Reversal of fentanyl/fluanisone neuroleptanalgesia in the rabbit using mixed agonist/antagonist opioids.

The reversal of the neuroleptanalgesic combination of fentanyl/fluanisone using mixed agonist/antagonist opioids has been investigated in the rabbit. All of the compounds studied (naloxone, nalbuphine, meptazinol, butorphanol, buprenorphine, pentazocine, doxapram) reversed the respiratory depression and sedation produced by fentanyl/fluanisone. Fentanyl/fluanisone produced profound analgesia for 180 min, which was rapidly and completely antagonized by naloxone. The mixed agonist/antagonist opioids produced a reduction in the degree of analgesia but, in contrast to naloxone, analgesic activity persisted from 120 min (meptazinol) to 420 min (buprenorphine). Administration of buprenorphine to rabbits anaesthetized with fentanyl/fluanisone and midazolam confirmed that the reversal of respiratory depression was accompanied by the return of arterial pH, PCO2 and PCO2 to preanaesthetic values. The use of neuroleptanalgesic anaesthetic regimens, which have been shown to provide effective surgical anaesthesia, combined with reversal using a mixed agonist/antagonist opioid to provide postoperative analgesia, appears to be a valuable refinement of current laboratory animal anaesthetic practice.

Development of inhibitory activity of sulpiride for synaptic [3H]-spiperone binding in the rat striatum.

To establish the functional development of striatal dopamine2 (DA2) receptors, the effects of NA+ and GTP on the potency of sulpiride in competing for specific [3H]-spiperone binding were investigated in the striatum of developing rats. The IC50 value of sulpiride for specific [3H]-spiperone binding was 31-fold decreased by 100 mM Na+ compared to that in 70-day-old control animals but not by 50 microM GTP. In the presence of Na+, the IC50 of sulpiride was low in fetuses at 18 days of gestation and high at 360 days of postnatal life. It is suggested that the Na+-dependent binding of sulpiride to DA2 receptors probably reaches functional maturity in fetuses at 18 days of gestation and that the Na+ dependence of the effect decreases during aging.

Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino (1,2-a) quinoline (compound 69/183). Part I: Hypotensive activity.

3-[gamma-(p-Fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazinol(1,2-a)quinoline (compound 69/183, centpyraquin) has been found to possess promising hypotensive activity in anaesthetised cat, dog and monkey- It also lowers the blood pressure of unanaesthetised cat, dog and hypertensive rat. The effective doses are between 0.5 to 2.0 mg/kg in all the species except rat, in which doses of 10.0 and 20.0 mg/kg are effective. The compound potentiates epinephrine and norepinephrine pressor responses but inhibits carotid occlusion, tyramine and DMPP induced pressor responses. The contraction of the nictitating membrane due to pre- as well as post-ganglionic sympathetic nerve stimulation is blocked equally. In mice the compound produces ptosis which is antagonised by N-benzyl-N-methylguanidine. Localisation of the compound either to the superior cervical ganglion of cat or to the central cardiovascular loci has no effect on the activities of either of them. No evidence of an initial catecholamine release by the compound could be obtained. It has weak smooth muscle relaxant activity. The mechanism of hypotensive action seems to be the blockade of adrenergic neurones along with direct smooth muscle relaxation.

The effects of dexetimide on pimozide-, haloperidol- and pipamperone-induced inhibition of brain self-stimulation in rats.

Pimozide (0.04, 0.16, 0.63 and 2.50 mg/kg), haloperidol (0.01, 0.04, 0.16 and 0.63 mg/kg) and pipamperone (2.50, 10.0, 40.0 and 160 mg/kg) were given subcutaneously to rats, pressing a lever for brain-stimulation through electrodes implanted in the lateral hypothalamic region of the medial forebrain bundle. The lowest dose of each neuroleptic did not affect self-stimulation; the second dose inhibited the response rate by approximately 50%, whereas the two highest doses completely suppressed self-stimulation behaviour. The centrally acting anticholinergic dexetimide (0.63 mg/kg, s.c.) completly antagonized the pimozide-induced inhibition; the haloperidol-induced inhibition was also completely antagonized except at its highest doses, whereas the effects of the sedative neuroleptic pipamperone were not antagonized. These data are consistent with a presumed dopaminergic cholinergic striatal interaction and show brain self-stimulation to be an effective measure of neuroleptic-anticholinergic interaction.