ABSTRACT
Opioid use disorders have become an epidemic in recent years with rates nearly quadrupling since 1999 according to the US Centers for Disease Control and Prevention (Centers for Disease Control, Wide-ranging online data for epidemiologic research (WONDER). CDC, National Center for Health Statistics, Atlanta. Retrieved December 19, 2017, from http://wonder.cdc.gov, 2016). To understand substance use disorder (SUD) as a disease, many aspects must be studied including the circuitry in the brain, adaptations to neuronal circuitry and neurotransmitters, genetic variations increasing the risk for SUD, and treatments available for SUD. The mechanism in which an exogenous opioid may cause SUD is nearly identical to the mechanism of an endogenous opioid. This chapter reviews the clinical and epidemiological aspects of opioid use disorder, as well as the interactions between endogenous and exogenous opioids. Additionally, this chapter discusses current scientific data regarding genetic variations and mechanisms within brain circuitry and the role of endogenous opioids in substance use disorders generally (and opioid use disorder specifically). Future applications of these data to treatment of substance use disorders are also discussed.
Subject(s)
Analgesics, Opioid , Opioid-Related Disorders , Humans , Opioid-Related Disorders/epidemiology , Opioid-Related Disorders/metabolism , Analgesics, Opioid/therapeutic use , Brain/metabolism , Brain/drug effects , Substance-Related Disorders/epidemiology , Substance-Related Disorders/metabolism , Opioid Peptides/metabolismABSTRACT
This second chapter in our trilogy reviews and critically appraises the scientific evidence for the role of endogenous opioid system (EOS) activity in the onset and progression of both obesity and eating disorders. Defining features of normative eating and maladaptive eating behaviors are discussed as a foundation. We review the scientific literature pertaining to the predisposing risk factors and pathophysiology for obesity and eating disorders. Research targeting the association between obesity, disordered eating, and psychiatric comorbidities is reviewed. We conclude by discussing the involvement of endogenous opioids in neurobiological and behavior traits, and the clinical evidence for the role of the EOS in obesity and eating disorders.
Subject(s)
Feeding and Eating Disorders , Obesity , Opioid Peptides , Humans , Obesity/metabolism , Obesity/physiopathology , Feeding and Eating Disorders/metabolism , Feeding and Eating Disorders/physiopathology , Opioid Peptides/metabolism , Feeding Behavior/physiologyABSTRACT
Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.
Subject(s)
Olfactory Tubercle , Opioid Peptides , Quality of Life , Smell , Humans , Animals , Smell/physiology , Opioid Peptides/metabolism , Opioid Peptides/physiology , Olfactory Tubercle/physiology , Olfactory Tubercle/metabolism , Olfaction Disorders/physiopathology , Olfaction Disorders/metabolismABSTRACT
The function of endogenous opioids spans from initiating behaviors that are critical for survival, to responding to rapidly changing environmental conditions. A network of interconnected systems throughout the body characterizes the endogenous opioid system (EOS). EOS receptors for beta-endorphin, enkephalin, dynorphin, and endomorphin underpin the diverse functions of the EOS across biological systems. This chapter presents a succinct yet comprehensive summary of the structure of the EOS, EOS receptors, and their relationship to other biological systems.
Subject(s)
Analgesics, Opioid , Receptors, Opioid , Animals , Humans , Analgesics, Opioid/metabolism , beta-Endorphin/metabolism , Dynorphins/metabolism , Enkephalins/metabolism , Opioid Peptides/metabolism , Receptors, Opioid/metabolismABSTRACT
The endogenous opioid system, which consists of opioid receptors and their ligands, is widely expressed in the nervous system and also found in the immune system. As a part of the body's defense machinery, the immune system is heavily regulated by endogenous opioid peptides. Many types of immune cells, including macrophages, dendritic cells, neutrophils, and lymphocytes are influenced by endogenous opioids, which affect cell activation, differentiation, proliferation, apoptosis, phagocytosis, and cytokine production. Additionally, immune cells also synthesize and secrete endogenous opioid peptides and participate peripheral analgesia. This chapter is structured into two sections. Part one focuses on immunoregulatory functions of central endogenous opioids; and part two describes how opioid peptide-containing immune cells participate in local analgesia.
