Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid

Summary This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 g of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors.     

Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms

Two classes of amine-aldehyde adducts, the tetrahydroisoquinoline (TIQ) and beta-carboline (THBC) compounds, have been implicated in the mechanism in the brain underlying the addictive drinking of alcohol. One part of this review focuses on the large amount of evidence unequivocally demonstrating not only the corporeal synthesis of the TIQs and THBCs but their sequestration in brain tissue as well. Experimental studies published recently have revealed that exposure to alcohol enhances markedly the endogenous formation of condensation products. Apart from their multiple neuropharmacological actions, certain adducts when delivered directly into the brain of either the rat or monkey, to circumvent the brain's blood-barrier system, can evoke an intense and dose-dependent increase in the voluntary drinking of solutions of alcohol even in noxious concentrations. That the abnormal intake of alcohol is related functionally to opioid receptors in the brain is likely on the basis of several distinct lines of evidence which include: the attenuation of alcohol drinking by opioid receptor antagonists; binding of a TIQ to opiate receptors in the brain; and marked differences in enkephalin values in animals genetically predisposed to the ingestion of alcohol. Finally, it is proposed that the dopaminergic reward pathways which traverse the meso-limbic-forebrain systems of the brain more than likely constitute an integrative anatomical substrate for the adduct-opioid cascade of neuronal events which promote and sustain the aberrant drinking of alcohol.     

Isoquinolines,beta-carbolines and alcohol drinking: Involvement of opioid and dopaminergic mechanisms

Summary Two classes of amine-aldehyde adducts, the tetrahydroisoquinoline (TIQ) and beta-carboline (THBC) compounds, have been implicated in the mechanism in the brain underlying the addictive drinking of alcohol. One part of this review focuses on the large amount of evidence unequivocally demonstrating not only the corporeal synthesis of the TIQs and THBCs but their sequestration in brain tissue as well. Experimental studies published recently have revealed that exposure to alcohol enhances markedly the endogenous formation of condensation products. Apart from their multiple neuropharmacological actions, certain adducts when delivered directly into the brain of either the rat or monkey, to circumvent the brain's blood-barrier system, can evoke an intense and dose-dependent increase in the voluntary drinking of solutions of alcohol even in noxious concentrations. That the abnormal intake of alcohol is related functionally to opioid receptors in the brain is likely on the basis of several dinstinct lines of evidence which include: the attenuation of alcohol drinking by opioid receptor antagoists; binding of a TIQ to opiate receptors in the brain; and marked differences in enkephalin values in animals genetically predisposed to the ingestion of alcohol. Finally, it is proposed that the dopaminergic reward pathways which traverse the meso-limbic-forebrain systems of the brain more than likely constitute an integrative anatomical substrate for the adduct-opioid cascade of neuronal events which promote and sustain the aberrant drinking of alcohol.     

Spontaneous morphine withdrawal from the rat spinal cord

A characteristic and reproducible sign of narcotic withdrawal is the naloxone induced increase in arterial pressure. In morphine-dependent rats allowed to undergo spontaneous withdrawal (6-24 h) and then transected at the spinal C-1 level, arterial pressure was maintained at a significantly higher level than either spinal-transected nondependent controls or morphine-dependent, spinal-transected rats pithed from C-1 to L-4. These findings indicate that the morphine-dependent spinal cord, independent of supraspinal influences, is able to exhibit an autonomic component of spontaneous withdrawal.     

Evidence for an inhibitory role of beta-endorphin and other opioids on human total T rosette formation

Beta-endorphin, met-enkephalin, leu-enkephalin and morphine significantly inhibit rosette formation between human T lymphocytes and sheep red blood cells. This effect is completely reversed by naloxone, a specific antagonist, while naloxone by itself does not influence rosette formation. A further link between the immune system and the neuroendocrine system is suggested.     

Spontaneous morphine withdrawal from the rat spinal cord

Summary A characteristic and reproducible sign of narcotic withdrawal is the naloxone induced increase in arterial pressure. In morphine-dependent rats allowed to undergo spontaneous withdrawal (6–24 h) and then transected at the spinal C-1 level, arterial pressure was maintained at a significantly higher level than either spinal-transected nondependent controls or morphine-dependent, spinal-transected rats pithed from C-1 to L-4. These findings indicate that the morphine-dependent spinal cord, independent of supraspinal influences, is able to exhibit an autonomic component of spontaneous withdrawal.This study was supported by the Medical Research Service of the Veterans Administration. A preliminary report of aspects of this work appeared in Soc. Neurosci. Abs.10 (1984) 1113.     

Behavioural effects of naloxone in rats

Summary Naloxone in rats induces a behavioural syndrome closely resembling that induced by intraliquorally injected ACTH peptides. This effect is probably due to a displacement of the ACTH peptides from other receptors (e.g. opiate receptors).Acknowledgments. The authors are indebted to Dr M. J. Ferster of Endo Laboratories (Brussels) for the kind supply of naloxone. The excellent technical assistance of Mr Gianni Montorsi is gratefully acknowledged.     

