Behavioral effects of food-derived opioid-like peptides in rodents: Implications for schizophrenia?

Lister J, Fletcher PJ, Nobrega JN, Remington G. (2015) Pharmacol Biochem Behav. 2015 Jul 134 70-78 doi: 10.1016/j.pbb.2015.01.020. Epub 2015 Feb 7.

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Abstract:

Dohan proposed that an overload of dietary peptides, such as those derived from wheat gluten and milk casein, could be a factor relevant to the development or maintenance of schizophrenia (SZ) symptoms in at least a subset of vulnerable individuals.

Rodent behavioral models may offer insight into the plausibility of Dohan's exorphin hypothesis by providing a means to directly study the effects of such peptides. Accordingly, a review of the literature on the behavioral effects of food-derived opioid-like peptides in rodents was undertaken. Studies using a variety of behavioral tests to examine the effects of several classes of food-derived opioid-like peptides were identified and reviewed.

Peptides derived from casein (β-casomorphins; BCMs, n=19), spinach (rubiscolins; RCs, n=4), and soy (soymorphins; SMs, n=1) were behaviorally active in various paradigms assessing nociception, spontaneous behavior, and memory. Surprisingly, only a single study evaluating a gluten-derived peptide (gliadorphin-7; GD-7, n=1) was identified and included in this review. In conclusion, food-derived peptides can affect rodent behavior, but more studies of GDs using diverse behavioral batteries are warranted. Assuming they occur in sufficient quantities during protein digestion and can access central opioid receptors (which entails crossing both the gastrointestinal and blood-brain barriers intact), these peptides may affect human behavior. Although BCMs and GDs may not be directly pathogenic in SZ, documented associations of casein and gluten sensitivity with SZ justify increased patient screening and dietary intervention where necessary.

FAB RESEARCH COMMENT:

This review examines the evidence from animal models that some symptoms of schizophrenia and related conditions (including autism, ADHD) may reflect a sensitivity to opioid peptides derived from the normal digestion of either gluten or A1 beta-casein (the form of casein found in standard cows' milk, but not other mammal milks).

These opioid peptides (gliadomorphin, and beta-casomorphin-7, or BCM-7) activate the same opioid receptors as morphine. However, they would only be expected to produce behavioural effects if both the gut lining and the blood-brain barrier are unusually permeable.

So-called 'Opioid theories' of both autism and schizophrenia have led to the proposal that gluten-free and casein-free diets may help to alleviate symptoms. Case studies and clinical reports have provided some evidence that such diets might be of benefit in some individual cases, but further research is still needed.

Psychiatric diagnoses like schizophrenia and autism are purely descriptive, and conceal huge individual variability in both symptoms and probable causes. It therefore seems a priori unlikely that this kind of dietary intervention would help more than a subset of patients.

However, given the severity of these conditions and the relative safety of dietary approaches, clinicians would do well to explore the possibiliy that unusual reactivity to gluten and/or casein might contribute to symptoms of schizophrenia, autism or related conditions.

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