Viktor Havlicek

Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity.

Central excitatory potency of morphine administered by cerebroventricular infusion in enhanced in derivatives substituted at the 3-position (phenolic group) and/or 6-position (alcoholic group). Morphine-3-glucuronide is several hundred times more potent than morphine in evoking dose-related hyperactive motor behavior which can progress to lethal convulsions. Excitatory potencies in decreasing order are: (1) 3-glucuronide; (2) 3-SO4; (3) 3-OAc, 6-OAc (heroin); (4) 6-OAc; (5) 3-OAc; (6) 3-OH, 6-OH (morphine); (7) 3-OCH3 (codeine); (8) 3-OCH3, 6-OCH3 (thebaine). Levorphanol, lacking a 6-OH group, is devoid of excitatory actions. In this series of substituted morphines, there is an inverse relationship between opiate receptor binding potency and central excitatory potency, but codeine and thebaine behave anomalously. These findings are compatible with the hypothesis that morphine acts upon a species of receptor which mediates behavioral and EEG excitation and is distinct from the recognized opiate receptor mediating sedation and analgesia.

β-endorphin concentration in the brain of intact and hypophysectomized rats

Abstract The brain concentration and distribution of β-endorphin immunoreactivity in the brain have been studied in intact and hypophysectomized rats. The results obtained with different methods for killing the animals and extracting β-endorphin are compared. Different methodologies of killing the rat and extracting the brain yield concentrations of β-endorphin which vary ten fold. Consistently the highest concentrations of β-endorphin have been found in the hypothalamus, midbrain and hindbrain. After hypophysectomy major reduction of β-endorphin concentration in the brain was observed.

Somatostatin and thyrotropin releasing hormone: Central effect on sleep and motor system☆

The hypothalamic hormones, somatostatin (SRIF or GH-RIH) and thyrotropin releasing hormone (TRH) applied intraventricularly into rat brain had a considerable effect on motor function and resulted in profound alterations in the sleep-waking pattern. While TRH induced primarily an increase in exploratory and motor stereotyped behavior, the effect of somatostatin was striking and prolonged: stereotyped circular running in many instances evolved into catatonia, paraplegia-in extension and/or tonic-clonic seizures.

Behavioural and motor excitation and inhibition induced by the administration of small and large doses of somatostatin into the amygdala.

Abstract The administration of lower (0.01, 0.1 μg) and higher (1.0, 10.0 μg) doses of somatostatin (SRIF) into the amygdaloid complex revealed a dose-dependent dissociation of effects on behaviour and motor control. While the lower doses generally induced a behavioural excitation accompanied by a variety of tremors and stereotyped movements, the higher doses prevented the expression of a normal behavioural pattern due to the severity of disturbances in motor control. The sleep-waking cycle was also affected; the duration of REM sleep showed a consistent dose-related reduction although the total sleeping time was not considerably altered. This was due to a paradoxical dose-related prolongation of shallow slow wave sleep (drowsiness) which typically accompanied the periods of immobilization caused by motor control difficulties. Electrophysiologically, this phenomenon was often reflected in a paradoxical pattern characterized by a dissociation of EEG from behaviour. The specificity of SRIF effects was tested by administration of some endocrinologically active and inactive analogues of SRIF via the same route. None of the analogues tested induced effects comparable to those observed after the administration of the same dose of the native hormone.

Cortical administration of somatostatin (SRIF): Effect on sleep and motor behavior☆

Cortical administration of SRIF in unrestrained, freely moving rats produced an early activation, stereotyped behavior patterns and later, coordination difficulties often associated with drowsiness. A few animals showed a tendency toward paraplegia-in-extension. A considerable, prolonged alteration in the sleep-waking cycle was also observed. Similar results were obtained in both intact and hypophysectomized animals. Intraperitoneal administration of SRIF induced several other effects in addition to those seen after cortical application. The latter were however, restricted in variety, intensity and duration.

Central site of action of somatostatin (SRIF): role of hippocampus.

Abstract The direct cerebral administration of somatotropin release inhibiting factor (SRIF) into two loci of the hippocampal formation induced a variety of behavioural, motor and electrophysiological changes. These were characterized by several patterns of stereotyped behaviour, alteration of the sleepwaking cycle and frequent dissociation of the EEG from behaviour. Both behavioural and electrophysiological phenomena were found to be dose-related. The administration of SRIF analogues via the same route failed to produce comparable effects, thus suggesting the specificity of SRIF action within the central nervous system. The results indicate that the hippocampus is involved in mediating the central, nonendocrine action of SRIF and are consistent with the hypothesis proposing the existence of a limbic pacemaker controlling stereotyped behaviour.

