dermorphin less effectively than morphine. Quaternary naloxone ICV administered antagonizes the intestinal effect of ICV dermorphin, while IP administered it is not effective until 8 mg/kg. The dose of dermorphin maximally active by the ICV route (0.56 micrograms/rat) is completely inactive when injected IP. Increasing doses of dermorphin IP (from 12 to 6400 micrograms/kg) inhibit intestinal propulsion to the same extent irrespectively of the doses employed, but never by more than 50%. Only a high dose of naloxone (30 mg/kg/IP) antagonizes this IP effect. The central and peripheral components of this intestinal effect of dermorphin are discussed.

Effect on intestinal transit of neurotensin administered intracerebroventricularly to rats.

Neurotensin (NT) administered intracerebroventricularly (i.c.v.) to rats, blocks intestinal transit (tested by charcoal meal) in linear relation to the log of the doses within the range of 0.6-2.5 nmoles/rat. NT in this test is about 40 times more active than morphine (M) and 6 times less active than dermorphin (DM) on a molar basis. Within this dose range NT does not induce analgesia (tail-flick test) or hypothermia (tested at 22 degrees C). The intestinal effect can also be elicited by injecting the peptide into the periaqueductal gray matter (PAG). NT injected intraperitoneally (i.p.) is inactive up to doses 4 times the maximal active i.c.v. dose. Naloxone (Nx) and dynorphin 1-13 could not antagonize the intestinal effect of i.c.v. NT. The relationship between this central intestinal effect and many other central effects of NT is discussed.