Effect of beta-endorphin on gastric acid secretion and serum gastrin concentration in humans

The effect of synthetic human β-endorphin on gastric acid secretion was studied in 9 healthy subjects. Neither 2.5 mg or 15 mg β-endorphin had a significant effect on acid secretion or on serum gastrin concentration despite the fact that this dose of opiate caused a significant increase in serum prolactin concentrations. The role of endogenous opiate-like peptides on gastric secretion is discussed.     

Endogenous opiates: 1979

Since the discovery in 1971 of opiate receptors and later of the opiate-like peptides, there has been widespread interest in determining their exact localization, number and kinds, nature, and physiological and pharmacological functions. Between 1971 and 1978, vast amounts of research investigated these problem areas, but in 1979 alone the literature on the opiate peptides nearly doubled. This review is the second of an annual series and summarizes the highlights of the work published during 1979.     

Endogenous opiates: 1979

Since the discovery in 1971 of opiate receptors and later of the opiate-like peptides, there has been widespread interest in determining their exact localization, number and kinds, nature, and physiological and pharmacological functions. Between 1971 and 1978, vast amounts of research investigated these problem areas, but in 1979 alone the literature on the opiate peptides nearly doubled. This review is the second of an annual series and summarizes the highlights of the work published during 1979.     

Presence of corticotropin-like and opiate-like hormones in rat and bovine placental tissues

Acid acetone powder of rat placentas was fractionated on Sephadex G-25 into a void volume peak (R-1) and three retarded peaks (R-2, R-3 and R-4). R-3 contained opiate-like activity and R-4 corticotropin-like activity, suggesting that separate corticotropin-like and opiate-like activities with molecular weight smaller than 5000 were present in rat placentas. Acid acetone powder of bovine placentas contained opiate-like activity which was unretarded on Sephadex G-25. Acid acetone powder of rat brains but not those of lungs, livers or kidneys possessed opiate receptor binding and steroidogenic activities, indicating that the activities in placentas were not due to enzymatically generated artifacts or to peptides contained in blood trapped in the organs.     

Opioid peptides, particularly dynorphin, after amygdaloid-kindled seizures

The influence of amygdaloid kindling on brain and pituitary content of immunoreactive dynorphin (IR-DYN) and other opioid peptides was studied in rabbits. The kindling was very effective in increasing the hippocampal levels of IR-DYN, alpha-neoendorphin and Leu-enkephalin, but remained without any significant effect on the levels of IR-DYN and beta-endorphin in the majority of brain structures studied. The concentration of IR-DYN in the hippocampus remained at the control level throughout the development but was increased dramatically after completion of kindling. Biochemical alterations persisted for at least one month following the completion of kindling. The obtained results suggest that the hippocampal IR-DYN and related peptides may play some role in the maintenance of amygdaloid-kindled seizures.     

Opiate-like peptides with primary structure different from that of enkephalins

Some new opiate-like peptides originating from opioid peptide precursors, dinorphine, histone H2b, major myeline protein, natriuretic atriopeptide and from the immunomodulating protein splenin whose primary structure differs essentially from that of enkephalins are described. Being intracysternally injected to mice, all the peptides under study caused a naloxone-sensitive analgetic effect as could be judged from the tail pinch tests. The effects of some opiate-like peptides were much stronger than that of leu-enkephalin. According to their primary structure, the opiate-like peptides can randomly be allocated into two families. Dipeptide Lys-Arg and free arginine also possess a marked analgetic activity which is abolished by naloxone. It seems likely that the epiate-like activity of the peptides under study is due to the similarity of their secondary and ternary structure to that of enkephalins of to their involvement in the regulation of opioid peptide metabolism.     

Failure of beta-endorphin antiserum, naloxone, and naltrexone to alter physiologic growth hormone and insulin secretion.

The role of endogenous opiate-like peptides in physiologic regulation of growth hormone (GH) and insulin (IRI) secretion was assessed by passive immunization with β-endorphin antiserum and by administration of the opiate antagonists naloxone and naltrexone. Six-hour secretory profiles were obtained from 5 groups of freely-moving chronically cannulated male rats following the i.v. administration of (I) β-endorphin antiserum, (II) normal rabbit serum, (III) naloxone (1 mg/kg), (IV) naltrexone (1 mg/kg), and (V) normal saline. The typical ultradian rhythm of GH secretion was evident in all groups with most peak GH values >400 ng/ml. No disruption in amplitude of periodicity of the GH rhythm was observed and there was no significant difference in mean 6-hr plasma GH levels. Plasma IRI levels fluctuated minimally over the 6-hr sampling period. There was no significant difference in mean 6-hr IRI levels between groups I and II, or between groups III, IV and V. These data do not support the view that endogenous opiate-like peptides play a physiologically important role in maintaining basal GH and IRI secretion.     

