893 Send Orders for Reprints to [email protected] Current Medicinal Chemistry, 2016, 23, 893-910 eISSN: 1875-533X ISSN: 0929-8673 Current Impact Factor: Food Proteins as Source of Opioid Peptides-A Review 3.85 Medicinal Chemistry The International Journal for Timely In-depth Reviews Swati Garg, Kulmira Nurgali and Vijay Kumar Mishra* in Medicinal Chemistry BENTHAM SCIENCE College of Health and Biomedicine, Victoria University, PO Box 14428, Melbourne, Victoria 8001, Australia Abstract: Traditional opioids, mainly alkaloids, have been used in the clinical management of pain for a number of years but are often associated with numerous side-effects including sedation, dizziness, physical dependence, tolerance, addiction, nausea, vomiting, constipa- tion and respiratory depression which prevent their effective use. Opioid peptides derived from food provide significant advantages as safe and natural alternative due to the possibility of their production using animal and plant proteins as well as comparatively less side-effects. This review aims to discuss the current literature on food-derived opioid peptides focusing on their produc- tion, methods of detection, isolation and purification. The need for screening more dietary proteins as a source of novel opioid peptides is emphasized in order to fully understand their potential in pain management either as a drug or as part of diet complementing therapeutic prescription. Keywords: Opioids, peptide, opioid-receptors, casomorphins, exorphin, fermentation. 1. INTRODUCTION dicinal effects are predominantly due to the presence of polyphenols, antioxidants, probiotics, tannins, polyun- Food provides energy and essential nutrients to the saturated fatty acids or bioactive peptides. body in the form of carbohydrates, proteins, fats, vita- mins and minerals which are necessary for proper Bioactive peptides are inactive within native pro- growth, development and functioning of the body. Im- teins but exert physiological functions upon release proper eating habits and lifestyle changes increase the from animal or plant proteins (dairy, cereals, vegeta- risk of a number of disorders, including obesity, heart bles, meat and their products) during gastrointestinal disease, hypertension, cancer, osteoporosis and arthri- (GI) digestion and/or after food processing. They may tis. Currently available clinical treatments are often exhibit opiate, anti-oxidant, anti-thrombotic, anti- associated with serious side-effects. Search for natural, hypertensive, anti-cancerous or immune-modulatory healthy and safe alternatives with minimum side- activity thus benefiting cardiovascular, nervous, diges- effects is required for beneficial effects to patients and tive and immune systems (Fig. 1) [3-8]. Hence, food improving quality of life. Nutraceuticals are promising can contribute to health, modulate immunity and pre- in this regard, as they are derived naturally from food, vent and help in clinical management of specific dis- hence are part of diet and should have minimal side- eases. It may be possible to use these peptides as part effects. The term “nutraceutical” is coined from the of complementary therapy along with other drugs. words "nutrition" and "pharmaceutical", and is defined Most commonly clinically used drugs for pain man- as "a food (or part of a food) that provides medical or agement are opioids such as morphine and codeine [9- health benefits, including the prevention and/or treat- 12]. However, they are often associated with side- ment of a disease [1]. “Let food be thy medicine and effects like sedation, dizziness, nausea, vomiting, con- medicine be thy food”, quoted by Hippocrates stipation, physical dependence, addiction, tolerance and 2,500 years ago is certainly the need of today [2]. respiratory depression [13, 14]. Food-derived opioid These foods have potential health benefits beyond ba- peptides possess weaker activity making them less sic nutrition and are called functional foods. These me- likely to cause side-effects and are relatively inexpen- sive to produce. Herein we summarize research on *Address correspondence to this author at the College of Health and Biomedicine, Victoria University, PO Box 14428, Melbourne, opioids, their receptors and classification with particu- Victoria 8001, Australia; Tel: +61 3 99198130; lar emphasis on food-derived opioid peptides, methods E-mail: [email protected] of production, detection, isolation and purification from 1875-533X/16 $58.00+.00 © 2016 Bentham Science Publishers Current Medicinal Chemistry Current 894 Current Medicinal Chemistry, 2016, Vol. 23, No. 9 Garg et al. anti-h ypertensive Milk and dairy products anti-oxidative Cardiovascular system anti-thrombotic Eggs hypocholesterolemic Nervous Meat and opioid system