Subject(s)
Immune System , Opioid Peptides , Receptors, Opioid , Animals , Humans , Immune System/metabolism , Immune System/immunology , Opioid Peptides/metabolism , Receptors, Opioid/metabolism , Receptors, Opioid/immunologyABSTRACT
It has become apparent that endogenous opioids act not only as neurotransmitters and neuromodulators, but have multiple functions in the body. Activation of the opioid system by opiate drugs is associated with a risk of cancer development through direct stimulation of tumor cell proliferation and through immunosuppression. In contrast, the endogenous peptide opioid [Met5]-enkephalin, now commonly referred to as Opioid Growth Factor (OGF), negatively regulates cell proliferation in a wide number of cells during development, homeostasis, and neoplasia. This action is mediated through the opioid growth factor receptor, originally designated the zeta (ζ) opioid receptor. Further, contrary to the traditional notion of opiates as immunosuppressive, endogenous OGF has been shown to possess a number of positive immunomodulatory properties and may provide a beneficial effect in cancer by augmenting the activity of cells involved in both innate and acquired immunity. Taken together, the evidence supports consideration of opioid peptides such as OGF as new strategies for cancer therapy.
Subject(s)
Neoplasms , Receptors, Opioid , Animals , Humans , Cell Proliferation/drug effects , Enkephalin, Methionine/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Opioid Peptides/metabolism , Receptors, Opioid/metabolismABSTRACT
Pain, fear, stress, and anxiety are separate yet interrelated phenomena. Each of these concepts has an extensive individual body of research, with some more recent work focusing on points of conceptual overlap. The role of the endogenous opioid system in each of these phenomena is only beginning to be examined and understood. Research examining the ways in which endogenous opioids (e.g., beta-endorphin; ßE) may mediate the relations among pain, fear, stress, and anxiety is even more nascent. This chapter explores the extant evidence for endogenous opioid activity as an underpinning mechanism of these related constructs, with an emphasis on research examining ßE.
Subject(s)
Anxiety , Fear , Pain , Stress, Psychological , Animals , Humans , Anxiety/metabolism , beta-Endorphin/metabolism , Fear/physiology , Opioid Peptides/metabolism , Pain/psychology , Pain/metabolism , Stress, Psychological/metabolismABSTRACT
This chapter will focus on the role exercise appears to have on activation and modulating factors within the central nervous system related to endogenous like opioids and its possible contribution to exercise-induced hypoalgesia. The implications for the exercise-mediated alterations of CNS activation factors related to opioids, specifically endorphins and enkephalins, will be presented. In this update, we discuss utilization of new technology and methods to monitor mechanisms of opioid involvement to suggest their contribution with exercise mediated hypoalgesia as well as their relationships to alterations of perceptions of pain and mood. Several special populations were included to suggest that not all individuals will respond to the exercise by mediating hypoalgesia. Factors that may confound the current understanding and suggestions from the recent literature will be presented as well as suggestions for future investigations.
Subject(s)
Exercise , Animals , Humans , Analgesics, Opioid/metabolism , Endorphins/metabolism , Enkephalins/metabolism , Exercise/physiology , Opioid Peptides/metabolism , Pain/metabolism , Pain Perception/physiologyABSTRACT
Pleasant emotions take a variety of forms and are a key part of the human experience. Although negative emotions have often been a focus of research, positive emotions, e.g., joy, pleasure, and love, have recently gained more attention. Each of these emotions is rich and complex in its own right. However, positive emotions appear to serve key evolutionary functions, which are mediated by complex biological substrates. This chapter summarizes key research and explores the biological underpinnings of positive emotions, with an emphasis on the roles that endogenous opioids play in the experience, expression, and development of positive emotions. The necessity of emphasizing positive emotions in research is also discussed.
