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.     

The protective properties of myelopeptides in the development of infectious processes caused by bacteria of the genus Salmonella

The protective properties of myelopeptides in the development of bacterial infection in mice and young pigs, caused by S. typhimurium 415, S. cholerae-suis 1422 and 370, have been studied. Myelopeptides have been found to possess protective properties when injected into animals infected with S. typhimurium and S. cholerae-suis in lethal doses. The best protective effect (survival rate of 100%) has been achieved by the injection of myelopeptides 24 hours before challenge. Myelopeptides have also been found to promote the weight gain of young pigs infected with S. cholerae-suis.     

Myelopeptide correction of the differentiation of hematopoietic precursor cells in mice with experimental T-immunodeficiency

The influence of myelopeptides on differentiation of bone marrow haemopoietic precursors cells in thymectomized and normal mice has been studied in vivo. The introduction of myelopeptides decreased the number of erythroid (E) colonies and increased that of granulocytic ones (G). This results in the decrease of initially raised E/G ratio in thymectomized mice (from 4.3) down to 1.3). Myelopeptides exerted no influence on haemopoietic precursors in normal mice (E/G-2.0).     

A new principle in the analysis of the analgesic action of morphine

Possible application of sensory decision theory of pain for the experimental assessment of neuropsychophysiological mechanisms of opiate analgesia has been demonstrated. The analgetic effect of morphine was found to be mediated through the influence on the measurement and estimation of pain stimulus.     

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.     

Effect of bone marrow opioid peptides on antibody formation in the productive phase of the immune response

The cells of intact spinal cord produce a group of biologically active peptides--myelopeptides (MP) stimulating antibody formation at peak of immune response and exerting an analgesic endorphin-like effect. The experiments on comparative studies of antibody-stimulating effect of synthetic opioid peptides and MP have shown that the mixture of opioid substances composed in aliquots corresponding to their content in MP has an antibody-stimulating effect similar to that of MP. Synthetic beta-endorphin also enhances the antibody formation during the productive phase of immune response at doses 1000-fold lower than its MP level. Leu- and met-enkephalins have no antibody-stimulating effect. An antagonist opiate, naloxone, blocks the antibody-stimulating activity of both opiates and MP. A close correlation between antibody-stimulating and analgetic endorphin-like MP activity has been established.     

Effect of the spinal pain syndrome on pain reactions caused by nociceptive thermal stimuli

It has been shown that the reaction of both limbs to thermal pain stimulation was suppressed during spinal pain syndrome development caused by generators of pathologically enhanced excitation (GPEE) formed in the dorsal horns of the spinal cord lumbosacral segments on one side. The analgetic effect on physiological pain was retained long after pain syndrome disappearance (48 hours), the effect was bilateral and was independent of the type of agent producing GPEE. It was shown that neuronal activity in the antinociceptive system key structure (nucleus raphe dorsal) increases. It is assumed that physiological pain relief is caused by enhanced activity in antinociceptive system structures in pain syndrome.     

Effect of benzodiazepines on neuropathologic syndromes of spinal origin

Comparative analysis of the effects of the drugs belonging to the same series was made in experiments on rats with generalized myoclonus and pain syndrome of spinal origin. The syndromes were produced by creating the generator of pathologically enhanced excitation in ventral and dorsal horns of the spinal cord. Phenazepam and clonazepam were found to be the most effective drugs for both forms of pathological conditions. They produced a marked anticonvulsant effect in myoclonus and analgetic effects in pain syndrome.     

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.     

Possible involvement of cerebroside sulfate in opiate receptor binding.

Cerebroside sulfate (CS) appears to fulfill most of the structural requirements of a hypothetical opiate receptor. It possesses many of the properties that are thought to be necessary for the identification of an "opiate receptor," exhibiting high affinity and stereoselective binding to a number of narcotic drugs. Although these properties are insufficient to establish identity of the receptor, it is highly significant that the affinity of this binding can be correlated with the analgetic potency of these drugs in both man and rodents. CS is an endogenous component of brain tissue, and a partially purified opiate receptor from mouse brain has been found to be CS. Other experiments indicate that reduced availability of brain CS decreases the analgetic effects of morphine and this is accompanied by a reduction in number of binding sites, suggesting that the interaction of opiates with CS observed in vitro may also have importance in vivo. CS was also found to be a component of the opiate receptor after marking with 125I-labeled diazosulfanilic acid. The possibility that CS or the SO4-2 group of this lipid may be the "anionic site" of the opiate receptor should be considered.     

The role of various opiate receptors in the regulation of the nociceptive reaction of the arterial pressure

The experiments on alert rats have shown that dissociation in opioid regulation of behavioural and hemodynamic pain manifestations is determined at a spinal opiate receptor level. Opiates and opioids suppress blood pressure nociceptive reactions to mu-opiate receptors, while sigma-opiate receptors are involved into the generation of autonomic activating effect in opiate analgesia.     