Naloxone selectively blocks dopamine response of Br-type neuron in Helix pomatia L.

The present study demonstrates that the potent opiate antagonist, naloxone can selectively block the DA induced inhibition of the bursting activity pattern of the RPal or Br-type neuron. The dopamine inhibitory affect can also be blocked by haloperidol, a established dopamine receptor blocker.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Piroxicam-induced analgesia: evidence for a central component which is not opioid mediated.

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p < 0.05) and 50% (p < 0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Naloxone selectively blocks dopamine response of Br-type neuron inHelix pomatia L.

Summary The present study demonstrates that the potent opiate antagonist, naloxone can selectively block the DA induced inhibition of the bursting activity pattern of the RPal or Br-type neuron. The dopamine inhibitory affect can also be blocked by haloperidol, a established dopamine receptor blocker.This work partially supported by a grant from the National Academy of Sciences and the Hungarian Academy of Sciences awarded to G.B.S. We also gratefully acknowledge thoughtful comments from Dr J. Salanki.     

Beneficial action of naloxone in splanchnic artery occlusion shock

Summary The effects of naloxone on mean arterial blood pressure, myocardial depressant factor (MDF) activity and survival, after splanchnic artery occlusion were studied in cats. Naloxone significantly improved survival in splanchnic artery occlusion shock and prevented the accumulation of MDF in the plasma.Supported in part by a research grant from the W. W. Smith Foundation.Acknowledgments. We gratefully acknowledge the expert technical assistance of Maureen Messenger.     

Role of the Raphe Magnus nucleus in morphine analgesia : studies with intracerebral microinjections in the rat]

Microinjections of low concentration of morphine (5 micrograms) into the nucleus Raphé Magnus of the Rat produce a strong analgesia that can be reversed by systemic naloxone, an opiate antagonist. The administration of naloxone (5 micrograms) into the Raphé Magnus considerably reduces the effects of intravenous morphine. The effects of microinjections of morphine are strongly reduced by Cinanserin, suggesting a role for serotoninergic mechanisms in morphine analgesia.     

Parasympathetically evoked parotid salivary secretion of chronically amitriptyline-treated rats

Summary Treatment of rats with amitriptyline for 4 weeks significantly decreased flow rate of saliva elicited from parotid glands in response to electrical stimulation of the parasympathetic innervation but did not alter calcium concentration of such saliva. The mechanism of the dissociation between flow rate and calcium concentration of parasympathetically evoked saliva induced by amitriptyline treatment remains to be explored, and may not involve an amitriptyline induced reduction in acetylcholine release.Acknowledgments. This work was supported by NIDR grant No. DE 02110. The authors wish to thank Dr C. A. Stone of Merck, Sharp and Dohme, Inc., West Point Pennsylvania 19466 for kindly supplying the amitriptyline used in these experiments.     

Circling behavior induced by phencyclidine in mice and its inhibition by naloxone

Phencyclidine (PCP), when given to mice, induces general hyperactivity and rapid circling, similar to that caused by morphine. These effects are partially antagonized by naloxone.     

Involvement of endorphins in the emotional behavior of pigs]

Social isolation and exposure to a new environment induce hyperactivity, vocalizations and ACTH release in weaned Piglets acutely submitted to this stress. These reactions are increased by pretreatment with morphine (0.5 and 1 mg/kg) and decreased by naloxone (1 mg/kg), suggesting that endogenous opiates modulate emotional behaviour in Pigs.     

Inhibitory effect of methionine- and leucine-enkephalin on contractions of the guinea-pig ileum elicited by PGE1

Summary Methionine-enkephalin and leucine-enkephalin (m-enk and l-enk) have been shown to antagonize contractions of the isolated guinea-pig intestine elicited by PGE₁. The inhibitory effect of these 2 pentapeptides is abolished by naloxone.     

Naloxone reduces abdominal muscle tone in mice and rats

Summary The effect of naloxone on muscle tone was investigated in mice and rats at various times after administration. The naloxone effect was also tested in diazepam-pretreated animals. Naloxone was found to display muscle relaxant activity. This effect appeared to be additive to that of diazepam.     

Intracerebroventricular injection of cerebrospinal fluid (CSF) from a patient with congenital indifference to pain induces analgesia in rats

CSF from a patient with congenital indifference to pain was found to produce analgesia in the rat following intracerebroventricular injections. The analgesic effect was attenuated by pretreatment with naloxone suggesting the involvement of hyperactive endogenous opiate mechanisms in this patient.     

Intracerebroventricular injection of cerebrospinal fluid (CSF) from a patient with congenital indifference to pain induces analgesia in rats

Summary CSF from a patient with congential indifference to pain was found to produce analgesia in the rat following intracerebroventricular injections. The analgesic effect was attenuated by pretreatment with naloxone suggesting the involvement of hyperactive endogenous opiate mechanisms in this patient.