Review

Authors: Elena E Bagley, Susan L Ingram

The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid receptors throughout the body. These receptors respond to endogenous opioid peptides that are expressed as polypeptide hormones that are processed by proteolytic cleavage. Endogenous opioids are expressed throughout the peripheral and central nervous system and regulate many different neuronal circuits and functions. One of the key functions of endogenous opioid peptides is to modulate our responses to pain. This review will focus on the descending pain modulatory circuit which consists of the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM). RVM projections modulate incoming nociceptive afferents at the level of the spinal cord. Stimulation within either the PAG or RVM results in analgesia and this circuit has been studied in detail in terms of the actions of exogenous opioids, such as morphine and fentanyl. Further emphasis on understanding the complex regulation of endogenous opioids will help to make rational decisions with regard to the use of opioids for pain. We also include a discussion of the actions of endogenous opioids in the amygdala, an upstream brain structure that has reciprocal connections to the PAG that contribute to the brain's response to pain.

Topics: Amygdala; Animals; Humans; Opioid Peptides; Pain; Pain Management; Pain Perception; Periaqueductal Gray; Receptors, Opioid

PubMed: 32422213
DOI: 10.1016/j.neuropharm.2020.108131

Authors: Chunyang Dong, Raajaram Gowrishankar, Yihan Jin...

Neuropeptides are ubiquitous in the nervous system. Research into neuropeptides has been limited by a lack of experimental tools that allow for the precise dissection of their complex and diverse dynamics in a circuit-specific manner. Opioid peptides modulate pain, reward and aversion and as such have high clinical relevance. To illuminate the spatiotemporal dynamics of endogenous opioid signaling in the brain, we developed a class of genetically encoded fluorescence sensors based on kappa, delta and mu opioid receptors: κLight, δLight and µLight, respectively. We characterized the pharmacological profiles of these sensors in mammalian cells and in dissociated neurons. We used κLight to identify electrical stimulation parameters that trigger endogenous opioid release and the spatiotemporal scale of dynorphin volume transmission in brain slices. Using in vivo fiber photometry in mice, we demonstrated the utility of these sensors in detecting optogenetically driven opioid release and observed differential opioid release dynamics in response to fearful and rewarding conditions.

Topics: Animals; Biosensing Techniques; Mice; Optogenetics; Neurons; Humans; Dynorphins; Male; Opioid Peptides; HEK293 Cells; Mice, Inbred C57BL; Brain; Neuropeptides; Receptors, Opioid; Electric Stimulation; Reward

PubMed: 39009835
DOI: 10.1038/s41593-024-01697-1

Review

Authors: Richard J Bodnar

This paper is the 29th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning 30 years of research. It summarizes papers published during 2006 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurological disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Topics: Animals; Behavior; Drug Tolerance; Female; Humans; Learning; Male; Opioid Peptides; Pain; Pregnancy; Receptors, Opioid; Stress, Physiological; Substance-Related Disorders

PubMed: 17949854
DOI: 10.1016/j.peptides.2007.09.002

Review

Authors: Koshi Murata, Ayako Maegawa, Yoshimasa Imoto...

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.

Topics: Humans; Quality of Life; Animals; Smell; Opioid Peptides; Olfactory Tubercle; Olfaction Disorders

PubMed: 38872907
DOI: 10.3389/fncir.2024.1408189

Review

Authors: Giovannamaria Petrocelli, Luca Pampanella, Provvidenza M Abruzzo...

Opioids are considered the oldest drugs known by humans and have been used for sedation and pain relief for several centuries. Nowadays, endogenous opioid peptides are divided into four families: enkephalins, dynorphins, endorphins, and nociceptin/orphanin FQ. They exert their action through the opioid receptors (ORs), transmembrane proteins belonging to the super-family of G-protein-coupled receptors, and are expressed throughout the body; the receptors are the δ opioid receptor (DOR), μ opioid receptor (MOR), κ opioid receptor (KOR), and nociceptin/orphanin FQ receptor (NOP). Endogenous opioids are mainly studied in the central nervous system (CNS), but their role has been investigated in other organs, both in physiological and in pathological conditions. Here, we revise their role in stem cell (SC) biology, since these cells are a subject of great scientific interest due to their peculiar features and their involvement in cell-based therapies in regenerative medicine. In particular, we focus on endogenous opioids' ability to modulate SC proliferation, stress response (to oxidative stress, starvation, or damage following ischemia-reperfusion), and differentiation towards different lineages, such as neurogenesis, vasculogenesis, and cardiogenesis.

Topics: Analgesics, Opioid; Humans; Opioid Peptides; Receptors, Opioid; Receptors, Opioid, kappa; Stem Cells

PubMed: 35409178
DOI: 10.3390/ijms23073819

Review

Authors: Michael Remesic, Yeon Sun Lee, Victor J Hruby...

For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

Topics: Animals; Humans; Opioid Peptides; Pain; Peptides, Cyclic; Receptors, Opioid

PubMed: 27117332
DOI: 10.2174/0929867323666160427123005

Review

Authors: Anna Abrimian, Tamar Kraft, Ying-Xian Pan...

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl ()-terminal variants, has the same receptor structures but contains different intracellular -terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM -terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM -terminal splice variants.

Topics: Alternative Splicing; Animals; Humans; Opioid Peptides; Protein Isoforms; RNA Precursors; Receptors, Opioid, mu

PubMed: 33917474
DOI: 10.3390/ijms22073779

Authors: Teresa Rinaldi

Topics: Dual Use Research; Genetic Engineering; Opioid Peptides; Papaver; Saccharomyces cerevisiae; Synthetic Biology

PubMed: 26415505
DOI: 10.15252/embr.201541367

Review

Authors: G A Olson, R D Olson, A J Kastin...

This paper is the sixteenth installment of our annual review of research concerning the opiate system. It is restricted to papers published during 1993 that concern the behavioral effects of the endogenous opiate peptides, and does not include papers dealing only with their analgesic properties. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; development; immunological responses; and other behaviors.

Topics: Affect; Animals; Body Temperature Regulation; Cardiovascular Physiological Phenomena; Cardiovascular System; Drinking; Drug Tolerance; Eating; Humans; Learning; Memory; Mental Disorders; Motor Activity; Nervous System Diseases; Opioid Peptides; Respiration; Reward; Seizures; Stress, Physiological; Substance-Related Disorders

PubMed: 7700854
DOI: 10.1016/0196-9781(94)90131-7

Review

Authors: Katarzyna Kaczyńska, Piotr Wojciechowski

Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.

Topics: Analgesics, Opioid; Animals; Cholecystokinin; Drug Tolerance; Ghrelin; Humans; Narcotic Antagonists; Oligopeptides; Opioid Peptides; Peptides; Receptors, Opioid; Nociceptin

PubMed: 34948415
DOI: 10.3390/ijms222413619