Subject(s)
Emotions , Opioid Peptides , Animals , Humans , Brain/metabolism , Emotions/physiology , Opioid Peptides/metabolism , Pleasure/physiology , Receptors, Opioid/metabolismABSTRACT
The human tendency to help others in need has been subject to trans-, inter-, and multidisciplinary studies (e.g., anthropology, neurobiology, evolutionary psychology, economy), within the frame of studying the mechanisms and adaptive significance of human prosocial behavior. Volunteering directed to unrelated and unfamiliar individuals is one common form of such helping behavior. Helping others may be adaptive for a species at a macro-level, which in turn is mediated by neurobiological mechanisms. A key target for analysis of the neurobiological underpinnings of volunteering is the endogenous opioid system (EOS). This chapter discusses EOS activity as a potential mediator of volunteering behavior. Evidence of the congruence between EOS involvement in social group behavior and social bonding and the role of these phenomena in volunteerism is reviewed. Models and empirical evidence of the mechanisms and adaptive value of helping unrelated others are discussed and integrated, including the mammalian caregiving system, the neurobiological model of prosocial behavior, synchrony promoting social bonding, and stress-driven motivation of prosocial action in immediate needs.
Subject(s)
Biological Evolution , Helping Behavior , Volunteers , Animals , Humans , Altruism , Opioid Peptides/metabolism , Social Behavior , Volunteers/psychologyABSTRACT
This chapter (part one of a trilogy) summarizes the neurobiological foundations of endogenous opioids in the regulation of energy balance and eating behavior, dysregulation of which translates to maladaptive dietary responses in individuals with obesity and eating disorders, including anorexia, bulimia, and binge eating disorder. Knowledge of these neurobiological foundations is vital to researchers' and clinicians' understanding of pathophysiology as well as the science-based development of multidisciplinary diagnoses and treatments for obesity and eating disorders. We highlight mechanisms of endogenous opioids in both homeostatic and hedonic feeding behavior, review research on the dysregulation of food reward that plays a role in a wide array of obesity and disordered eating, and the clinical implications of neurobiological responses to food for current science-based treatments for obesity and eating disorders.
Subject(s)
Feeding Behavior , Homeostasis , Hunger , Obesity , Opioid Peptides , Humans , Homeostasis/physiology , Hunger/physiology , Opioid Peptides/metabolism , Obesity/metabolism , Obesity/physiopathology , Feeding Behavior/physiology , Feeding and Eating Disorders/metabolism , Feeding and Eating Disorders/physiopathology , Satiation/physiology , Reward , Energy Metabolism/physiology , Eating/physiology , AnimalsABSTRACT
This third and final chapter in our trilogy introduces the clinical distinctions and phenotypical similarities between obesity and eating disorders. Research elaborating on the shared neurobiological substrates for obesity and eating disorders is discussed. We present an interprofessional model of treatment for both disordered eating and for obesity. Additionally, this chapter establishes the translational importance of research connecting endogenous opioid activity with both obesity and eating disorders, with an emphasis on clinical interventions. We conclude with a discussion of future directions for research.
Subject(s)
Feeding and Eating Disorders , Obesity , Humans , Feeding and Eating Disorders/metabolism , Feeding and Eating Disorders/therapy , Obesity/metabolism , Obesity/diagnosis , Obesity/therapy , Opioid Peptides/metabolismABSTRACT
Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.
Subject(s)
Nocebo Effect , Pain , Placebo Effect , Humans , Analgesics, Opioid , Antidepressive Agents/therapeutic use , Athletic Performance/physiology , Opioid Peptides/metabolism , Pain/drug therapy , Pain/metabolism , Pain/psychologyABSTRACT
The opioid system involves opioid receptors (OPRs) and endogenous opioid peptides.This chapter will focus on the distribution of OPRs in the cardiovascular system, the expression pattern in the heart, the activation by opioid peptides, and the effects of OPRs activation with potential relevance in cardiovascular performance. In the heart, OPRs are co-expressed with beta adrenergic receptors (ß-ARs) in the G-protein-coupled receptor (GPCR) superfamily, functionally cross-talk with ß-Ars and modify catecholamine-induced effects. They are involved in cardiac contractility, energy metabolism, myocyte survival or death, vascular resistance. The effects of the opioid system in the regulation of systemic circulation at both the central and peripheral level are presented. The pathways are discussed under physiological (i.e., aging) and pathological conditions (atherosclerosis, heart failure, essential hypertension, ischemic stress). Stimulation of OPRs not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury. An enhanced sensitivity to opioids of endocrine organs and neuronal systems is operative in hypertensive patients. The opioid system can be pharmacologically engaged to selectively mimic these responses via cardiac and nervous signaling. The clinical opportunities for the use of cardioprotective effects of opioids require future investigations to provide more specific details of the impact on cardiac performance and electrophysiological properties.
