Endometrial hyperplasia-related inflammation: its role in the development and progression of endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH) is one of the most common gynecologic diseases in the world. Different statistical categories implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a key role in the progression of endometrial hyperplasia. OBJECTIVE: The aim of this study is to evaluate the role of inflammation in the transformation and progression of endometrial hyperplasia, using local inflammatory cytokines and nonspecific protease levels, CD 45(+) expression, and histological examination. DESIGN: The study included 107 patients (ages 29-49 years) with different forms of endometrial hyperplasia. The enrolled patients were randomized into one of the four groups: normal endometrium (n = 18) as the control group, simple hyperplasia (n = 41), complex hyperplasia without atypia (n = 36), complex atypical hyperplasia or endometrioid adenocarcinoma (n = 12). METHODS: The following were evaluated for patients with different forms of EH: steroid hormone levels in blood serum and uterine flushings, immunohistochemical estrogen and progesterone receptor expression patterns in the endometrial tissue, CD 45(+) (common leukocyte antigen) expression, the levels of the cytokines IL-1ß, IL-6, and TNF-α, and nonspecific proteases and their inhibitors. RESULTS: The level of estradiol in blood serum and especially in uterine flushings was elevated dramatically in simple EH as compared to that of controls, but there was no significant difference between estradiol levels among the different forms of EH. The estimation of CD 45(+), the levels of the cytokines IL-1ß, IL-6, and TNF-α, and the activity of proteases (elastase-like and trypsin-like activities) and their inhibitors showed that levels of nonspecific inflammatory markers increase with EH progression. CONCLUSIONS: We suggest that the initial responsibility for the development of simple endometrial hyperplasia belongs to systemic hyperestrogenemia and, in particular, local hyperestrogenia, but that the role of inflammatory processes increases in complex and atypical EH. Development of inflammatory changes in endometrial hyperplasia may be considered as a factor in the promotion and progression of pathology, as well as an attributed risk factor for malignancy in endometrial hyperplasia. In this study, we have established a role for CD 45(+) expression cells, non-specific proteases, and the inflammatory cytokines IL-1ß, IL-6, and TNF-α in endometrial hyperplasia-related inflammation.

Specific features of learning with nociceptive electrical reinforcement in rats of different genetic strains: role of brain neurotransmitter systems.

The interaction between neurotransmitter systems and opioid system in rats of different strains was studied during learning and emotional stress. The interaction between noradrenergic, serotoninergic, and opioid systems in the brain is the main neurochemical mechanism underlying learning reinforced by nociceptive electrical stimulation, which determine individual differences in the rate and type of learning.

HLDF-6 peptide relieves symptoms of abstinence syndrome during experimental opium abuse.

Experiments were performed on rats with opium abuse induced by chronic administration of morphine in increasing doses. We studied the effect of HLDF-6 peptide on symptoms of naloxone abstinence. Repeated administration of HLDF-6 peptide in a dose of 0.2 mg/kg 24 and 0.5 h before naloxone relieved the major symptoms of the abstinence syndrome. A possible neurochemical mechanism underlying the effect of HLDF-6 peptide is inhibition of enkephalinase A in structures of the endogenous antinociceptive system.

Use of HLDF-6 peptide for correction of disturbances in the endogenous opioid system in offspring of morphine-tolerant animals.

We studied the effect of bioactive peptide HLDF-6 on functional activity of the endogenous antinociceptive system in the offspring of morphine-tolerant animals. Disturbances in this system included changes in the thermonociceptive threshold and enkephalinase A activity in various brain structures. The peptide acted as a potent regulator of the homeostasis in systems responsible for the synthesis and catabolism of endogenous opioids. HLDF-6 effectively corrected disorders of the endogenous antinociceptive system.

Formation of morphine tolerance in offspring of morphine-tolerant animals: neurochemical and neuroimmune correlates.

We carried out a complex physiological, neurochemical, and neuroimmunologic study of the formation of tolerance to analgetic effect of morphine and analyzed enkephalinase A activity in different brain structures and serotonin antibodies in the serum. More early development of morphine tolerance and a sharp increase in serum antibody titer was found in the offspring of morphine-tolerant rats. This points to an imbalance in the neurotransmitter system and can serve as a diagnostic marker of endogenous opioid system pathology.

The use of naloxone in small doses in complex therapy of postabstinent heroin syndrome: enkephalinase mechanisms.