Potent tetrapeptide enkephalins

Small peptides with opiate-like activity have generally had structures closely resembling that of the opioid pentapeptide enkephalin: Tyr-Gly-Gly-Phe-Met-COOH. Single deletions of any one of the amino acids has been demonstrated to reduce opiate activity drastically. In this work we show that the potency losses resulting from the removal of glycine³ can be fully attenuated by substitution of D-alanine in position two and derivatization of the acid to the amide. This tetrapeptide (Tyr-DAla-Phe-Met-NH₂) has narcotic activity similar to the parent pentapeptide in the guinea pig ileum and mouse tail-flick tests. This enhanced potency, relative to the unaltered tetrapeptide, is theorized to arise from increased resistance to enzymatic destruction. the data presented show that a five amino acid sequence is not mandatory for the expression of opiate activity in enkephalin analogs.     

Role of neuropeptides in the mechanisms of chronic epileptization of the brain

We describe experimental studies of the anticonvulsive effects of neuropeptides from the kyotorphin family (kyotorphin, neokyotorphin, and 2-ser-neokyotorphin) and galanin tested in a model of picrotoxin-induced kindling in rats. Intraventricular injections of the above neuropeptides demonstrated their clear anticonvulsive efficacy: the latency of the first convulsive reactions increased, and the intensity of seizures decreased. A protective efficacy of these peptides observed under conditions of the kindling model (which is the most steady with respect to the effects of antiepileptic drugs, and whose phenomenology is the closest to clinical manifestations of epilepsy) allows us to believe that further studies of anticonvulsive action of the peptides is expedient.     

An inhibitor of opiate receptor binding from human erythrocytes identified as a glutathione-copper complex.

A “peptide-like” inhibitor of opiate receptor binding and of N-methyltransferase previously purified by us from rabbit brain was also found in human red blood cells. Boiled extracts of erythrocytes were fractionated on Sephadex followed by chromatography of the active fractions on silica gel layers. Both, a migrating ninhydrin-positive spot and a naturally blue substance which did not migrate from the origin coincided with the active fractions. The blue substance was identified as copper and the ninhydrin-positive material was identified as oxidized glutathione. While glutathione $\text{per se}$ has no effect, copper and other transition metals are potent inhibitors of opiate receptor binding. A mixture of glutathione and copper plus serum albumin in proportions simulating erythrocyte extracts gave results identical to the latter. Several other laboratories have extracted, from various tissues and body fluids, “opiate-like peptides” which are distinct from the β-LPH derived endorphins. In view of our findings it is possible that metal bound to glutathione or to other peptide ligand may be a complicating factor in some of these studies.     

GABA in morphine analgesia and tolerance

Drugs affecting various steps of GABA transmission exhibit analgesia in a variety of experimental models in animals; this analgesic response generally requires high doses of the drugs and does not appear to be opiate-like since the GABAergic analgesia is naloxone-insensitive and lacks dependence liability. The outcome of the analgesia response is variable when opiate and GABAergic drugs are administered together; however, directly acting GABA receptor stimulants and GABA-transaminase inhibitors generally enhance the analgesic effect of opiates. The development of newer GABAergic drugs with greater potency and specificity may offer an alternative to opiate analgesics. The results obtained over the years, on the possible involvement of the GABA system in morphine tolerance and dependence are equivocal. Studies on region-specific changes in opiate-GABA interaction as well as opiate-GABA-benzodiazepine interaction are needed to further elucidate the role of GABA on opiate system.     

Endogenous opiates: 1985

This paper is the eighth installment of our annual review of research involving the endogenous opiate peptides. It is restricted to the non-analgesic and behavioral studies of the opiate peptides published in 1985. The specific topics this year include stress, tolerance and dependence, eating, drinking and alcohol consumption, gastrointestinal and renal activity, mental illness, learning and memory, cardiovascular responses, respiration and thermoregulation, seizures and neurological disorders, activity, and some other selected topics.     

Materials with opiate receptor binding activity in bovine testis and ovine pancreas

Two groups of opiate-like materials, one with a molecular weight equal to or greater than 5000 daltons and another with a molecular weight smaller than 5000 daltons as judged by gel filtration on Sephadex G-25, were detected in bovine testes. The existence of opiate-like materials with a molecular weight smaller than 5000 daltons was demonstrated in ovine pancreas. The pancreatic fraction most strongly adsorbed on CM-cellulose possessed the highest opiate receptor binding activity. Bovine testis contained corticotropin-like material(s) which stimulated corticosterone production by isolated rat adrenal cells.     

Endogenous opiates: 1986

This is the ninth installment of our annual review of research involving the endogenous opiate peptides. It is restricted to the non-analgesic and behavioral studies of the opiate peptides published in 1986. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic processes; mental illness; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; activity; sex, pregnancy, and development; and some other behaviors.     

