Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 ß-Casein.

This is the first systematic review, to our knowledge, of published studies investigating the gastrointestinal effects of A1-type bovine ß-casein (A1) compared with A2-type bovine ß-casein (A2). The review is relevant to nutrition practice given the increasing availability and promotion in a range of countries of dairy products free of A1 for both infant and adult nutrition. In vitro and in vivo studies (all species) were included. In vivo studies were limited to oral consumption. Inclusion criteria encompassed all English-language primary research studies, but not reviews, involving milk, fresh-milk products, ß-casein, and ß-casomorphins published through 12 April 2017. Studies involving cheese and fermented milk products were excluded. Only studies with a specific gastrointestinal focus were included. However, inclusion was not delimited by specific gastrointestinal outcome nor by a specific mechanism. Inclusion criteria were satisfied by 39 studies. In vivo consumption of A1 relative to A2 delays intestinal transit in rodents via an opioid-mediated mechanism. Rodent models also link consumption of A1 to the initiation of inflammatory response markers plus enhanced Toll-like receptor expression relative to both A2 and nonmilk controls. Although most rodent responses are confirmed as opioid-mediated, there is evidence that dipeptidyl peptidase 4 stimulation in the jejunum of rodents is via a nonopioid mechanism. In humans, there is evidence from a limited number of studies that A1 consumption is also associated with delayed intestinal transit (1 clinical study) and looser stool consistency (2 clinical studies). In addition, digestive discomfort is correlated with inflammatory markers in humans for A1 but not A2. Further research is required in humans to investigate the digestive function effects of A1 relative to A2 in different populations and dietary settings.

Differential neurogenic effects of casein-derived opioid peptides on neuronal stem cells: implications for redox-based epigenetic changes.

Food-derived peptides, such as ß-casomorphin BCM7, have potential to cross the gastrointestinal tract and blood-brain barrier and are associated with neurological disorders and neurodevelopmental disorders. We previously established a novel mechanism through which BCM7 affects the antioxidant levels in neuronal cells leading to inflammatory consequences. In the current study, we elucidated the effects of casein-derived peptides on neuronal development by using the neurogenesis of neural stem cells (NSCs) as an experimental model. First, the transient changes in intracellular thiol metabolites during NSC differentiation (neurogenesis) were investigated. Next, the neurogenic effects of food-derived opioid peptides were measured, along with changes in intracellular thiol metabolites, redox status and global DNA methylation levels. We observed that the neurogenesis of NSCs was promoted by human BCM7 to a greater extent, followed by A2-derived BCM9 in contrast to bovine BCM7, which induced increased astrocyte formation. The effect was most apparent when human BCM7 was administered for 1day starting on 3days postplating, consistent with immunocytochemistry. Furthermore, neurogenic changes regulated by bovine BCM7 and morphine were associated with an increase in the glutathione/glutathione disulfide ratio and a decrease in the S-adenosylmethionine/S-adenosylhomocysteine ratio, indicative of changes in the redox and the methylation states. Finally, bovine BCM7 and morphine decreased DNA methylation in differentiating NSCs. In conclusion, these results suggest that food-derived opioid peptides and morphine regulated neurogenesis and differentiation of NSCs through changes in the redox state and epigenetic regulation.

Comparative evaluation of cow ß-casein variants (A1/A2) consumption on Th2-mediated inflammatory response in mouse gut.

