Morphine-like activity of the enkephalin analog Tyr-D-Ala-Gly-Phe-NH2

The analgetic activity of the tetrapeptide enkephalin analog, its influence on the interneuronal transmission of excitation in various areas of the central nervous system and on opiate receptors of vas deferens were studied. The tetrapeptide was found to have a marked analgetic effect during intravenous injection to mice but to be less active than morphine. The tetrapeptide as well as morphine inhibited the impulse summation in rabbits and both spontaneous and bradykinin-induced neuronal activity in the rat sensory motor cortex. The tetrapeptide inhibited the contractions of isolated vas deferens in mice. The opiate antagonist naloxone eliminated both analgetic effect of the tetrapeptide and its inhibitory effect on the impulse summation, neuronal activity and contractions of vas deferens.     

Effects of substance P and its fragments in physiological and pathological pain

It has been shown that substance P and its fragments can produce under certain conditions an analgetic effect on both physiological and pathological pain (i.e. on pain syndrome of spinal origin). The data obtained give evidence that prolonged hypoalgesia is caused by the injection of substance P and its fragments to nucleus raphe dorsal--a structure of the antinociceptive system. This analgetic effect can be initiated by the activation of the antinociceptive system influenced by substance P and or its fragments.     

Auditory afference of the central gray tissue in the rat midbrain (morphofunctional and electrophysiological research)

Afferent connections between the central gray substance of the midbrain and central nuclei of the inferior colliculi have been revealed by horseradish peroxidase axonal transport technique in albino rats. Functional properties of neurones in the central gray substance of the midbrain were investigated by extracellular recording of their spike activity in response to continuous and amplitude-modulated tones. The results obtained are discussed in relation to integrity of structural and functional organization of the acoustico-vocalizational system of the brain.     

The effect of substance P on the neuronal activity of the antinociceptive system

The experiments on rats showed that the 1 micrograms substance P injection to dorsal raphe nucleus caused prolonged (24 hours of study) analgetic effect--it enhances the reaction latent period to thermal nociceptive stimulation, intensifies the background impulse activity, rises the middle frequency of neuron discharges and creates high-frequency neurons as well as the neurons with burst impulse activity. The supposition is being confirmed that the mechanism of antinociceptive structures activation leads to analgesia caused by substance P.     

Effects of C-terminal fragment of substance P-CP 5-11 on the activity of neurons of the dorsal raphe nucleus]

The experiments on Wistar rats showed that microinjection of C-terminal fragment of substance P-CP5-11 (1 microgram) into one of the antinociceptive system structure--dorsal raphe nucleus, caused a prolonged (24 hours of observation) analgetic effect by the hot plate test. Neuronal activity of dorsal raphe nucleus simultaneously enhanced. The CP5-11 antinociceptive activity was higher than the CP1-11 one. The conclusion is that CP1-11 and in particular its C-terminal fragment CP5-11 play a role in activation of antinociceptive system.     

Change in the antinociceptive effect occurring on stimulation of the midbrain under the action of analgesics and tranquilizers

It was shown in chronic experiments on cats that analgetics in subanalgetic doses not only revealed the antinociceptive effect under subthreshold stimulation of the midbrain, but also enhanced the analgetic effect of the central stimulation. The tranquilizers promoted only the analgetic action under the subthreshold stimulation of the midbrain. Possible causes of different effect of the drugs under study are discussed.     

Paradoxical correlations of the effectiveness of the intranasal and intraperitoneal administration of dermorphins in rats

The analgetic activity of dermorphin and its analogue A-2 was assessed by the tail-flick test. Following intraperitoneal administration at doses 5 mg/kg and above the peptides showed significant effects. After intranasal application of the peptides a significant effect was observed in the range of low doses 0.001-0.1 mg/kg. After intranasal application of high dermorphin doses (1 or 5 mg/kg) the analgetic activity decreased. The effect of analogue A-2 lasted longer after intranasal, than after intraperitoneal administration. It is assumed that the neurophysiological mechanisms of the analgetic activity of dermorphins depend on the route of their administration.     

