Mechanism of the analgesic effect of narcotic analgetics]

A study was made of the effect of morphine, promedol, phentanyl, pentazacine and psychostimulant d,l-amphetamine on the threshold of pain sensitivity and self-stimulation of the hypothalamus and the septum in rats. Electrical stimulation of the systems of positive reinforcement of the hypothalamus and the septum, and also analgetics increased the threshold of pain sensitivity, whereas d,l-amphetamine failed to influence it. D,l-amphetamine and morphine facilitated, promedol failed to influence, phentanyl decreased and pentazacine completely depressed the hypothalamic self-stimulation. The septal self-stimulation remained unaltered under the effect of morphine, promedol, phentanyl, but was decreased under the effect of pentazacine and increased against the background of d,l-amphetamine. A conclusion was drawn that the analgetic action and that activating the positive emotion were independent effects of the psychotropic agents.     

Experimental study of the interaction of nonsteroidal anti-inflammatory agents--voltaren and acetylsalicylic acid--with beta-adrenoblockers

It has been demonstrated in rat experiments that the beta-adrenoblockers propranolol and pindolol differ in the influence on the therapeutic and toxic effects of voltaren and acetylsalicylic acid. Propranolol has an analgetic action of its own, reducing the analgetic and antiinflammatory effects of voltaren and acetylsalicylic acid. It potentiates the antipyretic effect of voltaren and ulcerogenic action of both nonsteroidal antiinflammatory drugs. Pindolol exerts both analgetic and antiinflammatory action and does not affect the antipyretic effect of voltaren and ulcerogenic action of nonsteroidal antiinflammatory drugs. The difference in the action of the beta-adrenoblockers under study is likely to be linked with the characteristics of their pharmacological action spectrum.     

Changes in the functional parameters of the brain structures under the influence of enkephalin-like tetrapeptidamide

In complex neurophysiological and cytobiochemical study single injections of tetrapeptide amide (TPA) caused a short-term analgetic effect which manifested itself in the absence of motor reactions and EEG changes of cortical and subcortical brain structures after painful stimulation of extremities. This effect was accompanied by changes of some indices of transmitter (monoamine oxidase) and protein metabolism in the cerebral hemispheres at cellular and subcellular levels. In 30-40 min after a TPA injection, EEG suppression and absence of EPs to light flashes were observed in cortical and subcortical structures. Simultaneously motor disorders developed. The observed EEG changes had an undulatory character: on the second day EEGs were restored and on the third day--suppressed once again. This period of TPA action was accompanied by varied changes of the investigated types of metabolism. The question of the necessity of systemic approach to the study of TPA action is discussed, as such an approach allows to reveal complex neurophysiological and fine biochemical relations in the reactions of brain structures and in animal behaviour.     

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.     

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.     

Enkephalins and gastrin fragments: possible existence of different analgesic mechanisms

The mechanism of analgetic action of pentagastrin, its tripeptide fragment (MAF), synthetic met- and leu-enkephalins was studied in rats. The analgetic effect of the peptides was evaluated from the tail extracting test. Also, the content of biogenic amines in the rat brain and interaction of the peptides with opiate receptors of the guinea-pig ileum were examined. It was demonstrated that analgesia induced by pentagastrin or MAF differs from that obtained after intraventricular injection of the enkephalins. The effect of the latter ones is not consequent on their interaction with classic opiate receptors. It was also discovered that pentagastrin, MAF and enkephalins produce a different action on metabolism of biogenic amines. The possibility of analgesia unmediated by specific peptide binding to opiate receptors is discussed.     

Effect of myelopeptides on physiological and pathological pain

The action of bone marrow low-molecular peptides (myelopeptides) was studied in the models of physiologic and pathologic pain. Myelopeptides were demonstrated to have a pronounced analgetic effect: they increased the latent period of the rats' response in the hot plate test (physiologic pain) and suppressed severe spinal pain syndrome induced by the generator of pathologically enhanced excitation in the dorsal horn of the spinal cord (pathologic pain). In the experiments with naloxone (an opiate receptor blocker) the data on the opiate properties of myelopeptides were further substantiated. The analgetic effect of myelopeptides can be compared to that of morphine and promedol. Myelopeptides even in considerable doses did not have the side effects characteristic of the majority of opiate analgesics. Therefore, they may be recommended for clinical trials.     

Effects of auricular electrostimulation and naloxone on nociceptive sensitivity in rabbits

Auriculo-acupuncture electrostimulation (AES) (15 H2) decreased the amplitude of somatosensory evoked potential (EP) in response to tooth pulp electrostimulation in 64% of acupuncture-sensitive unanesthetized rabbits and didn't induce the changes of EP in 36% of animals (acupuncture-resistant rabbits). The systemic naloxone (0.2 mg/kg) injection reversed the AES analgetic effect and induced the hyperalgesic one in acupuncture-sensitive rabbits but induced the analgetic effect in acupuncture-resistant animals. It has been suggested that the differences of individual characteristics of endogenous opioid system determined different naloxone action in acupuncture-sensitive and acupuncture-resistant rabbits.     

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.     