Effects of high and low molecular soluble factors of the bone marrow on antibody formation and pain sensitivity in animals

In addition to the immunostimulating activity, bone marrow mediators, myelopeptides (MP) show the dose-dependent effect on the development of pain sensitivity in mice. When injected in nanogram amounts, MP induce hyperalgesia and 3-9 fold higher production of antibodies against SREC. When injected in milligram amounts, they exhibit hypoalgesic effect and no influence on antibody production. Immunostimulating effect in MP (mol, mass less than 1 KD, fraction 3) is accompanied with hypoalgesia. Bone marrow factors of mol. masses 40-150 KD (fraction 1) eluted at Sephadex G-25 gel-filtration before MP enhance the pain sensitivity tHreshold and show a potent immunodepressive effect. Thus the bone marrow factors are capable of exhibiting the opposite effects on the immune system in the pain control system that evidences the tight interrelation between these systems.     

Mechanism of the suppression of the spinal pain syndrome by serotonin derivatives

The ability of serotonin derivatives to stimulate cAMP accumulation in isolated nerve terminals and lumbar enlargement of the spinal cord of normal rats was compared. The effect of the compounds on the intensity of spinal pain syndrome was also assessed. It has been established that substitutes injected into NH2-group of serotonin in 5-OH position attenuate the ability to stimulate cAMP accumulation in synaptosomes, with the effect more pronounced with substitutes of larger volume. A certain correlation between the ability of serotonin derivatives to stimulate adenylate cyclase in vivo and in vitro, on the one hand, and their analgetic effect, on the other hand, is suggested.     

Stereospecific binding of narcotics to brain cerebrosides

Cerebrosides were shown to bind etorphine and naloxone stereo-specifically with high affinity. The relative potency of several narcotic analgesics in preventing the binding of etorphine and naloxone to cerebrosides correlated well with their reported intraventricular analgetic activity. The data indicate similarities between cerebroside sulfate and a purified opiate receptor from mouse brain which has been reported to be a proteolipid. Explanations for the apparent proteo-like behavior of the opiate receptor are provided.     

Long-term enhancement of morphine hypalgesia as a result of periodic blockade of opiate receptors using naloxone

A significant enhancement of the analgetic effect of morphine (6 mg/kg, subcutaneously; tail withdrawal reflex at 60 degrees C) was observed in rats 3-4 hours after single naloxone (1 mg/kg) administration. Periodical naloxone injection (0.5 mg/kg, subcutaneously, 3 times per day at 3.5-hour intervals for 3 days) led to a prominent and long-term (testing on the 20th and 105th hour after the last naloxone administration) enhancement of morphine analgesia (2.6 mg/kg subcutaneously) and insignificant inhibition of stress analgesia during two-hour immobilization of animals. These modifications of morphine and stress analgetic effects are considered a result of adaptive changes of opiate receptors after their blockade.     

Multiple opiate receptors on neurons of the mammalian central nervous system. In vivo and in vitro studies

Experiments were performed in rat spinal cord cells in vivo and on hippocampal pyramidal cells in vitro. These investigations suggest that acute and chronic treatment renders the neurons subsensitive to opiate alkaloids without altering their sensitivity to opioid peptides. The experiments performed in the dorsal horn of the spinal cord provide evidence that in this structure mu- and delta-receptors may also be localized on the same cell. The evidence for the existence of distinct types of opiate receptors as originally proposed by (1) and suggested by the differing pattern of opiate and opioid peptide activity in various assay systems has been substantiated by investigations involving the selective development of tolerance and the protection of a particular receptor subtype by chemical manipulation. Furthermore, they have been characterized by the use of low concentrations of radiolabelled agonists and antagonists and through the ability of GTP to influence differentially their binding to the opiate receptor (for refs. see: 2). Recently autoradiographic techniques were able to provide direct evidence by mu- and delta-receptors in the mammalian brain (3; 4; 5; 6; and cits. therein). The presence of multiple opiate receptors located on the same cell is suggested by the present study.     

Effect of beta-endorphin and myelopeptides on the cAMP level and proliferation of lymphocytes in vitro

Beta-endorphin (10(-11)-10(-9) M) has been shown to induce naloxone-independent depression of the proliferative activity of human peripheral lymphocytes (HL), stimulated by pokeweed mitogen without affecting PHA-stimulated HL proliferation. Beta-endorphin (10(-10)-10(-7) M) also caused changes in HL cAMP level, that were blocked by naloxone. Marked individual sensitivity to beta-endorphin effects has been noted. It has been also shown that a bone marrow preparation, stimulating antibody production (myelopeptides), causes naloxone-independent depression in the proliferative activity of HL, stimulated by PHA and pokeweed mitogen, as well as naloxone-blocked decrease in cAMP HL level. It has been concluded that beta-endorphin interacts with several types of opiate lymphocyte receptors and that opioids, contained in myelopeptides, are involved in the realization of myelopeptide effect on lymphocytes.     

Endogenous opioid system in the realization of the analgesic effect of alpha-tocopherol in reference to algomenorrhea

Beta-endorphin-like immunoreactivity was studied in 7 patients with algomenorrhea during pain attack and 15 minutes after alpha-tocopherol administration with a therapeutic aim (till the analgetic effect was reached). There was an increase in beta-endorphin-like immunoreactivity after alpha-tocopherol administration. Naloxone administration to 9 patients with algomenorrhea of various etiology resumed the pain. The effect of alpha-tocopherol application for pain relief depended on the pathogenesis of algomenorrhea. At the same time naloxone administration failed to resume the pain in patients, in whom alpha-tocopherol had a strong analgetic effect. It is assumed that the endogenous opioid system participates in alpha-tocopherol effect on pain relief in patients with algomenorrhea.     

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.