Subject(s)
Receptors, Opioid , Animals , Humans , Analgesics, Opioid/metabolism , Cardiotonic Agents/pharmacology , Heart/drug effects , Opioid Peptides/metabolism , Receptors, Opioid/metabolismABSTRACT
Endogenous opioids and their associated receptors form a system that maintains survival by positively reinforcing behaviors that are vital to life. Cancer and cancer treatment side effects capitalize on this system pathogenically, leading to maladaptive biological responses (e.g., inflammation), as well as cognitive and emotional consequences, most notably depression. Psychologists who treat people with cancer frequently find depression to be a primary target for intervention. However, in people with cancer, the etiology of depression is unique and complex. This complexity necessitates that psycho-oncologists have a fundamental working knowledge of the biological substrates that underlie depression/cancer comorbidity. Building on other chapters in this volume pertaining to cancer and endogenous opioids, this chapter focuses on the clinical applications of basic scientific findings.
Subject(s)
Depression , Inflammation , Neoplasms , Opioid Peptides , Humans , Analgesics, Opioid/therapeutic use , Depression/metabolism , Depression/drug therapy , Inflammation/metabolism , Neoplasms/metabolism , Neoplasms/drug therapy , Opioid Peptides/metabolismABSTRACT
This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Subject(s)
Opioid Peptides , Receptors, Opioid , Humans , Opioid Peptides/metabolism , Animals , Receptors, Opioid/metabolism , Pain/drug therapy , Pain/metabolism , Analgesics, Opioid/pharmacology , Behavior/drug effectsABSTRACT
Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release. We characterized the affinity, pharmacological profile, spectral properties, kinetics, ligand selectivity, and potential interaction with intracellular signal transducers of NOPLight in vitro. Its functionality was established in acute brain slices by exogeneous N/OFQ application and chemogenetic induction of endogenous N/OFQ release from PNOC neurons. In vivo studies with fibre photometry enabled direct recording of NOPLight binding to exogenous N/OFQ receptor ligands, as well as detection of endogenous N/OFQ release within the paranigral ventral tegmental area (pnVTA) during natural behaviors and chemogenetic activation of PNOC neurons. In summary, we show here that NOPLight can be used to detect N/OFQ opioid peptide signal dynamics in tissue and freely behaving animals.
Subject(s)
Neurons , Nociceptin , Opioid Peptides , Receptors, Opioid , Animals , Opioid Peptides/metabolism , Receptors, Opioid/metabolism , Receptors, Opioid/genetics , Neurons/metabolism , Humans , Mice , Male , Ventral Tegmental Area/metabolism , Nociceptin Receptor , HEK293 Cells , Brain/metabolism , Mice, Inbred C57BL , Ligands , Biosensing Techniques/methodsABSTRACT
Bovine milk is an essential supplement due to its rich energy- and nutrient-rich qualities. Caseins constitute the vast majority of the proteins in milk. Among these, ß-casein comprises around 37% of all caseins, and it is an important type of casein with several different variants. The A1 and A2 variants of ß-casein are the most researched genotypes due to the changes in their composition. It is accepted that the A2 variant is ancestral, while a point mutation in the 67th amino acid created the A1 variant. The digestion derived of both A1 and A2 milk is BCM-7. Digestion of A2 milk in the human intestine also forms BCM-9 peptide molecule. The opioid-like characteristics of BCM-7 are highlighted for their potential triggering effect on several diseases. Most research has been focused on gastrointestinal-related diseases; however other metabolic and nervous system-based diseases are also potentially triggered. By manipulating the mechanisms of these diseases, BCM-7 can induce certain situations, such as conformational changes, reduction in protein activity, and the creation of undesired activity in the biological system. Furthermore, the genotype of casein can also play a role in bone health, such as altering fracture rates, and calcium contents can change the characteristics of dietary products. The context between opioid molecules and BCM-7 points to a potential triggering mechanism for the central nervous system and other metabolic diseases discussed.