PURPOSE: Recently, apprehension has been raised regarding "A1/A2 hypothesis" suggesting relationship between consumption of A1 "like" variants of cow ß-casein and various physiological disorders. The information available is based on either the human epidemiological data of milk consumption or in vitro trials on cell lines with ß-casomorphin peptides. The direct scientific evidence establishing the link between consumption of A1/A2 "like" milk and health is scanty. Thus, under present investigation, in vivo trials in mice were undertaken to study the effect of feeding three genetic variants (A1A1, A1A2 and A2A2) of cow ß-casein milk on gastrointestinal immune system as it is the first and foremost site of immunological interactions. METHODS: Animals were divided into four groups for feeding with basal diet (control) and ß-casein isolated from milk of genotyped (A1A1, A1A2 and A2A2) dairy animals, respectively. Gut immune response was analyzed by spectrophotometric assessment of MPO activity, quantitative sandwich ELISA of inflammatory cytokines (MCP-1 and IL-4), antibodies (total IgE, IgG, sIgA, IgG1 and IgG2a) and qRT-PCR of mRNA expression for toll-like receptors (TLR-2 and TLR-4). Histological enumeration of goblet cells, total leukocytes and IgA(+) cells was also carried out. RESULTS: It was observed that consumption of A1 "like" variants (A1A1 and A1A2) significantly increased (p < 0.01) the levels of MPO, MCP-1, IL-4, total IgE, IgG, IgG1, IgG2a and leukocyte infiltration in intestine. TLR-2 and TLR-4 mRNA expression was also up-regulated (p < 0.01) on administration of A1 "like" variants. However, no changes in sIgA, IgA(+) and goblet cell numbers were recorded on consumption of any of the ß-casein variants. CONCLUSION: It is reasonable to conclude that consumption of A1 "like" variants of ß-casein induced inflammatory response in gut by activating Th2 pathway as compared to A2A2 variants. The present study thus supports the purported deleterious impacts of consumption of A1 "like" variants of ß-casein and suggests possible aggravation of inflammatory response for etiology of various health disorders.

Side-effects of analgesic kyotorphin derivatives: advantages over clinical opioid drugs.

The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP-NH2) and ibuprofen-KTP-NH2 (IbKTP-NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP-NH2 and IbKTP-NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP-NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP-NH2-treatment. The side-effect profile of KTP-NH2 and IbKTP-NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP-NH2 and IbKTP-NH2 as advantageous alternatives over current opioids.

The A2 milk case: a critical review.

This review outlines a hypothesis that A1 one of the common variants of beta-casein, a major protein in cows milk could facilitate the immunological processes that lead to type I diabetes (DM-I). It was subsequently suggested that A1 beta-casein may also be a risk factor for coronary heart disease (CHD), based on between-country correlations of CHD mortality with estimated national consumption of A1 beta-casein in a selected number of developed countries. A company, A2 Corporation was set up in New Zealand in the late 1990s to test cows and market milk in several countries with only the A2 variant of beta-casein, which appeared not to have the disadvantages of A1 beta-casein. The second part of this review is a critique of the A1/A2 hypothesis. For both DM-I and CHD, the between-country correlation method is shown to be unreliable and negated by recalculation with more countries and by prospective studies in individuals. The animal experiments with diabetes-prone rodents that supported the hypothesis about diabetes were not confirmed by larger, better standardised multicentre experiments. The single animal experiment supporting an A1 beta-casein and CHD link was small, short, in an unsuitable animal model and had other design weaknesses. The A1/A2 milk hypothesis was ingenious. If the scientific evidence had worked out it would have required huge adjustments in the world's dairy industries. This review concludes, however, that there is no convincing or even probable evidence that the A1 beta-casein of cow milk has any adverse effect in humans. This review has been independent of examination of evidence related to A1 and A2 milk by the Australian and New Zealand food standard and food safety authorities, which have not published the evidence they have examined and the analysis of it. They stated in 2003 that no relationship has been established between A1 or A2 milk and diabetes, CHD or other diseases.

Comparative cardiopulmonary effects of intramuscularly administered etorphine and carfentanil in goats.