Hormones with adrenocorticotropic and opiate-like activities from the carp (Cyprinus carpio) pituitary

Carp (Cyprinus carpio) pituitary acetone powder was extracted with a mixture of water, hydrochloric acid and acetone. An acid acetone powder was formed by adding the pituitary extract into a large volume of chilled acetone and subsequently recovering the precipitate. The powder was subjected to ion exchange chromatography on CM cellulose. Fractions adsorbed on the ion exchanger exhibited ACTH-like activity as evidenced in the ability to stimulate lipolysis in isolated hamster adipocytes and corticosterone production in isolated rat adrenal decapsular cells and also in cross-reactivity in an ACTH-specific radioimmunoassay. A portion of the ACTH-like bioactivity and immunoactivity was unadsorbed on the ion exchanger. Opiate-like activity in opiate receptor binding assay, employing [3H]D-ala2-D-leu5 enkephalin or [3H]naloxone as ligand, also resided in fractions adsorbed on CM cellulose. The data indicate a separation of ACTH-like and opiate-like activities, and the presence of opiate-like molecules with different affinities of binding to mu and delta opiate receptors.     

Endogenous opiates: 1984

This paper is the seventh in an annual series of reviews of research involving the endogenous opiate peptides, each installment being restricted to work published during the previous year. As in the past three years, the review this year is limited to non-analgesic and behavioral studies of the opiate peptides. The specific topics this year include: stress, tolerance and dependence, consummatory responses, gastric and renal activity, alcohol, mental illness, learning and memory, cardiovascular responses, respiratory effects, thermoregulation, seizures and neurological disorders, activity, and miscellaneous other topics.     

Effects of neurotropin on seizure activity in picrotoxin kindling]

It is shown that both intracerebral and intraperitoneal neurotropin administration resulted in a decrease of seizure susceptibility of preliminary picrotoxin--kindled rats. On the other hand, neurotropin did not change the course of kindling development. Under conditions of acute picrotoxin--induced seizures it was observed that preliminary cycloheximide (protein-synthesis blocker) administration abolished anticonvulsant properties of neurotropin. It is concluded that anticonvulsant effects of neurotropin are realized via modulation of endogenous peptides synthesis and, in particular, cerulein.     

Accumulation of 7S SNARE complexes in hippocampal synaptosomes from chronically kindled rats

Kindling is a model of complex partial epilepsy wherein periodic application of an initially subconvulsive stimulus leads to first limbic and then generalized tonic-clonic seizures. Several laboratories have reported that augmented neurotransmitter release of l-glutamate is associated with the chronically kindled state. Neurotransmitter release requires membrane proteins called SNAREs, which form transmembrane complexes that participate in vesicle docking and are required for membrane fusion. We show here that kindling by entorhinal stimulation is associated with an accumulation of 7S SNARE complexes in the ipsilateral hippocampus. This increase of 7S SNARE complexes appears to begin early in the kindling process, achieves a peak with full kindling, and remains at this level for at least a month following cessation of further kindling stimuli. The increase is focal and permanently limited to the ipsilateral hippocampus despite progression to generalized electrographic and behavioral seizures. It is not seen in animals that receive electroconvulsive seizures, suggesting it is related to the kindling process itself. The duration and focality of increased 7S SNARE complexes with entorhinal kindling suggest that this is an altered molecular process associated with epileptogenesis.     

Effect of shitei-to, a traditional Chinese medicine formulation, on pentylenetetrazol-induced kindling in mice.

This study measured the effects of Shitei-To (STT), a traditional Chinese Medicine, which is a mixture of extracts from three medicinal herbs, Shitei (SI, Kaki Calyx; calyx of Diospyros kaki L. f.), Shokyo (SK, Zingiberis Rhizoma; rhizome of Zingiber officinale Roscoe) and Choji (CJ, Caryophylli flos; flowerbud of Syzygium aromaticum [L.] Merrill et. Perry), has long been used for the treatment of hiccups in Japan and China, against fully pentylenetetrazol-kindled seizures and on the development of pentylenetetrazol kindling in mice. Repeated administration of STT (3.0 g/kg p.o.) mildly retards the development of pentylenetetrazol-induced kindling in mice. STT also decreased the number of tonic-clonic convulsions resulting from progression kindling. On the other hand, STT had no effect on convulsions in fully pentylenetetrazol-kindled mice. These findings suggest that STT protects against the development of convulsions, and that STT may have therapeutic effects in the prevention of secondarily generalized seizures.     

Endogenous opiates: 1988

This paper is the eleventh installment in our annual review of the research during the past year involving the endogenous opiate system. It is concerned with nonanalgesic and behavioral studies of the opiate peptides that were published during 1988. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic functions; mental illness; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical activity; locomotor activity; sex, pregnancy, and development; immunology and cancer; and other behavior.