meat products Bioactive peptides cytomodulatory Immune system Cereals immunomodulatory anti-microbial Digestive Vegetables system mineral-binding anti-apetizing Fig. (1). Effects of food-derived bioactive peptides on various system. food, as well as their fate after digestion in order to and KOP receptors exert analgesic effects mainly in fully understand their potential use. peripheral tissues [9]. Activation of these receptors by opioid ligands leads to change in Ca++ and K+ channel 2. OPIOID RECEPTORS conductance and protein phosphorylation via inhibition Opioid receptors belong to the superfamily of G- of cyclic AMP (cAMP) [11]. cAMP acts as a second protein coupled receptors and are distributed within the messenger activating protein kinases and gene tran- central and peripheral nervous system [15, 16]. Interna- scription which can result in effects including analge- tional Union of Basic and Clinical Pharmacology Re- sia, respiratory depression, euphoria, release of hor- ceptor Nomenclature Committee (NC-IUPHAR) ap- mones, and reduction of GI transit [21]. proved nomenclature for opioid peptide receptors as μ 3. CLASSIFICATION OF OPIOID LIGANDS (mu or MOP), δ (delta or DOP) and κ (kappa or KOP) [15]. A fourth opioid peptide receptor is selectively Opioid ligand is any substance that binds specifi- activated by endogenous ligand, nociceptin and termed cally to opioid receptor to produce morphine like ef- as NOP (nociceptin opioid peptide) and it is not an- fects and the activity is reversed by non-specific an- tagonized by naloxone unlike the other three receptors tagonist, naloxone [12]. Opioids were initially re- [15]. All of these receptors have close structural ho- stricted to be alkaloids by nature (morphine, codeine mology and are members of one family of proteins [17- and thebaine), but now peptides having opioid activity 20], with differences between the receptor types arising (enkephalin, dynorphin, exogenous peptides) have also due to gene duplication events during evolution [15]. been identified (Fig. 2). The affinity for the specific receptors influences the differences in activity of opioids [11]. Activation of 3.1. Opioid Alkaloids MOP receptors mediates the most potent antinocicep- Naturally occurring opioids are obtained from tive effects, however, they are prone to induce depend- opium poppy plant, Papaver somniferum, and include ence; DOP receptors have lower efficacy in pain relief; morphine and structurally related alkaloids including Food Proteins as Source of Opioid Peptides-A Review Current Medicinal Chemistry, 2016, Vol. 23, No. 9 895 codeine, noscapine (narcotine), thebaine, and papaver- tanyl, meperidine, alfentanil, loperamide) and diphen- ine [12]. Out of them, morphine and codeine are most ylheptanes (propoxyphene, methadone) [11]. widely used opioid analgesics. Morphine is an agonist ligand primarily binding to µ receptors and has less 3.2. Opioid Peptides affinity for δ and κ receptors [9]. Codeine has weak Opioid peptides were first identified in 1975 when affinity for µ opioid receptors and its analgesic activity met-enkephalin and leu-enkephalin from brain were is attributed to its principal metabolite, morphine [22, found to have opioid activity [24]. Further investiga- 23]. Semisynthetic opioids are produced from naturally tions confirmed that endorphins, dynorphins and ex- occurring alkaloids and include heroin, hydromor- ogenous peptides from food have also opioid activity phone, oxymorphone, hydrocodone and oxycodone. which opened a new era in the history of opioid ligands Synthetic opioids are chemically synthesized in the [25-29]. Majority of peptide ligands are opioid agonists laboratory from compounds unrelated to natural alka- except casoxins and lactoferroxins which are opioid loids and include fentanyl, tramadol or methadone (Fig. antagonists [30, 31]. Opioid peptides can be classified 2) [12]. into endogenous or exogenous based on their origin as These opioid ligands have different affinity described below (Fig. 2). (strength of interaction) and efficacy (strength of activ- 3.2.1. Endogenous Opioid Peptides ity) against opioid receptors and are classified into agonist, partial agonist or antagonist based on their ac- Endogenous opioid peptides are produced naturally tion [16]. While an agonist has both affinity and effi- in the body and may function as hormones (secreted by cacy (morphine, hydromorphone and fentanyl); an an- gland and delivered to target tissues) or neuromodula- tagonist has affinity, but no efficacy (naloxone and tors (secreted by nerve cells and act in the central and naltrexone); and a partial agonist (agonist/antagonist) peripheral nervous system) [9, 32, 33]. These peptides has affinity, but only partial efficacy (buprenorphine,