Antagonist effects of nalbuphine in opioid-dependent human volunteers.

The subjective, physiological and behavioral effects of nalbuphine, an opioid mixed agonist/antagonist analgesic, naloxone and hydromorphone were studied on adult, male, methadone-dependent volunteers living on a clinical research ward. The purpose was to assess nalbuphine's agonist properties vs. antagonist properties relative to a standard agonist (hydromorphone) and a standard antagonist (naloxone) in opioid-dependent subjects. Drug conditions included saline placebo, nalbuphine hydrochloride (0.375, 0.75, 1.5, 3 and 6 mg), naloxone hydrochloride (0.1 and 0.2 mg) and hydromorphone hydrochloride (4 and 8 mg). Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5 hr experimental sessions. Physiologic measures were monitored continuously before and for 2 hr after drug administration: pupil diameter and subject- and observer-rated behavioral responses were measured intermittently over this same period. Hydromorphone increased ratings significantly on subjective measures typical of morphine-like effects. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Nalbuphine produced effects which were qualitatively similar to the effects of naloxone and showed no evidence of opioid agonist effects in these methadone-dependent subjects. The withdrawal syndrome precipitated by nalbuphine was indistinguishable from that produced by naloxone.

Intermittent naloxone attenuates the development of physical dependence on methadone in rhesus monkeys.

Rhesus monkeys that received 15 daily injections of methadone (2 mg/kg i.m.) exhibited a characteristic opiate withdrawal syndrome after injection of naloxone (0.5 mg/kg i.m.) on the 16th day. In comparison, injection of naloxone (0.5 mg/kg i.m.) once every 2 days during a similar 15 day methadone treatment period in these same monkeys significantly attenuated the severity of the opiate withdrawal syndrome exhibited after naloxone injection on the 16th day. Each naloxone administration during the 15 day methadone treatment period elicited an opiate withdrawal syndrome that did not significantly differ on each of the 7 days it was given and was less severe than the syndrome precipitated by naloxone following 15 days of methadone without intermittent naloxone. The lack of increments in the withdrawal response to the seven naloxone injections during the 15 days of methadone treatment and the attenuation of the withdrawal response to naloxone on day 16 after intermittent naloxone administration during the 15 day methadone treatment period support the hypothesis that naloxone modifies opiate receptor mechanisms so that they revert to an agonist-naive state following antagonist exposure. These findings suggest that various agonist and antagonist opiate drug combinations or mixed agonist-antagonist drug could be clinically useful in the management of situations where physical dependence on opiates is a problem.

Suppression of opiate withdrawal by cyclosporin A and dietary modification.

It has been demonstrated in a murine model that a defined diet (Purina Basal Diet 5755) has immunosuppressive effects similar to cyclosporin A (CsA). It was also shown that CsA treatment in opiate dependent rats can attenuate the severity of opiate withdrawal. In this study, an opiate dependence model was established in Balb/c mice to assess the effects of the 5755 diet and CsA on morphine withdrawal - a CNS mediated phenomenon. Three groups of mice were used; a chow-fed control group (Purina 5008), a chow fed CsA treated group, and a group maintained on the 5755 diet. Morphine dependence was established by subcutaneous implantation of a 100 mg morphine base pellet under ether anesthesia. Seventy-two hours after pellet implantation, withdrawal was precipitated by a single injection of the opiate antagonist naloxone (2 mg/kg ip). Two indicators of withdrawal were assessed; jumping and diarrhea. The data demonstrated that both CsA and the 5755 diet resulted in significant attenuation of withdrawal symptoms with the 5755 diet being the most effective of the two. These findings suggest that immune modulation elicited by the 5755 diet and CsA treatment has a direct impact on the CNS opioid function.

Butorphanol-precipitated withdrawal in opioid-dependent human volunteers.

The subjective, physiological and behavioral effects of hydromorphone, naloxone and butorphanol, an opioid agonist/antagonist analgesic, were studied in adult, male, methadone-dependent volunteers living on a clinical research ward. Drug conditions included saline placebo, 4 and 8 mg of hydromorphone HCl, 0.375, 0.75, 1.5, 3 and 6 mg of butorphanol tartrate and 0.1 and 0.2 mg of naloxone HCl. Drug conditions, given by i.m. injection, were tested in five subjects under double-blind conditions in 2.5-hr experimental sessions. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 2 hr after drug administration. Hydromorphone decreased pupil diameter, and significantly increased ratings of "Good Effects" on the subjective measures. Naloxone precipitated opioid abstinence which was measurable on several subject- and observer-rated behavioral measures and physiological measures. Butorphanol produced effects which were generally similar to the effects of naloxone, indicating that butorphanol doses precipitate withdrawal signs and symptoms when administered to methadone-dependent humans. There were some differences in the withdrawal syndromes precipitated by naloxone vs. butorphanol, suggesting that multiple mechanisms may be involved in opioid withdrawal precipitation.

Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats.

Ibogaine, an indole alkaloid, administered intracerebroventricularly 4-16 micrograms, attenuated a naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. It appears that ibogaine has a more consistent effect on certain selective withdrawal signs related to the locomotion. This might explain an attenuating effect of ibogaine on some withdrawal signs. However, due to complex interaction of ibogaine with serotonin and other neurotransmitter systems, the mechanism of ibogaine antiwithdrawal effect remains unknown and requires further elucidation.

Comparison of peripheral and central administration of naloxone in precipitating abstinence in morphine-dependent rats.

Although it has been known that a morphine abstinence syndrome can be induced by naloxone administered centrally or peripherally, data on a detailed qualitative and quantitative comparison are not available. In the present study morphine pellets were implanted into rats and naloxone was administered intracerebroventricularly (i.c.v.) or subcutaneously (s.c.) 72 h later. A full array of abstinence signs with similar latency, duration, and intensity was seen in morphine-dependent rats following naloxone by either route. There were no major differences in the spectrum of withdrawal signs or in the proportion of rats showing the individual signs. In terms of body weight and temperature, the highest doses tested by each route produced similar quantitative effects. Our results demonstrate that naloxone given i.c.v. can precipitate the full morphine abstinence syndrome in rats at about 1/3 the dose needed for comparable effects when the antagonist is administered s.c.

A simple and rapid method of inducing physical dependence with benzodiazepines in mice.

Physical dependence was rapidly induced in mice by administering diazepam intraperitoneally twice daily using an incremental dosing regimen (50 to 450 mg/kg) for nine consecutive days. Withdrawal was induced (24 hr after the last dose) by administration of a benzodiazepine antagonist, RO-15-1788 (10 mg/kg, IP). All of the mice exhibited clear-cut withdrawal symptoms (i.e., convulsions) within minutes of antagonist treatment. This method offers a simple, reliable, high throughput procedure for the assessment of benzodiazepine-like physical dependence liability and withdrawal, and it would be useful for screening purposes.

Neuroimmune intercommunication, central opioids, and the immune response to bacterial endotoxin.

Muramyl dipeptide is the smallest biologically active fragment of the lipopolysaccharide (LPS) moiety of gram-negative bacteria cell walls. The present report demonstrates that this product, associated with the immune response to bacterial infection, can modify CNS activity. Specifically, it is demonstrated that 6-0-stearoyl-muramyl dipeptide (MDP) can attenuate opiate withdrawal severity in a dose-dependent fashion when injected directly into areas of the brain essential for this phenomenon. In addition, MDP alters both baseline and postnarcotic electrophysiologic responses of four brain areas essential for various opioid activities. Similar findings have been reported for interferon-alpha (IFN-alpha), a peptide associated with the immune response to virus. Yet, even though MDP and IFN are shown to exert similar effects on opioid activity, there are also some very distinct differences in the actions of both of these immune response products. These observations suggest that central opioid systems may provide targets for the perception as well as the differentiation of afferent immunologic sensory input to the brain.

Immune response products alter CNS activity: interferon modulates central opioid functions.

The present report provides evidence to support the hypothesis that peptides released during an immune response alter CNS activity and thus may provide a means for the immune system to transmit afferent signals into the brain. Specifically, it is demonstrated that recombinant interferon-alpha (rIFN-alpha), a peptide associated with the immune response to viral infection, can alter opiate withdrawal severity in a dose-dependent manner upon direct injection into brain areas essential for this phenomenon. These results are compared and contrasted with the effect of systemically injected rIFN-alpha upon opiate withdrawal. In addition, an electrophysiological investigation into the basis of the interaction of opioids and rIFN-alpha in brain structures essential for the expression of opioid activities is also presented. Finally, the effects of rIFN-alpha upon the functions of both the CNS and other systems is discussed in terms of the effects reported for other peptides associated with immune responses.

Prolonged morphine treatment increases rat brain dihydropyridine binding sites: possible involvement in development of morphine dependence.

