A novel delta opioid receptor specific peptide reduces craving in an animal model of cocaine seeking
Pnina Shirel Itzhak-IsraeliHevroni YaelErez MatsreeHilla Pe’er-NissanShira Ofer LancmanRoyi BarneaGalia LuboshitsMenachem MotieiOshra BetzerIris GispanRachela PopovtzerYaakov AnkerFirer MAGal Yadid
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Abstract:
Substance use disorder, and particularly cocaine use disorder, is a complex disease that affects societal, economic, and psychological factors. Endogenous β-endorphin released after prolonged cocaine withdrawal has been reported to activate the accumbal delta-opioid receptor (DOR), leading to attenuated cocaine seeking. However, using DOR β-endorphin activation to treat cocaine use disorder is impractical since β-endorphin does not cross the blood-brain barrier. Also, only activation of the sub-group DOR1 efficiently attenuates craving, as activation of DOR2 yields an opposite effect. Here, we isolated a specific peptide, PEP1, from a phage display peptide library with similar biological properties to β–endorphin, demonstrating specificity for DOR1 and functioning as full receptor agonists. Our pharmacodynamic results showed fast trafficking incorporation of DOR into the cell membrane, interpreted as superior rehabilitation of the receptor and its bioavailability compared to commercial agonists. We administered PEP1, either intrabrain or intranasal, to rats trained to self-administer cocaine. PEP1 induced a significant decrease in cocaine-craving behavior and reinstatement in three different animal models of addiction. Also, PEP1 did not exhibit rewarding properties and did not interfere with the natural reward system. ICP-OES analysis revealed that at least one hour post-administration, PEP1 was retained in the brain rather than in peripheral organs. These findings render PEP1 a potential novel regulator of cocaine craving, especially for being non-addictive. Hence, PEP1 should be further examined as a possible new therapy for substance use disorder.Keywords:
δ-opioid receptor
δ-opioid receptor
Inverse agonist
B2 receptor
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Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
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The sections in this article are: 1 Opioid Peptides 1.1 Pro-opiomelanocortin 1.2 Proenkephalin A 1.3 Proenkephalin B 1.4 Morphine 2 Opioid Receptors 3 Opioid Peptide Processing Enzymes 4 Localization of Opioid Peptides and Receptors in Gut 4.1 Proenkephalin A 4.2 Proenkephalin B 4.3 Pro-opiomelanocortin 5 Mechanism of Opioid Action in Gut 6 Physiological Functions of Endogenous Opioid Peptides 6.1 Gastrointestinal Motility 6.1.1 Esophagus and Stomach 6.1.2 Small Bowel 6.1.3 Large Bowel 6.2 Antisecretory Actions of Opioid Peptides 6.3 Gallbladder and Bile Ducts 6.4 Opioid Effects on Pancreas
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Opioids are involved in the physiological control of numerous functions of the central nervous system, particularly nociception. It appears that some endogenous neuropeptides, called "anti-opioids", participate in an homeostatic system tending to reduce the effects of opioids. Neuropeptide FF (NPFF) and cholecystokinin (CCK) possess these properties and, paradoxically, the opioid peptides nociceptin and dynorphin display some anti-opioid activity. All these peptides exhibit complex properties as they are able to both counteract and potentiate opioid activity, acting rather as modulators of opioid functions. The purpose of this review is to highlight that two different mechanisms are clearly involved in the control of opioid functions by opioid-modulating peptides: a "circuitry-induced" mechanism for nociceptin and dynorphin, and a "cellular anti-opioid" mechanism for NPFF and CCK. The knowledge of these mechanisms has potential therapeutic interest in the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse. Keywords: opioids, neuropeptide ff, nociceptin/orphanin fq, cholecystokinin, morphine, pain, analgesia, tolerance
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Opioid receptors and opioid peptides constitute the endogenous opioid system. The most relevant function of the opioid system seems to be the inhibitory modulation of nociceptive information at supraspinal, spinal and peripheral sites, although it is also implicated in the modulation of many other processes in the body. Centrally acting plant opiates, such as morphine, are the most frequently used analgesics for the relief of severe pain, even though their undesired side-effects are serious limitation to their usefulness. Opioid peptides have the potential to be pharmaceutical agents for the treatment of pain, devoid of side-effects accompanying morphine. Unfortunately, peptides are generally hydrophilic compounds that will not enter the central nervous system via passive diffusion, due to the existence of the blood-brain barrier. Peptides are also easily degraded by proteolytic enzymes which further reduces their therapeutic value. Therefore, the design of peptide analogs based on the sequence of endogenous opioid peptides must be focused on increasing bioavailability and enhancing brain uptake.
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Three families of endogenous opioid peptides, each derived from distinct precursor, as well as their localization, affinity and interaction with different subtypes of opioid receptors are described. The release of opioid peptides upon various stimulation procedures is also presented. The emphasis is made on the role of opioid peptides in analgesia by describing their antinociceptive potency and discussing the role of peptides deriving from the different precursors in conveying the acute pain stimuli and on the changes in activity of opioid peptide systems in chronic pain.
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Opioid agonistic and antagonistic peptides which are inactive within the sequence of the precursor milk proteins can be released and thus activated by enzymatic proteolysis, for example during gastrointestinal digestion or during food processing. Activated opioid peptides are potential modulators of various regulatory processes in the body. Opioid peptides can interact with subepithelial opioid receptors or specific luminal binding sites in the intestinal tract. Furthermore, they may be absorbed and then reach endogenous opioid receptors.
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