ceruletide and Morphine-Dependence

The possible effect of a cholecystokinin-8 agonist (caerulein) and antagonists (MK-329 and L365,260) on the development of morphine dependence and withdrawal were investigated in rats. Caerulein treatment (0.01 and 0.1 mg/kg) increased the incidence of naloxone-induced withdrawal syndromes and delayed the extinction of morphine-conditioned place preference in morphine-dependent animals. The signs of the morphine withdrawal syndromes and the formation of morphine-conditioned place preference were suppressed by pretreatment with L365,260 (0.1 and 1 mg/kg) and not affected by pretreatment with MK-329 (0.1 and 1 mg/kg). The present study demonstrated CCK, acting on CCK-B receptors, participates in the development of the opiate dependence. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention the relapse of opiate addicts.

Topics: Animals; Benzodiazepinones; Ceruletide; Conditioning, Psychological; Devazepide; Hormone Antagonists; Male; Morphine Dependence; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Substance Withdrawal Syndrome

The aim of present study was to reveal the role of cholecystokinin (CCK) in the jumping behaviour induced by the opioid antagonist naloxone (30 mg/kg) after the acute administration of morphine (200 mg/kg) in mice. Treatment with caerulein (0.01-1 microg/kg), a nonselective agonist of CCK receptors, induced a large reduction of jumping frequency without parallel suppression of locomotor activity. The CCK(B) receptor agonist CCK tetrapeptide (CCK-4. 0.125-32 mg/kg) caused the same effect, but it happened at much higher doses (above 0.5 mg/kg). Devazepide (1 microg/kg), a preferential CCK(A) receptor antagonist, completely reversed the action of caerulein (0.1 gmg/kg) and CCK-4 (2 mg/kg). A preferential CCK(B) receptor antagonists LY 288,513 at a high dose (4 mg/kg) blocked the action of CCK-4, but not that of caerulein. Acetorphan (16-128 mg/kg), an inhibitor of enkephalin metabolism, did not block naloxone-precipitated jumping behaviour. However, the combination of subthreshold doses of caerulein (0.001 microg/kg) and CCK-4 (0.25 mg/kg) with acetorphan (64 mg/kg) potently antagonized the behaviour induced by naloxone. In conclusion, the antagonism of CCK agonists against naloxone-precipitated jumping behaviour is apparently mediated via the CCK(A) receptor subtype. The stimulation of CCK(A) receptors seems to increase the release of endogenous enkephalins.

Topics: Animals; Ceruletide; Devazepide; Dose-Response Relationship, Drug; Hormone Antagonists; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Pyrazoles; Receptors, Cholecystokinin; Substance Withdrawal Syndrome; Tetragastrin; Thiorphan

In the present study, effect of cholecystokinin (CCK) agonists and on dependence to morphine in mice has been investigated. The influence of dopaminergic, adrenergic, cholinergic and serotonergic on attenuation of naloxone-induced jumping in morphine-dependent mice by CCK agonists were also considered. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 a.m. 1 p.m. and 4 p.m.) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the 4th day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study effects of CCK receptor agonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. The CCK agonists CCK-8 (0.001-0.1 mg/kg), unsulfated CCK-8 (CCK-8U; 0.001-0.1 mg/kg) and caerulein (0.00001-0.01 mg/kg) were able to prevent withdrawal signs precipitated by naloxone (5 mg/kg). Sulpiride and pimozide increased response induced by CCK-8 agonists. The dopamine antagonists also attenuates jumping by themselves. SCH 23390 did not alter the CCK-8 effect, but decreased the jumping by itself. Phenoxybenzamine, propranolol, methysergide and atropine did not change the caerulein effect significantly. However, single administration of atropine increased and methysergide decreased jumping. It is concluded that CCK mechanism(s) may be involved in morphine dependence, and dopaminergic mechanism(s) may interact with CCK in attenuation of naloxone-induced jumping.

Topics: Adrenergic Antagonists; Animals; Atropine; Benzazepines; Ceruletide; Dopamine Antagonists; Male; Methysergide; Mice; Morphine; Morphine Dependence; Movement Disorders; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Phenoxybenzamine; Pimozide; Propranolol; Receptors, Cholecystokinin; Serotonin Antagonists; Sincalide; Substance Withdrawal Syndrome; Sulpiride

In the present study, the effect of cholecystokinin agonists and antagonists on dependence to morphine in mice has been investigated. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily for 2-4 days, and a last dose of morphine (50 mg/kg) was administered on day 3, 4 or 5. Withdrawal syndrome (jumping) was precipitated by naloxone (2.5, 5 and 10 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study the effects of cholecystokinin receptor agonists or antagonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Cholecystokinin-8 (0.001-0.01 mg/kg), low doses of the cholecystokinin agonists caerulein (0.00001 and 0.0001 mg/kg) and, unsulfated cholecystokinin (but not high doses) as well as the antagonists MK-329 (0.5-1 mg/kg) and L-365,260 (0.5-1 mg/kg) elicit reduction of the nalaxone-induced jumping. The inhibition of jumping induced by caerulein was reduced with the selective cholecystokinin antagonists MK-329 and L-365,260. It is concluded that cholecystokinin mechanism(s) may be involved in morphine dependence, that the agonists may act on a presynaptic receptors and that the antagonists may work on postsynaptic receptors.

Topics: Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Devazepide; Drug Interactions; Hormone Antagonists; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, Cholecystokinin; Substance Withdrawal Syndrome