Subject(s)
Caseins , Endorphins , Humans , Animals , Caseins/chemistry , Caseins/metabolism , Caseins/genetics , Endorphins/chemistry , Endorphins/metabolism , Milk/chemistry , Milk/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Peptide Fragments/genetics , Opioid Peptides/chemistry , Opioid Peptides/metabolism , CattleABSTRACT
The nucleus accumbens (NAc) is a critical region for regulating the appetitive and consummatory aspects of motivated behavior. Previous work has shown differential effects of NAc µ-, δ-, and κ- receptor stimulation on food intake and for shifting motivation within an effort-based choice (EBC) task. However, the motivational role of the nociceptin opioid peptide (NOP) receptor, a fourth member of the opioid receptor family, is less well understood. These experiments therefore characterized the effect of NAc injections of nociceptin, the endogenous ligand for the NOP receptor, on consummatory and appetitive motivation. Three groups of male Sprague-Dawley rats received nociceptin injections into the NAc core prior to testing in a progressive ratio lever pressing task, an EBC task, or a palatable feeding assay. In the feeding experiment, 10 nmol of nociceptin increased consumption in the first 30 min, but this increase was not sustained through the end of the 2-hr session. Additionally, nociceptin injections did not alter breakpoint in the progressive ratio task. However, in the EBC task, nociceptin significantly decreased breakpoint for sugar pellets without affecting consumption of rat chow. These data suggest that NAc NOP receptor stimulation transiently increases consummatory motivation toward palatable diets and inhibits appetitive motivation when alternate food options are freely available. This pattern of effects contrasts with those obtained following NAc stimulation of other opioid receptors, suggesting that the four opioid receptor classes each serve unique roles in modulating food-directed motivation within the NAc core.
Subject(s)
Feeding Behavior , Motivation , Nociceptin , Nucleus Accumbens , Animals , Male , Rats , Nociceptin/metabolism , Nociceptin Receptor , Opioid Peptides/metabolism , Rats, Sprague-Dawley , Receptors, Opioid/metabolismABSTRACT
Traumatic brain injury (TBI) is a major cause of mortality and disability around the world, for which no treatment has been found. Nociceptin/Orphanin FQ (N/OFQ) and the nociceptin opioid peptide (NOP) receptor are rapidly increased in response to fluid percussion, stab injury, and controlled cortical impact (CCI) TBI. TBI-induced upregulation of N/OFQ contributes to cerebrovascular impairment, increased excitotoxicity, and neurobehavioral deficits. Our objective was to identify changes in N/OFQ and NOP receptor peptide, protein, and mRNA relative to the expression of injury markers and extracellular regulated kinase (ERK) 24 h following mild (mTBI) and moderate TBI (ModTBI) in wildtype (WT) and NOP receptor-knockout (KO) rats. N/OFQ was quantified by radioimmunoassay, mRNA expression was assessed using real-time PCR and protein levels were determined by immunoblot analysis. This study revealed increased N/OFQ mRNA and peptide levels in the CSF and ipsilateral tissue of WT, but not KO, rats 24 h post-TBI; NOP receptor mRNA increased after ModTBI. Cofilin-1 activation increased in the brain tissue of WT but not KO rats, ERK activation increased in all rats following ModTBI; no changes in injury marker levels were noted in brain tissue at this time. In conclusion, this study elucidates transcriptional and translational changes in the N/OFQ-NOP receptor system relative to TBI-induced neurological deficits and initiation of signaling cascades that support the investigation of the NOP receptor as a therapeutic target for TBI.