gamma-endorphin--des-tyr(1)- and des-enkephalin-gamma-endorphin

The pharmacological actions of gamma-type endorphins show similarities to those of the neuroleptics. Two fragments of gamma-endorphin (beta-LPH 61-77) were therefore tested in patients with schizophrenic and schizo-affective psychoses who had shown an insufficient response to neuroleptics. The fragments were DT gamma E (beta-LPH 62-77) and DE gamma E (beta-LPH 66-77). Some of the patients studied responded favorably to this treatment. A number of criteria of differentiation between responders and nonresponders are discussed. The influence of DT gamma E on the central DA metabolism differs from that of the neuroleptics. It is therefore conceivable that gamma-type endorphins represent a different principle of action. The therapeutic efficacy of these compounds lends support to the hypothesis that disorders of central endorphin metabolism may play a role in the pathogenesis of psychoses of the schizophrenic type.

Topics: beta-Endorphin; Brain; Clinical Trials as Topic; Dopamine; Double-Blind Method; Endorphins; gamma-Endorphin; Humans; Peptide Fragments; Psychotic Disorders; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology

Topics: Adult; beta-Endorphin; Brain; Clinical Trials as Topic; Dopamine; Double-Blind Method; Endorphins; Female; gamma-Endorphin; Humans; Male; Middle Aged; Peptide Fragments; Schizophrenia

The effect exerted by two gamma-endorphin derivatives (DTgammaE and DEgammaE) was investigated on morphine-induced inhibition on the electrically induced contractions of guinea pig ileum in vitro. Morphine (1x10(-8)-5x10 (-8)-1x10 (-7) M) dose dependently and significantly reduced the E.C. of guinea pig ileum, IC50=6.5x10(-8) M (Confidence limits: 3.7x10 (-8)-9.1x10 (-8)). DTgammaE and DEgammaE per se (1x10 (-6)-5x10 (-6)-1x10 (-5) M) did not modify significantly the E.C. of guinea pig ileum. Furthermore, DTgammaE or DEgammaE injection 10-30-60 min before morphine, did not affect the inhibitory effect of morphine on the E.C. of guinea pig ileum. By contrast, ilea from guinea-pigs treated for 4 days with DTgammaE or DEgammaE (1 mg/Kg/i.p.) were less sensitive to the inhibitory effect of morphine, IC50=8.3x10 (-7) M (Confidence limits: 1.4x10(-6)-3.5x10(-7)) for DTgammaE and IC50=7.7x10(-7) M (Confidence limits: 2.7x10(-6)-8.7x10(-7 )) for DEgammaE . The effect exerted by two beta-endorphin fragments (DTgammaE and DEgammaE) was investigated on the acute opiate withdrawal induced by micro, kappa and delta receptor agonists in vitro. After a exposure in vitro for 4 min to morphine (less selective micro agonist), DAGO (highly selective micro agonist), U50-488H (highly selective kappa agonist) and beta-endorphin (selective micro- delta agonist), a strong contracture of isolated guinea pig ileum was observed after the addition of naloxone. This effect was also observed when isolated rabbit jejunum was pretreated with deltorphin (highly selective delta agonist). DTgammaE or DEgammaE injection before or after treatment with morphine, DAGO, U50-488H, beta-endorphin or deltorphin was able of both preventing and reversing the naloxone-induced contracture after exposure to the opioid agonists in a concentration-dependent fashion. Our results indicate that both DTgammaE or DEgammaE are able to reduce significantly opiate withdrawal in vitro, suggesting an important functional interaction beween beta-endorphin fragments and opioid withdrawal at both micro, kappa and delta receptor level. Our results indicate that chronic treatment of guinea pigs with DTgammaE or DEgammaE induces a significant reduction of the inhibitory effect of morphine on the E.C. of guinea-pig ileum thus confirming an important functional interaction between gamma-endorphin derivatives and opioid system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Animals; beta-Endorphin; Electric Stimulation; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guinea Pigs; Ileum; In Vitro Techniques; Jejunum; Male; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Oligopeptides; Peptide Fragments; Rabbits; Substance Withdrawal Syndrome

The effect exerted by two beta-endorphin fragments (DTgammaE and DEgammaE) was investigated on the acute opioid dependence induced by mu, kappa and delta receptor agonists in vitro. After a 4-min in vitro exposure to morphine (less selective mu agonist), DAGO (highly selective mu agonist), U50-488H (highly selective kappa agonist) and beta-endorphin (selective mu-delta agonist), a strong contracture of guinea pig isolated ileum was observed after the addition of naloxone. This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (highly selective delta agonist). DTgammaE or DEgammaE injection treatment before or after morphine, DAGO, U50-488H, beta-endorphin or deltorphin were able to both prevent and reverse the naloxone-induced contracture after exposure to the opioid agonists in a concentration-dependent fashion. Our results indicate that both DTgammaE or DEgammaE are able to reduce significantly opioid dependence in vitro, suggesting an important functional interaction between beta-endorphin fragments and opioid dependence induced by mu, kappa and delta receptors.