Changes in the activity of rat cortical and hippocampal neurones after the iontophoretic administration of beta-endorphin, glutamate and GABA

The effect of microiontophoretically administered beta-endorphin on the activity of 62 cortical and hippocampal neurones was studied in acute experiments on 14 rats. The effectiveness of beta-endorphin was first of all verified in the isolated guinea pig ileum, the mouse was deferens and in a study if its analgetic and catatonic effect in rats. Beta-endorphin only mildly depressed the spontaneous activity of cortical neurones, but markedly inhibited the activity stimulated by the microiontophoretic administration of glutamate. In the hippocampus, beta-endorphin stimulated the activity of all the studied neurones when only low ejection currents were used and activation persisted for 1-4 min after terminating administration. With higher ejection currents, the discharge frequency rose enormously and not even GABA blocked this effect. The excitatory effect of beta-endorphin on the hippocampal neurones may possibly be the basis of the epileptogenic action of this substance.     

Iron and Aluminum Increase in the Substantia Nigra of Patients with Parkinson''s Disease: An X-Ray Microanalysis

The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls. In control brains, only iron, potassium, silicum, sodium, sulfur, and zinc were within the limit of detection of the technique. The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance. In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values. Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy. Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum. Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death. This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration.     

Influence of captopril on the in vitro and in vivo effects of leu- and met-enkephalins

Captopril (10(-6) g/ml) enhanced and prolonged the inhibitory effect of leu- and met-enkephalins on the contractions of the isolated guinea-pig ileum section induced by electrical stimulation. In mice, the drug (25 mg/kg, subcutaneously) increased the degree and duration of the analgetic effect of enkephalins. It is concluded that the analgetic effect of captopril is related to the influence on the activity of the endogenous antinociceptive system.     

Comparative study of substance P and its fragments: analgesic properties, effect on behavior and monoaminergic processes

The effect of substance P (SP) and of its fragments 5-11, 8-11, 9-11, 10-11 administered into the brain ventricles in doses of 5, 25 and 50 nM on the behavior and content of biogenic monoamines of the rat brain was studied. The analgetic properties of the substances under consideration and those of fragment SP 10-11 in doses of 5, 25, 50 and 100 nM were also subjected to examination. It was found that SP and fragment 5-11 stimulate and enhance the locomotor activity in rats, while fragments 8-11 and 9-11 provoke hypoactivity. The substances under study increase the serotonin and dopamine turnover, whereas SP and fragment 8-11 lower the serotonin content as well. After administration of SP and fragment 5-11 analgesia was seen to transform to hyperalgesia depending on the dose. Fragments 8-11 and 9-11 produce analgetic effect. It is suggested that both SP fragments and the whole SP molecule can influence the neurochemical process that regulate behavior and pain perception.     

The effect of blood serum proteins from the seal on the analgetic action of narcotic analgesics]

The protein fraction isolated from blood of seal, Phoca groenlandica, has been found to produce hyperalgesic effect on rats exposed to thermic or electrocutaneous nociceptive stimulation, but fail to affect writhes provoked by intraperitoneal injection of acetic acid solution on mice. When combined with morphine, the fraction lowered completely its narcotic analgetic action in the above mentioned tests. On the contrary, these same proteins combined with promedol or fentanil enhanced and prolonged analgetic effect of the latter. Tested in vitro the protein showed neither opioid nor anti-opioid activity. Therefore it is reasonable to suppose that neurophysiological activity of the isolated fraction is due to the peptides formed on enzymatic hydrolysis of proteins in vivo rather than these proteins as such.     

Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria terminalis project to the midbrain central gray in the rat.