The use of naloxone hydrochloride (0.2-0.4 mg) in complex therapy of adolescent heroin addicts significantly prolonged the half-life of serum leu-enkephalin, slightly elevated the thresholds of thermal nociceptive reactions, and improved some clinical indices (considerably reduced drug addiction, eliminated affective disorders, etc.), which are important for deactualization of drug addiction and promoting remission.

Changes in thermonociceptive thresholds and the role of enkephalinase A in homeostasis in morphine-tolerant rat offspring.

The dynamics of thermonociceptive thresholds as a marker of the state of the endogenous opioid system was studied in the offspring of morphine-tolerant rats. Significant, age-dependent increase in thermonociceptive thresholds and higher levels of enkephalinase A in structures of the endogenous antinociceptive system were observed in the offspring compared with the control. These findings attest to disturbances of the opioid system in the progeny of morphine-tolerant rats and confirm the key role of enkephalinase A in the maintenance of homeostasis disturbed by chronic prenatal morphine treatment.

[A comprehensive study of the neurochemical and immune mechanisms of morphine tolerance: the effects of naloxone]. / Kompleksnoe izuchenie neirokhimicheskikh i immunnykh mekhanizmov morfinnoi tolerantnosti: éffekty naloksona.

To test the authors' hypothesis about the role of endopeptidase (enkephalinase A, in particular) in mechanisms of morphine tolerance and blocking action of small doses of naloxone, they studied nociception reactions, morphine antibodies titres and enkephalinase A activity after morphine, d-phenylalanine and naloxone injection in brain structures. It is shown that activity of enkephalinase A in structures of endogenous antinociceptive system increased simultaneously with morphine antibodies titres in tolerance condition. Injection of small dose naloxone inhibited enkephalinase activity in brain structures and decreased morphine antibodies titres to these in control morphine-sensitive rats and therefore suppressed morphine tolerance. Prolonged naloxone injection decreased morphine antibodies titres to the levels of intact animals and highly increased titers of antiidiotypic morphine antibodies. Thus, these results confirm the role of enkephalinase as a neuromodulator. A strong relationship exists between enkephalinase and immune mechanisms of development of morphine tolerance which can be blocked by small naloxone doses. It is concluded that naloxone in small doses can be used in patients to suppress morphine tolerance.

[Morphine antibodies in the mechanisms of morphine resistance, morphine tolerance and of the action of an antagonist]. / Antitela k morfinu v mekhanizmakh morfinnoi rezistentnosti, morfinnoi tolerantnosti i deistviia antagonista.

It was found that the absence of the analgesic effect of morphine, as determined by the tail-flick test, in morphine-resistant and morphine-tolerant rats, as well as in naloxane blockade of morphine analgesia in morphine-sensitive rats was attended with a four- to eight-fold increase in morphine antibodies in the plasma, as determined by the ELISA method. It is suggested that a pharmacokinetic factor mediated through immune reactions of morphine antibodies formation is one of the mechanisms of such conditions.

[Opioid mechanisms of the analgesic action of cocaine]. / Opioidnye mekhanizmy anal'geticheskogo deistviia kokaina.

Rat experiments revealed a dose-dependent and naloxone-dependent analgetic effect of cocaine (0.5-3.0 mg/kg), evaluated by the tail-flick test. The cocaine-sensitive animals were morphine-sensitive and the cocaine-insensitive ones were morphine-insensitive. In some cocaine-insensitive rats, the use of cocaine led to that the first phase characterized by the lack of changes in nociception was followed by a hyperalgesic phase. It is suggested that cocaine produces an analgetic effect mainly via the delta-opioid mechanism.

[Enkephalinase mechanisms of tolerance of analgetic action of opioids. Effects of D-phenylalanine and naloxone]. / Enkefalinaznye mekhanizmy tolerantnosti k anal'geticheskomu deistviiu opioidov. Effekty D-fenilalanina i naloksona.

The paper reviews the data available in the literature and the authors own data demonstrating the differences in the levels of endogenous opioids and in the effects of enkephalinase inhibitor and naloxone in morphine-responsive and morphine-resistant and -tolerant animals. In the morphine-tolerant animals, a single administration of enkephalinase inhibitor or some doses of naloxone was found to produce an analgesic effect leading to a short-term analgesic effect of morphine. Chronic administration of naloxone causing a gradual decrease in and subsequent cessation of its analgesic effect leads to recovery of morphine's analgesic effect in the drug-resistant and -tolerant animals. It is suggested that the morphine-resistant animals have a congenital high activity of enkephalinase, while the drug-tolerant ones have its acquired high activity. Naloxone in certain doses with the high activity of enkephalinase act as its inhibitor, but in high doses acts as its opioid antagonist.

