Brain Opioid System Research Articles

Effects of naloxone on ethanol dependence in rats

Adult male Long-Evans rats were maintained on an ethanol-containing liquid diet. During development of ethanol dependence, the rats were given daily i.p. injections of either naloxone (2 mg/kg) or saline daily. At the beginning of ethanol withdrawal, the rats were injected with either naloxone (10 mg/kg) or saline i.p. Rats injected with naloxone during the development of ethanol dependence consumed significantly more of the ethanol diet and therefore more ethanol than rats injected with saline. Rats treated with naloxone throughout both the development of ethanol dependence and during ethanol-withdrawal showed delayed or reduced withdrawal symptomatology compared to rats injected with (1) only saline, (2) naloxone only during the development of dependence and (3) naloxone only during ethanol withdrawal. These results indicate that naloxone can alter the effects of chronic ethanol exposure and further suggest that ethanol may exert some of its actions via the brain opioid system.

Comparison of the Antinociceptive Effect between the Cyclic Dipeptide Cyclo [Tyr(Et)-Homoarginine] and the Linear Dipeptide Boc-Tyr(Et)-Homoarginine-OMe in Rats*

The antinociceptive effect of the cyclic dipeptide cyclo[Tyr(Et)-homo-arginine] (C.TEHA) was examined utilizing the tail flick test and the digitus pinching test in rats in comparison with the linear dipeptide Boc-Tyr(Et)-homoarginine-OMe (B.TEHM). Though both dipeptides administered into the lateral, 3rd and 4th cerebroventricles produced antinociceptive effects equipotent to morphine, except for the 4th cerebroventricular administration of B.TEHM, the administration into the spinal subarachnoid space was without effect. The effect of B.TEHM was completely antagonized by the pretreatment of naloxone (i.p.) when administered into the 3rd cerebroventricle where its effect was demonstrated to be the most potent. However, naloxone had no significant effect on C.TEHA administered into the 3rd cerebroventricle in both tests. It was concluded that both dipeptides act on the upper brain stem, especially around the 3rd cerebroventricle. Moreover, it was also thought that the effect of B.TEHM may be involved in the brain opioid system, and that of C.TEHA can be produced via a naloxone-resistant opioid system or a non-opioid system.

The behavioural depression of hippocampal kindled rats is attenuated by subcutaneous and intracerebroventricular naltrexone

1. Two questions were asked: Does naltrexone attenuate the behavioural depression (BD) in other models of limbic epilepsy besides amygdala kindling? Does intracerebroventricular (ICV) administration produce the same effects as subcutaneous injection i.e., attenuation of the BD. 2. Male wistar rats with bipolar electrodes implanted bilaterally in the dorsal hippocampus and a metal cannula in the lateral ventricle were kindled through 1 electrode and EEG recorded through the contralateral electrode. 3. Subcutaneous (sc) and ICV naltrexone administration attenuated the BD of hippocampal kindled rats. 4. These results further implicate the brain opioid system in the postictal phase of kindling and possibly epilepsy.

Comparison of the antinociceptive effect between cyclic dipeptide, cyclo[Tyr(Et)-homoarginine]r and linear dipeptide, Boc-Tyr(Et)-homoarginine-OMe, in rats

The antinociceptive effect of cyclic dipeptide, cyclo[Tyr(Et)-homoarginine](C.TEHA) was examined using tail flick test and digitus pinching test in rats in comparison with linear dipeptide, Boc-Tyr(Et)-homoarginine-OMe(B.TEHM). Though both dipep-tides administered into the lateral, the 3rd and the 4th cere-broventricle produced antinociceptive effect eguipotent to morphine,except the 4th cerebroventricle administration of B.TEHM, the administration into the spinal subarachnoid space was without effect. The effect of B.TEHM was completely antagonized by the pretreatment of naloxone(i.ρ.) when administered into the 3rd cerebroventricle where its effect was demonstrated to be the strongest, but naloxone had no significant effect on C.TEHA administered into the 3rd cerebroventricle in both tests. It was concluded that both dipep-tides act on the upper brain stem, especially around the 3rd cerebroventricle. Moreover, it was also thought that the effect of B.TEHM may be involved in the brain opioid system,and that of C.TEHA can be produced via naloxone-resistant opioid system or non-opioid system.

Hypophysectomy increases the sensitivity of rats to naloxone-induced hypothermia.

Abstract Three experiments were done to explore the role of pituitary endorphins in thermoregulation. Hypophysectomized rats were found to be hypothermic when compared to intact rats, but to show a hyperthermic response to handling-induced stress of equal magnitude to that seen in intact animals. In unstressed intact and hypophysectomized animals, the specific opiate antagonist, naloxone, produced a dose-dependent hypothermia, but hypophysectomized animals were found to be ten times more sensitive to naloxone than were the intact animals. In contrast, short-term blockade of pituitary endorphins by dexamethasone had no effect on the magnitude of the naloxone-inducted hypothermia. It was concluded that endorphins of pituitary origin play a long-term tonic role in the modulation of the sensitivity of the brain opioid systems.

Memory, opiate receptors, and aging

In a series of studies, we investigated differences in retention of avoidance responses in young and aged rats. The aged rats showed poorer retention performance of an inhibitory avoidance response, but better performance of an active avoidance response. In a swim escape task, when training trials were given close together in time, the aged rats showed impaired acquisition as compared to younger animals. We then investigated the effects of naloxone on learning and retention performance in young and old rats. Our findings indicated that in some cases, the direction of the opiate antagonist effect depends upon the age of the animal. With low footshock, naloxone either impairs or has no effect on the retention performance of old rats, but with high footshock, naloxone enhances their retention performance indicating that age-related changes in opioid systems may underly some behavioral differences between young and aged animals Therefore, we examined, in vitro, opiate receptor binding in various brain regions of young and old rats. Analysis of dihydromorphine binding indicated that opiate receptor concentrations in aged rats are reduced in some brain regions and that these changes are different in aged male and female rats. Studies of in vivo bindings of opiate receptors have yielded relationships between receptor changes and differences in response to footshock in the flinch-jump test. These findings suggest that age-related alterations in brain opioid systems may underlie some of the changes in learning and memory processes that occur with age.

Regional analysis of brain opiate receptors in rats with hereditary hypothalamic diabetes insipidus

The regional distribution of stereospecific 3H-dihydromorphine binding sites in Brattleboro rats with hereditary hypothalamic diabetes insipidus was studied. Control animals were homozygous normal Brattleboro rats and rats heterozygous for the vasopressin deficiency. Scatchard plots of 3H-dihydromorphine binding in a washed membrane preparation showed that rats with diabetes insipidus exhibited higher receptor concentrations in all assayed areas of the cerebral hemispheres. In the diencephalon, receptor concentrations were lower in diabetes insipidus rats. The results point to the existence of interactions between brain opioid systems and neurohypophyseal peptides.