Topics: Analgesics, Opioid; Animals; Antidepressive Agents; beta-Endorphin; Dose-Response Relationship, Drug; Endorphins; Guinea Pigs; Ileum; Male; Morphine; Muscle Contraction; Opioid-Related Disorders; Peptide Fragments; Substance Withdrawal Syndrome

The effect exerted by two gamma-endorphin derivatives (DTgammaE and DEgammaE) was investigated on morphine-induced inhibition on the electrically contractions of guinea pig ileum in vitro. Morphine (1x10(-8)-5x10(-8)-1x10(-7) M) dose dependently and significantly reduced the E.C. of guinea pig ileum, IC50=6.5x10(-8) M (Confidence limits: 3.7x10(-8)-9.1x10(-8)). DTgammaE and DEgammaEper se (1x10(-6)-5x10(-6)-1x10(-5) M) did not modify significantly the E.C. of guinea pig ileum. Furthermore, DTgammaE or DEgammaE injection 10-30-60 min before morphine, did not affect the inhibitory effect of morphine on the E.C. of guinea pig ileum. By contrast, ilea from guinea-pigs treated for 4 days with DTgammaE or DEgammaE (1 mg/Kg/i.p.) resulted less sensitive to the inhibitory effect of morphine, IC50=8.3x10(-7) M (Confidence limits: 1.4x10(-6)-3.5x10(-7)) for DTgammaE and IC50=7.7x10(-7) M (Confidence limits: 2.7x10(-6)-8.7x10(-7)) for DEgammaE. Our results indicate that chronic treatment of guinea pigs with DTgammaE or DEgammaE induces a significant reduction of the inhibitory effect of morphine on the E.C. of guinea-pig ileum thus confirming an important functional interaction between gamma-endorphin derivatives and opioid system.

Topics: Analgesics, Opioid; Animals; beta-Endorphin; Electric Stimulation; Endorphins; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphine; Muscle Contraction; Muscle, Smooth, Vascular; Narcotic Antagonists; Peptide Fragments; Time Factors

The effects of some beta-endorphin fragments with neuroleptic-like properties, i.e., tau-endorphin, des-tyr1-tau-endorphin (DT tau E), desenkephalin-tau-endorphin (DE tau E), in comparison with the dopaminergic antagonist haloperidol,- were studied on the EEG and behavioral alterations induced by beta-endorphin in the rabbit. beta-Endorphin administered i.c.v. (5-30 nmol) induced EEG nonconvulsive limbic seizures as well as EEG background and behavioral alterations which were antagonized by naloxone administered i.v. (1-2 mg/kg). Haloperidol, tau-endorphin, DT tau E and DE tau E were unable to prevent beta-endorphin-induced alterations when injected in a single dose i.v. (25-50 micrograms/kg), 15 min before beta-endorphin. Subchronic i.v. administration of DT tau E or DE tau E (25 micrograms/kg/day) for 4 consecutive days prevented completely EEG limbic seizures as well as EEG background and behavioral alterations induced by i.c.v. beta-endorphin injected 15 min after the fourth dose; however, haloperidol (30 micrograms/kg/day) administered with the same schedule as DT tau E or DE tau E was able to prevent only EEG epileptiform and EEG background alterations induced by beta-endorphin. tau-Endorphin administered i.v. for 4 consecutive days (25 micrograms/kg/day) did not consistently influence any of the beta-endorphin effects. Our results show that DT tau E and DE tau E, which are devoid of opioid activity, exert a strong antagonism on ictal seizures as well as on other EEG alterations and behavioral alterations induced by beta-endorphin, and suggest that the antagonism shown by these drugs and by haloperidol on the EEG effects induced by beta-endorphin are exerted at least in part through an indirect action, i.e., an interaction with the dopaminergic system.