[The enkephalinase mechanisms of the resistance and tolerance to the analgesic effect of morphine in rats. Differences in the effects of the action of D-phenylalanine in morphine-sensitive, morphine-tolerant and morphine-resistant rats]. / Enkefalinaznye mekhanizmy rezistentnosti i tolerantnosti k analgeticheskomu éffektu morfina u krys. Razlichiia éffektov deistviia D-fenilalanina u morfinchuvstvitel'nykh, morfintolerantnykh i morfinrezistentnykh krys.

In morphine-sensitive (s.c. 1.5 mg/kg) Wistar rats (60%) i.p. inoculation of 300-600 mg/kg d-Phenylalanine (d-Pha) did not change the nociception (tail-flick test), but in morphine-resistant rats (40%) evoked a dose-dependent analgetic effect. In morphine-sensitive rats (40%) chronic morphine administration induced the tolerance and d-Pha injection evoked analgetic effect. Morphine injection just after d-Pha analgesia was over evoked analgetic effect in morphine-resistant and -tolerant rats. It is suggested that morphine-resistant rats have a congenital and morphine-tolerant rats an acquired high level of enkephalinase activity which blocked the morphine analgetic action.

[The enkephalinase mechanisms of the resistance and tolerance to the analgesic effect of morphine in rats. Differences in the effects of naloxone in morphine-sensitive, morphine-resistant and morphine-tolerant rats]. / Enkefalinaznye mekhanizmy rezistentnosti i tolerantnosti k analgeticheskomu éffektu morfina u krys. Razlichiia éffektov naloksona u morfinchuvstvitel'nykh, morfinrezistentnykh i morfintolerantnykh krys.

In morphine-sensitive (s. c. 1.5 mg/kg) Wistar rats i.p. injection of 0.3 mg/kg naloxone either did not change nociception (tail-flick test) or induced hyperalgesia. In morphine-resistant rats 0.2-0.7 mg/kg naloxone injection induced analgetic effect but 1.0 mg/kg induced hyperalgesia. In morphine-sensitive rats chronic morphine administration induced the tolerance and naloxone injection evoked analgetic effect. Morphine inoculation just after naloxone analgesia was over induced analgetic effect. In morphine-resistant and -tolerant rats chronic naloxone administration induced gradual decrease and subsequent disappearance of its analgetic effect and subsequent morphine injections induced analgetic effect for some days. It is suggested that naloxone in morphine-resistant and -tolerant rats with high level of enkephalinase activity functions as its inhibitor. Chronic naloxone administration evoked progressive inhibition of enkephalinase activity that induced the morphine analgetic effect in morphine-resistant and -tolerant rats.

[The action of neurotropin on the processes of conditioned-reflex avoidance in rats]. / Deistvie neirotropina na protsessy uslovnoreflektornogo izbeganiia u krys.

Preliminary neurotropin administration improved subsequent conditioned avoidance learning of rats in a shuttle-box: increased the number of conditioned avoidance reactions and decreased their latency in comparison with the control but did not change the number of intertrial responses. "The demolition" (5 series of negative reinforcements applied despite of avoidance occurrence) caused behavioural stress reactions and inhibited the conditioned and unconditioned avoidance learned reactions. Neurotropin injection before the demolition abolished such disturbances, that having been done after the demolition restored conditioned avoidance. The positive effects of neurotropin were suggested to be due to its antistress property and ability to improve the formation of a result of an acceptor of action.

[The antihyperalgesic and selective analgesic effects of neurotropin]. / Antigiperal'geticheskii i izbiratel'nyi anal'geticheskii éffekty neirotropina.

In experiments of albino rats neurotropin injection was shown to increase the latency of the tail-flick test in response to the nociceptive thermal stimulus and didn't change the threshold of the test in response to the nociceptive electroskin stimulus. The administration of the antiserum to beta-endorphin lowered the threshold and the latency of the tail-flick test in response to both stimuli. The preliminary administration of neurotropin reduced the hyperalgesic effect of the antiserum on both nociceptive stimuli.