The central nucleus of the amygdala, bed nucleus of the stria terminalis, and central gray are important components of the neural circuitry responsible for autonomic and behavioral responses to threatening or stressful stimuli. Neurons of the amygdala and bed nucleus of the stria terminalis that project to the midbrain central gray were tested for the presence of peptide immunoreactivity. To accomplish this aim, a combined immunohistochemical and retrograde tracing technique was used. Maximal retrograde labeling was observed in the amygdala and bed nucleus of the stria terminalis after injections of retrograde tracer into the caudal ventrolateral midbrain central gray. The majority of the retrogradely labeled neurons in the amygdala were located in the medial central nucleus, although many neurons were also observed in the lateral subdivision of the central nucleus. Most of the retrogradely labeled neurons in the BST were located in the ventral and posterior lateral subdivisions, although cells were also observed in most other subdivisions. Retrogradely labeled neurotensin, corticotropin releasing factor (CRF), and somatostatin neurons were mainly observed in the lateral central nucleus and the dorsal lateral BST. Retrogradely labeled substance P-immunoreactive cells were found in the medial central nucleus and the posterior and ventral lateral BST. Enkephalin-immunoreactive retrogradely labeled cells were not observed in the amygdala or bed nucleus of the stria terminalis. A few cells in the hypothalamus (paraventricular and lateral hypothalamic nuclei) that project to the central gray also contained CRF and neurotensin immunoreactivity. The results suggest the amygdala and the bed nucleus of the stria terminalis are a major forebrain source of CRF, neurotensin, somatostatin, and substance P terminals in the midbrain central gray.     

Effects of aspartate,substance P,and serotonin on neuronal activity in the central gray substance:In vitro experiments

Effects of aspartate (2 · 10^–5 M), substance P (10^–7–10^–8 M), and serotonin (5-hydroxytryptamine, 5-HT; 5 · 10^–5 M) on the background activity of neurons in the central gray substance (CGS) were studied on slices of the rat midbrain. Aspartate and substance P (transmitters of nociceptive signals), and 5-HT (modulator of transmission of nociceptive influences) were found either to facilitate or to depress the activity of CGS neurons. The predominant effect of substance P or 5-HT applications to neurons of the dorsal CGS part was facilitation, and to neurons of the ventral CGS part, inhibition. The effects of aspartate application on studied CGS neurons were of varying nature, but inhibitory effects were found to prevail.The findings support our earlier hypothesis that assigned the studied neurons to spontaneously discharging inhibitory CGS interneurons, which control the activity of efferent CGS neurons. The role of tested substances in the regulation of CGS neuronal activity and the antinociceptive CGS effects is discussed.Neirofiziologiya/Neurophysiology, Vol. 25, No. 5, pp. 354–362, September–October, 1993.     

Antagonism of RO 15-1788 with benzodiazepines in the effect on motivated aggression and the action of analgesics

The influence of Ro 15-1788 and bicuculline on the action of GABA-positive drugs (muscimol), GABA cethyl ester, piracetam and depakine and benzodiazepine tranquilizers (diazepam, phenazepam) on motivated aggression has been studied. It has been shown that Ro 15-1788 which has a weak antiaggressive effect selectively antagonizes the anti-aggressive effect of tranquilizers but not that of GABA-positive drugs. Bicuculline antagonizes antiaggressive activity of the drugs of both types. The action of these antagonists on the effect of the drugs under study as regards the analgetic activity of morphine was also studied. It has been shown that Ro 15-1788 antagonizes the potentiation of morphine analgesia caused by diazepam. At the same time Ro 15-1788 does not influence morphine analgesia potentiated by muscimol. Bicuculline removes the potentiation of morphine analgesia caused both by diazepam and muscimol it is concluded that bicuculline-sensitive GABA receptors modulate the antiaggressive effect of benzodiazepines and their influence on the analgetic action of opiates.     

Activity and localization of cerebral cysteinic cathepsins after the action of ionizing radiation

The effect of total X-ray irradiation (0.155 C/kg) on the activity of cathepsin L (KF 3.4.22.15) from the light mitochondrial fraction and microsomal soluble fraction of the gray substance of the neocortex was studied in rats. The estimations were performed 1, 24, 48, and 120 h after irradiation. The changes in the cathepsin L activity observed in acute radiation pathology were complex and multiphasic.     

Effect of stimulation of the amygdala and subthalamus on unit activity of the mesencephalic central gray matter

Characteristics of unit activity of the mesencephalic central gray matter were studied during electrical stimulation of the amygdala and subthalamus (chiefly the zona incerta) in acute experiments on rats. Stimulation of the amygdala evoked chiefly inhibitory unit responses (72%), whereas stimulation of the zona incerta evoked chiefly excitatory responses (59%). The effectiveness of regular (5 Hz) stimulation of the amygdala in producing prolonged changes in unit activity was noted and points to the modulating character of the influence of this structure on the central gray matter. In 31 of 114 neurons tested convergence of impulses from the amgydala and zona incerta was observed. The two types of stimulation most frequently induced inhibition (71%).Institute of Physiology, Siberian Branch, Academy of Medical Sciences of the USSR, Novosibirsk. Translated from Neirofiziologiya, Vol. 10, No. 3, pp. 245–251, May–June, 1978.     