Changes in beta-endorphin content in discrete areas of the hypothalmus throughout proestrus and diestrus of the rat

The aim of the present study is to investigate changes in beta-endorphin content in the hypothalamus during different stages of the estrous cycle. Groups of 9 to 10 Sprague-Dawley rats were sacrificed every two hours on proestrus from 8.00 to 18.00 h and groups of 7 to 8 rats were sacrificed on diestrus at 8.00, 12.00, 14.00 and 18.00 h. Preoptic suprachiasmatic region, posterior hypothalamus, arcuate nucleus and median eminence were dissected and assayed for beta-endorphin. A significant increase in beta-endorphin content was detected in the arcuate nucleus during proestrus (9.00 h: 1.76 +/- .31; 14.00 h: 4.10 +/- .85 microgram/g tissue wet weight). Levels did not change during diestrus (1.18 +/- .06 microgram/g). The increase caused significant differences in beta-endorphin values between both days at 12.00, 14.00 and 18.00 h, while the concentrations at 8.00 h were similar. The opposite pattern was observed in the median eminence with significantly higher proestrous beta-endorphin levels at 8.00 h (11.24 +/- 3.1 vs 3.52 +/- .64 microgram/g) and nonsignificant differences for the rest of the day. No significant change in beta-endorphin concentration was seen in the preoptic suprachiasmatic region over the day of proestrus (1.35 +/- .09 microgram/g). Diestrous beta-endorphin concentrations in this region were higher during the morning (2.60 +/- .65 microgram/g) and lower at 18.00 h (0.94 +/- .12 microgram/g) when compared to proestrous values. This pattern was caused by a 50% increase in beta-endorphin during the afternoon of diestrus. No changes were observed in the posterior hypothalamus on either day with comparable levels of beta-endorphin except at 18.00 h, when values were significantly higher on proestrus (1.66 +/- .30 vs 0.83 +/- .06 microgram/g).

Paradoxical stimulation of food intake by larger loads of glucose, fructose and mannose: Evidence for a positive feedback effect☆

Abstract The phenomenon of paradoxical stimulation of food intake by larger alimentary loads of isotonic glucose was studied with regard to a variety of experimental and nutritional conditions. Thus, paradoxical feeding response was induced not only by the infusions of glucose but also of the other insulinogenic sugars—fructose and mannose. Stimulation of food intake was further observed following the administration of larger volumes of isotonic glucose solutions via the duodenal and intraperitoneal infusion routes in free feeding as well as in 12 hr food-deprived animals. This paradoxical alimentary response was not eliminated or reduced by repeating these infusions daily over a longer period of time; in fact, food in the first postinfusions hour and, unexpectedly, also the total daily food intakes, showed a gradually increasing trend with daily repetitions. Drinking of isotonic glucose for 1 hr in 12 hr water-deprived animals did not suppress the subsequent intake of regular food despite the substantial amount of glucose drunk (94.1 ml vs 76.5 ml of water in controls during the same time period). The conbination of glucose drinking with subsequent food intake resulted in a significant caloric imbalance during the first hour which was not fully compensated within the 24 hr. These findings indicate that larger loads of insulinogenic sugar loads are capable of triggering an antiregulatory positive feedback alimentary response which can induce caloric imbalance and thus adversely affects the short-term maintenance of energy balance.

Lack of effect of baclofen on substance P and somatostatin release from the spinal cord in vitro

SummaryHigh concentrations of K+ increase the release of substance P (SP) and somatostatin (SRIF) from superfused slices of rat spinal cord. This increase is Ca-dependent. Baclofen (100–500 μM) does not significantly alter the K+-evoked release of SP or SRIF. Stereoisomers of baclofen and GABA, similarly, are without effect. The spinal analgesic action of baclofen does not appear to be due to alterations in the release of SP or SRIF.

Caloric imbalance induced by failure of food intake to compensate for caloric supply provided by diurnal or nocturnal drinking of isotonic glucose

Abstract Free-feeding rabbits allowed to drink isotonic glucose failed to reduce food intake sufficiently to compensate for the extra caloric supply. This resulted in a considerable caloric imbalance which was not compensated during the diurnal or nocturnal periods when the animals were drinking glucose. Reductions of food intake were smaller or even paradoxically reversed following repeated exposures to glucose despite the fact that the intake of fluids was more doubled. Equi-osmotic equi-volumic saccharin solutions drank voluntarily or infused into the duodenum did not produce paradoxical feeding response. Blockade of insulin-dependent lipogenesis by Atromid S prevented the paradoxical stimulation of food intake by larger duodenal loads of glucose.