OBJECTIVE: To determine comparative cardiopulmonary effects of IM administered etorphine and carfentanil in goats. ANIMALS: Seven clinically normal adult female goats. DESIGN: Each goat received at least 9 drug treatments (etorphine HCl, 5 [twice], 10, 20, and 40 and carfentanil citrate, 5, 10, 20 and 40 micrograms/kg of body weight), with a minimal 2-day interval between trials. Although drug dosages were randomized, etorphine and carfentanil treatments were alternated. To assess for drug tolerance, the first and last treatments always were etorphine (5 micrograms/kg). PROCEDURE: All goats were instrumented for long-term cardiopulmonary variable data collection. RESULTS: Both drugs induced rapid catatonic immobilization, characterized by limb and neck hyperextension, with occasional vocalization and bruxation. Etorphine elicited transient violent struggling and vocalization immediately. Time to immobilization appeared dose-dependent, and was more rapid with carfentanil (< or = 5 minutes) than etorphine (5 to 10 minutes) at all dosages. Recovery to standing occurred earlier for etorphine (1 to 2 hours) than carfentanil (> 2 hours) at all dosages. Both drugs at all dosages significantly (P < or = 0.05) increased systemic and left ventricular (LV) end-diastolic pressures, LV peak negative dP/dt, total peripheral resistance (TPR), hemoglobin concentration, and left atrial (LA) and pulmonary O2 contents. They also significantly decreased heart and respiration rates, and TPR. A significant increase was observed at some dosages for LV stroke volume and index, LV peak positive dP/dt, mean pulmonary artery pressure, PaO2, pulmonary artery oxygen partial pressure, PaCO2, pulmonary mixed venous carbon dioxide partial pressure, LA hemoglobin saturation, LA transport index, and body temperature. Pulmonary and systemic mixed venous carbon dioxide and oxygen contents were significantly decreased at some dosages. CONCLUSIONS: Intramuscularly administered etorphine and carfentanil induce hypertension, bradycardia, and bradypnea in goats. The hypertension appears attributable to an increase in TPR. CLINICAL RELEVANCE: Although the cardiopulmonary effects of carfentanil occurred more rapidly, these effects were similar in magnitude for etorphine and carfentanil over the evaluated dosage range.

Los opioides endógenos en el proceso de habituación / Endogenous opioids in the habituation process

El fenómeno de habituación en el sistema nervioso central consiste en la disminución progresiva de la respuesta que se produce cuando un estímulo, en un princípio nuevo, se presenta repetidamente a intervalos fijos. Aunque la habituación está bien documentada a nivel fenomenológico, aún no están claros los mecanismos mediante los cuales se lleva a cabo en la médula espinal del mamífero. Se han propuesto tres hipótesis, por lo menos, para la explicación de este fenómeno: a) depresión sináptica, b) inhibición activa, c) desensibilización postsináptica. La primera propone la disminución progresiva de la salida de neurotransmisor de la neurona sensitiva presináptica, producida por estimulación repetida; la segunda propone una acción inhibitoria progresiva de interneuronas sobre motoneuromas efectoras; la tercera implica la falta de respuesta del elemento postsináptico, es decir, la desensibilización del receptor. El papel de los péptidos opioides en la modulación de la información sensorial nociceptiva y cutánea en la médula espinal del mamífero está amplamente documentado, con trabajos fisiológicos, farmacológicos y neuroanatómicos. Estos pépticos han sido recientemente postulados como los posibles mediadores en el mecanismo responsable de la habituación en la médula espinal

Role of epidural and intrathecal narcotics and peptides in the management of cancer pain.

The spinal administration of opioids may provide analgesia of long duration to patients with bilateral or midline lower abdominal or pelvic cancer pain. However, cross-tolerance to orally and parenterally administered narcotics and the rapid development of tolerance to spinal narcotics have limited their usefulness. Opioids have extensive distribution in the CSF and plasma when administered into the epidural or intrathecal space, and delivery of drug to brain stem sites may account for many of the toxic and therapeutic effects of spinal opioids. Further clinical and pharmacokinetic studies are required to provide the information regarding: the optimal opioids for use as spinal analgesics; equieffective dose ratios of spinal opioids in comparison to parenteral or oral opioids; strategies useful to forestall the development of tolerance of spinally administered opioids; the analgesic efficacy of this therapy in opioid-tolerant patients; and the role of spinally administered nonopioid analgesics in the management of cancer pain in the tolerant patient. These questions will need resolution before this therapy can be recommended for routine use in the management of cancer pain.

A comparative study on the antipsychotic properties of desenkephalin-gamma-endorphin and ceruletide in schizophrenic patients.