Reflexogenic changes in the spontaneous and evoked activity of the parafascicular neurons in the rat thalamus during electroacupuncture stimulation

Acute experiments on cats were made to study the electroacupuncture (EAP) effect on neuronal impulse activity in the parafascicular complex (PFC) of the thalamus in response to solitary peripheral nociceptive and non-nociceptive stimuli. EAP stimulation affects the pattern of spontaneous and evoked activity of PFC neurons and forms their new functional status. It is suggested that the analgetic effect is brought about by the changes in neuronal activity in subcortical structures of the brain including the thalamic nuclei which transmit the ascending nociceptive input.     

Changes in the background activity of neurons of the central gray substance when serotonin is applied to it or its synthesis is blocked

The changes in the background activity (BA) of neurons of the central gray substance upon the iontophoretic application of serotonin (ST) to them in a concentration of 1·10^–4 mole/liter, and following the blockage of its synthesis by pchlorophenylalanine (PCPA), were investigated in hexenal-anesthetized rats. The application of ST led to changes in the BA only in group III neurons, in which the BA was distinguished by continuous action potential generation. The application of ST elicited an increase in the frequency of the BA in 21.2% of such neurons, suppression in 45.5%, and the BA remained unchanged in 33.3% of the units. The identified changes in the BA in these neurons coincided with those which arose as the result of stimulation of the monoaminergic structures. When the application of ST was combined with stimulation of the locus coeruleus (LC), the substantia nigra (SN), and the nucleus raphe magnus (NRM), the suppression of the BA was intensified; however, when the LS and the SN were stimulated, the suppression was more pronounced than with stimulation of the NRM. The intensity of the suppressant effect of the NRM decreased after preliminary administration of PCPA, but it did not disappear completely, and the influences elicited by the LS and the SN intensified. The mechanisms of the serotoninergic control of the activity of the neurons of the central gray substance are discussed.A. A. Bogomolets Institute of Physiology, Ukrainian Academy of Sciences, Kiev. Translated from Neirofiziologiya, Vo. 24, No. 2, pp. 169–177, March–April, 1992.     

Inhibition of jaw opening reflexes by stimulation of the central gray matter and raphe nuclei in cats

The effect of stimulation of the mesencephalic central gray matter and raphe nuclei on jaw opening reflexes evoked by excitation of high-threshold (dental pulp) and low-threshold (A-alpha) fibers of the infraorbital nerve afferents was studied in cats anesthetized with chloralose and pentobarbital. The jaw opening reflex evoked by stimulation of the dental pulp was shown to be effectively suppressed by conditioning stimulation of the central gray matter and raphe nuclei. The reflex evoked by stimulation of low-threshold infraorbital nerve afferents also was depressed (but less deeply and for a shorter period than the reflex evoked by stimulation of the dental pulp) during stimulation of the raphe nuclei and caudal zone of the central gray matter, but was unchanged after stimulation of the points located in the rostral zone of the central gray matter. Application of single stimuli or bursts of five stimuli with a frequency of 100 Hz had no effect on the reflexes studied. Short-term stimulation with a burst of 10–20 stimuli with a following frequency of 200–400 Hz led to inhibition of the reflexes, which lasted 450–1000 msec. Long-term stimulation of the central gray matter and raphe nuclei for 30 sec with a frequency of 50 Hz caused inhibition of jaw opening reflexes evoked by stimulation of both high- and low-threshold afferents for 60 min. Impulses from the central gray matter and raphe nuclei thus have a mainly inhibitory action on the jaw opening reflex evoked by stimulation of high-threshold afferents, but they act less effectively on the reflex evoked by stimulation of low-thres-hold afferents. The duration of inhibition depends essentially on the parameters of stimulation.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 16, No. 3, pp. 374–387, May–June, 1984.