Topics: Animals; Behavior, Animal; beta-Endorphin; Electroencephalography; Endorphins; Haloperidol; Injections, Intraventricular; Male; Naloxone; Peptide Fragments; Rabbits; Seizures

The beta-endorphin (beta E) fragment des-Tyr1-gamma-endorphin (DT gamma E, beta E-(2-17)) has been reported to interact with neuroleptic binding in vivo but not in vitro. We have attempted to replicate the in vivo experiments and extended the work to include conditions in which des-enkephalin-gamma-endorphin (DE gamma E, beta E-(6-17)) exhibited behavioral activity. Systemically administered haloperidol significantly elevated plasma and decreased striatal [3H]spiperone. DE gamma E significantly elevated plasma [3H]apomorphine when both substances were injected directly into the nucleus accumbens. gamma-type endorphins consistently but non significantly decreased brain spiperone or apomorphine binding. It is concluded that the interaction between gamma-type endorphins and dopaminergic binding sites may be either indirect or limited to a subset of these sites.

Topics: Animals; Apomorphine; beta-Endorphin; Brain; Endorphins; Motor Activity; Peptide Fragments; Rats; Receptors, Dopamine; Spiperone

In order to investigate whether genetic factors are involved in the response of schizophrenic patients to treatment with gamma-type endorphins, we typed 32 Dutch schizophrenic patients for the HLA-A, -B, -C and -DR antigens. The total patient group showed an increase of HLA-Bw4 and HLA-Cw1. A subgroup of 20 paranoid patients showed an increase of HLA-Cw1 and a significant heterogeneity for the HLA-C locus. In 16 patients who responded moderately or markedly to treatment with gamma-type endorphins, an increase of HLA-B15/Cw3 and a decrease of HLA-B17 were found as compared to 16 patients with no or a slight response. Moreover, HLA-B15 was particularly increased in those patients who responded markedly and remained free of psychotic symptoms for a period of at least 6 months after treatment with gamma-type endorphins (RR = 24.6, Puncorr. = 0.0015). Our results suggest that genetic factors coded for within the HLA region are associated with paranoid schizophrenia, and that HLA-B15/Cw3 is associated with a marked and prolonged response to treatment with gamma-type endorphins.

Topics: beta-Endorphin; Endorphins; gamma-Endorphin; HLA Antigens; HLA-B Antigens; HLA-B15 Antigen; HLA-C Antigens; Humans; Peptide Fragments; Schizophrenia

Des-enkephalin-gamma-endorphin (beta-endorphin6-17; DE gamma E) causes a significant reduction of the serotonin concentration of the raphe area of the mesencephalon and of the dorsal hippocampus of the rat. DE gamma E does not, however, alter the pargyline-induced accumulation of serotonin in either of these two brain regions or in the mediobasal hypothalamus. Des-Tyr1-a-endorphin (beta-endorphin2-16; DTaE), on the other hand, inhibits the accumulation of serotonin following MAO-inhibition by pargyline in all 3 brain regions, while, in addition to causing a transient reduction in the serotonin concentration of the raphe area, it decreases the serotonin concentration of the mediobasal hypothalamus. These results indicate that DE gamma E and DTaE, which have been shown to exert opposite effects on behavior in various behavioral tests, both affect regional serotonin metabolism in rat brain and that they do so differently.

Topics: Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Brain; Dose-Response Relationship, Drug; Endorphins; Enkephalins; Hippocampus; Hypothalamus, Middle; Male; Mesencephalon; Peptide Fragments; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin

The potency of two beta-endorphin fragments, des-Tyr1-gamma-endorphin (DT gamma E, beta E-(2-17) and des-enkephalin-gamma-endorphin (DE gamma E-(6-17) was compared on extinction of pole-jumping avoidance behavior and on retention of a one-trial step-through passive avoidance procedure. Both peptides facilitated the extinction of pole-jumping avoidance behavior and attenuated passive avoidance behavior. The gamma-type endorphin exhibited an inverted U-shaped dose-response curve on passive avoidance behavior but not on extinction of pole-jumping avoidance behavior. DE gamma E appeared to be approximately three times more potent than DT gamma E on extinction of pole-jumping avoidance behavior but one hundred times more potent on passive avoidance behavior. It is suggested that DE gamma E rather than DT gamma E represents the endogenous neuroleptic-like neuropeptide derived from beta-endorphin.

Topics: Animals; Avoidance Learning; Behavior, Animal; beta-Endorphin; Dose-Response Relationship, Drug; Endorphins; Male; Peptide Fragments; Rats; Rats, Inbred Strains

Topics: Animals; Antipsychotic Agents; Behavior, Animal; beta-Endorphin; Dopamine; Double-Blind Method; Endorphins; gamma-Endorphin; Humans; Peptide Fragments; Psychiatric Status Rating Scales; Psychotic Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Schizophrenia; Schizophrenic Psychology