The neuropeptides desenkephalin-gamma-endorphin (DE gamma E) and ceruletide were administered intramuscularly to patients with schizophrenic psychoses following a double-blind placebo-controlled design, including a total of 44 subjects. Neuroleptic medication was continued during the experimental period, which was started with one placebo injection for all patients. One week later subjects received a single intramuscular injection with 3 mg DE gamma E, 40 micrograms ceruletide or placebo. After an interval of 10 days, the patients received six similar injections over a period of 2 weeks. Treatment with either peptides resulted in a decrease of psychotic symptomatology as compared to placebo treatment. The beneficial effect of the peptides lasted at least 2 weeks after the experimental treatment period. Of the 14 patients treated with placebo only, three showed a slight response. Of the 30 patients treated with the neuropeptides, eight did not respond (DE gamma E: 3; ceruletide: 5), eight had a slight response (DE gamma E: 6; ceruletide: 2) and 14 responded moderately or markedly (DE gamma E: 6; ceruletide: 8). No obvious difference between the effects of the two neuropeptides was found, besides a somewhat earlier onset of the effect of ceruletide. Patients presenting relatively less negative psychotic symptoms were particularly susceptible to treatment with either peptide. Apart from slight and short-lasting gastrointestinal complaints after the first injections with ceruletide in some patients, no side effects were observed.

Paradoxical excitement to sedative-hypnotics in mentally retarded clients.

The relationships among "paradoxical" excitement to sedative--hypnotic medication, self-injurious behavior, and perinatal trauma were evaluated. Mentally retarded patients were classified as either paradoxical or normal responders to sedative-hypnotics. Paradoxical responders to these medications have a lower MA, a history of perinatal trauma, self-injurious behavior (SIB), and aggressive behavior when compared to normal responders. These findings confirmed and extended previous reports that a type of SIB may be indexed by paradoxical response to sedative-hypnotics. Results also suggested that perinatal trauma may be of etiological importance in the development of SIB. Because perinatal trauma or fetal distress results in excessive levels of B-endorphin, in utero, an impaired endogenous opiate system may be a critical factor maintaining a syndrome of SIB. Thus, these data may indicate psychopharmacological markers of SIB that may have both treatment and etiological significance.

Intrathecal administration of beta-endorphin and dynorphin-(1-13) for the treatment of intractable pain.

Seven cases of chronic pain were treated by intrathecal administration of 30 micrograms of beta-endorphin and dynorphin-(1-13). Compared with saline, both peptides were able to suppress pain for periods up to 4.5 and 7 hours on the average, respectively. No significant side reactions were noticed during the entire investigation.

Behavioral change in a cancer patient following intrathecal beta-endorphin administration.

A patient with a disseminated malignancy received 3 mg of synthetic beta-endorphin administered intrathecally by lumbar puncture. A marked behavioral syndrome characterized by confusion, hypomanic/manic behavior, and psychosis followed drug administration and persisted for more than 2 days.

Effect of (Des-Tyr)-gamma-endorphin in schizophrenia.

Des-tyrosine-gamma-endorphin (DT gamma E), a derivative of gamma-endorphin, which has been reported to have some neuroleptic-like properties in man, was administered to eight hospitalized schizophrenic patients (six chronic, one subacute, one acute) in an open study. Following an initial drug-free period, patients were given DT gamma E for 12 days in doses ranging from 1 to 10 mg/day. Two of the patients were markedly improved after receiving DT gamma E. The improvement was sustained for 2 months in one subjects, while the other deteriorated to pretreatment status within 48 hours of the discontinuation of DT gamma E. Of the other six patients, one showed moderate improvement, three showed minimal improvement, and two showed no change. Improvement was mainly in the area of social functioning; change in positive psychotic symptoms was less noticeable. The positive results obtained in this study in some subjects could have been nonspecific effects, rather than pharmacological action, since social functioning, the main area of improvement, may be especially sensitive to expectancy effects in open trials. Nevertheless, further study of DT gamma E in acute schizophrenics for longer periods appears indicated.

Physical dependence on physiologically released endogenous opiates.

Mice which had been submitted to a chronic schedule of warm water swimming exhibited a naloxone precipitated withdrawal behaviour which was remarkably similar to that produced in mice following chronic morphine treatment. These results are consistent with the activation of endogenous opiates during swim stress in mice and present the possibility that opiate receptors are activated in a manner analogous to the repeated application of exogenous opiates, producing both tolerance and withdrawal-like behaviour.