Regulation of L-type Ca2+ channels by morphine in rat brain was determined by the binding of [3H]nimodipine. Morphine, administered by subcutaneous pellet implantation, increased the density of [3H]nimodipine binding sites in a time- and dose-dependent manner and this effect was reversible upon removal of the pellets. Increases in these dihydropyridine sites were localized to the cortex, hippocampus, hypothalamus and brainstem but not to the cerebellum and striatum. Additional experiments were performed to test the ability of different Ca2+ channel antagonists to affect naloxone-precipitated withdrawal in morphine-dependent mice and rats. These drugs effectively reduced the incidence of naloxone-induced jumping in mice and several of the withdrawal signs in rats. Taken together, our study underscores the plasticity of brain L-type Ca2+ channels and suggests that their upregulation might contribute to morphine dependence.

Irradiation exposure modulates central opioid functions.

Exposure to low doses of gamma irradiation results in the modification of both the antinociceptive properties of morphine and the severity of naloxone-precipitated withdrawal in morphine-dependent rats. To better define the interactions between gamma irradiation and these opiate-mediated phenomena, dose-response studies were undertaken of the effect of irradiation on morphine-induced antinociception, and on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. In addition, electrophysiologic studies were conducted in rats after irradiation exposure and morphine treatment correlating with the behavioral studies. The observations obtained demonstrated that the antinociceptive effects of morphine as well as naloxone-precipitated withdrawal were modified in a dose-dependent manner by irradiation exposure. In addition, irradiation-induced changes in the evoked responses obtained from four different brain regions demonstrated transient alterations in both baseline and morphine-treated responses that may reflect the alterations observed in the behavioral paradigms. These results suggest that the effects of irradiation on opiate activities resulted from physiologic alterations of central endogenous opioid systems due to alterations manifested within peripheral targets.

Platelet uptake of serotonin (5-HT) during ethanol withdrawal in male alcoholics.

Changes in the kinetic variables of the platelet serotonin uptake, Km and Vmax, were studied in 7 male alcoholics, admitted for detoxification and in sex- and age-matched volunteers. On admission the alcoholics had lower Km values than reference subjects (p less than 0.05). During detoxification the Km values normalized. Vmax was normal throughout the study in spite of the changes in platelet count. The results of the study suggest that the affinity of serotonin to its uptake receptor is transiently increased after a period of heavy drinking.

[Antiabstinent action of fenibut and baclofen on a model of abstinence induced by the benzodiazepine receptor antagonist CGS 8216 in rats receiving diazepam]. / Antiabstinentnoe deistvie fenibuta i baklofena na modeli abstinentsii, vyzvannoi antagonistom benzodiapepinovykh retseptorov CGS 8216 u krys, poluchavshikh diazepam.

Benzodiazepine receptor antagonist CGS 8216 (2.5 mg/kg) induced clear-cut signs of abstinence lasting 1-1.5 hours in rats after discontinuation of diazepam treatment (10-20 mg/kg/day, 20 days). Diazepam (10-20 mg/kg) and GABAB-receptor agonists: phenibut (10-100 mg/kg) and baclofen (1.25-5.0 mg/kg) abolished the signs of abstinence. Conversely, GABAB-receptor agonist THIP enhanced the signs of abstinence. It is suggested that anti-abstinence effect of phenibut and baclofen may reflect their tranquilizing activity.

Participation of lymphoid cells in the withdrawal syndrome of opiate dependent rats.

Treatment of rats with 500 Rads whole-body ionizing irradiation prior to chronic administration of morphine reduced the severity of the naloxone induced withdrawal signs. In contrast, adoptive transfer of 2-6 X 10(8) lymphoid cells to irradiated rats prior to chronic morphine treatment completely restored the ability to manifest the withdrawal signs precipitated by naloxone. These observations offer the possibility that the immune system participates in opiate addiction.

Locomotor activity and contracture of isolated ileum precipitated by naloxone following treatment of guinea-pigs with a single dose of morphine.

Guinea-pigs treated with a single dose of morphine, 15 mg kg-1 s.c., exhibited an increase in locomotor activity 2 h later on injection of naloxone, 4 mg kg-1 i.p. At the same time, contracture of ileal preparations isolated from morphine-treated guinea-pigs occurred on addition of naloxone 1 microM. Contracture of the ileum was inhibited by the tachykinin antagonist, spantide, and was therefore presumably mediated by a substance P-like agent. This study has established a useful model for the parallel investigation of central and enteric nervous system mechanisms of opiate dependence.