Role of tricyclic antidepressants in the central regulation of hyperalgesia and stress analgesia

The effect of hypophysectomy (HE) on pain thresholds was studied in female noninbred rats. Hyperalgesia was observed after HE since the first till the sixth day of the observation period. Droperidol (1 mg/kg i.p.) and amitryptyline (5 mg/kg i.p.) produced hyperalgesia in sham-operated rats, which was potentiated in hypophysectomized animals. In rats taken into the experiment 3 days after operation, no increase in the pain threshold was recordable during the 30-minute painful stress, and poststress autoanalgesia did not develop subsequently. The opposing data were obtained in sham-operated animals. On intraperitoneal administration of phentanyl (25 micrograms/kg) after the 30-minute painful stress hypophysectomized rats did not manifest any potentiation of its analgesic effect in contradistinction to sham-operated animals. Simultaneous administration of phentanyl at the same dose and melipramine (5 mg/kg i.p.) produced considerable potentiation of analgesia if administered after stress. In hypophysectomized rats, that effect was somewhat reduced.     

Experimental study of the effect of captopril on pain reactions

The experiments on the electrical stimulation of the isolated guinea-pig ileum have shown that captopril (10(-6)-10(-4) g/ml) caused dose-dependent inhibition of the organ contractions, abrogated by naloxone. In mice, the drug in the doses of 0.1 to 0.5 mg/kg administered subcutaneously had hyperalgesic effect and, with the dose increase (1-25 mg/kg), progressively attenuated the degree of nociceptive reactions caused by thermal and chemical stimulation. When kininogen accumulations were depleted due to the injection of kininogenase activator-cellulose sulfate, captopril in all the doses studied had an analgetic effect, with it reduced by naloxone. The data obtained show that dipeptidyl-carboxypeptidase inhibition by captopril can affect the degree of nociceptive reactions caused by various nociceptive stimuli.     

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.     

Effect of electroacupuncture on the activity of neurons in the central gray matter of the midbrain

The effect of electroacupuncture in locally-segment and general analgetic points on background impulse activity of central gray substance neurons and their activity caused by nociceptive stimulation of the dental pulp, infraorbital nerve and forearm skin surface was studied in acute experiments on cats. It has been established that general analgetic points are better represented in the central gray substance, as compared to locally-segment points. Different degree involvement of central gray substance in the realization of acupuncture analgetic effect in different points is postulated. The role of dorsal and ventral compartments of the central gray substance in acupunctural analgesia is discussed.     

Effect of cesium, lithium and rubidium on several effects of morphine

The effect of chlorous salts of cesium, lithium, and rubidium on the analgetic action of morphine (according to the vocalization test) and also on the pattern of the dependence on it (according to the so-called "two-bottle test") was studied. As shown, the salts under investigation decreased both the algesic reaction threshold and the duration of morphine-induced analgesia; cesium chloride proved most active in this respect. All the compounds studied decrease the morphine preference coefficient. The greatest effect was found in cesium chloride which decreased the morphine preference coefficient 40-fold as compared to the control.     

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.     

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.     

Selective analgetic effects of angiotensin and bombesin during the action of dental and cutaneous nociceptive irritants

In non-anesthesized rabbits intraventricular injection of angiotensin II reduced the amplitude of somatosensory evoked potential to nociceptive tooth pulp, but not to nociceptive electrocutaneous stimulation. The same injection of bombesin induced the contrary analgetic effect. The systemic naloxone (0.1 mg/kg) injection didn't reverse the peptides analgetic effects. It's suggested that selective analgetic effects of angiotensin II and bombesin are determined by the presence of the specific different peptide mechanisms for nociception with the different pain genesis.     

Role of catecholamine neurons in the reticular lateral nuclei in regulating sensitivity to pain during exposure to reflex stimuli

Experiments were made on rats in which the effects of catecholaminergic neuronal systems of lateral reticular A-1 nuclei were eliminated with 6-OHDA. The latency of pain reactions tested by the hot-plate and tail-flick tests remained unchanged after operation. After auricular electric acupuncture the rats manifested no changes in the above reactions as compared with the initial level, which evidences that A-1 nuclei play an important role in the mechanisms of analgesia under consideration. Stimulation of the small pelvis organs (SSPO) entailed a short-term and significant inhibition of the analgetic effect as regards the control which also points to the involvement of A-1 nuclei into activation of antinociceptive processes. Besides, during SSPO, there was a significant elevation of the response measured by the tail-flick test as compared to the initial level of the pain reaction.     

Effect of bone marrow mediator myelopeptides on the summation-threshold index and behavioral reactions of rats

Transmitter peptides having immunostimulant and endorphine-like properties were isolated from supernatant of medullary cell culture. Bioregulatory peptides were called myelopeptides. Myelopeptides provoked changes of the summation-threshold index in rats, which augmented in time. These changes pointed to the realization of the analgetic effect of myelopeptides via the spinal-stem structures of the central nervous system. Having a remarkable analgesic effect myelopeptides administered in the doses tested did not produce any action on the behavioral responses. The latter circumstance makes them differ from narcotic analgesics and known endorphines.     

Effect of auricular electroacupuncture on the motor manifestations of nociceptive reactions

The effect of low frequency auricular electroacupuncture (EAP) on electromyographic responses (EMGR) of the anterior belly of the digastruc muscle, elicited by stimulation of tooth pulp was studied in cat experiments. It was shown that observed augmentation of the EMGR amplitude produced by EAP depended on tonic activation of gamma-motoneurons of the muscle. This activation directly correlated with EAP intensity. At the same time the latent period of EMGR increased by one-two synapses on account of inhibiting shorter pathways in the afferent part of the reflex arch with intensive EAP. The inhibition of EAP-induced augmentation of EMGR can be achieved by administration of small doses of barbiturates that potentiate the analgetic action of EAP.