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The Lancet. Psychiatry Aug 2016Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward... (Review)
Review
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
Topics: Brain; Humans; Neural Pathways; Neurobiology; Substance-Related Disorders
PubMed: 27475769
DOI: 10.1016/S2215-0366(16)00104-8 -
Annual Review of Neuroscience Jul 2018Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and... (Review)
Review
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
Topics: Analgesics, Opioid; Animals; Humans; Pain; Pain Perception; Receptors, G-Protein-Coupled
PubMed: 29852083
DOI: 10.1146/annurev-neuro-080317-061522 -
Cell Jan 2023Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid...
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
Topics: Humans; Analgesics, Opioid; Opioid Peptides; Receptors, Opioid, mu; Receptors, Opioid
PubMed: 36638794
DOI: 10.1016/j.cell.2022.12.026 -
Frontiers in Endocrinology 2022The discovery of kisspeptin as a critical central regulatory factor of GnRH release has given people a novel understanding of the neuroendocrine regulation in human... (Review)
Review
The discovery of kisspeptin as a critical central regulatory factor of GnRH release has given people a novel understanding of the neuroendocrine regulation in human reproduction. Kisspeptin activates the signaling pathway by binding to its receptor kisspeptin receptor (KISS1R) to promote GnRH secretion, thereby regulating the hypothalamic-pituitary-gonadal axis (HPG) axis. Recent studies have shown that kisspeptin neurons located in arcuate nucleus (ARC) co-express neurokinin B (NKB) and dynorphin (Dyn). Such neurons are called KNDy neurons. KNDy neurons participate in the positive and negative feedback of estrogen to GnRH secretion. In addition, kisspeptin is a key factor in the initiation of puberty, and also regulates the processes of female follicle development, oocyte maturation, and ovulation through the HPG axis. In male reproduction, kisspeptin also plays an important role, getting involved in the regulation of Leydig cells, spermatogenesis, sperm functions and reproductive behaviors. Mutations in the gene or disorders of the kisspeptin/KISS1R system may lead to clinical symptoms such as idiopathic hypogonadotropic hypogonadism (iHH), central precocious puberty (CPP) and female infertility. Understanding the influence of kisspeptin on the reproductive axis and related mechanisms will help the future application of kisspeptin in disease diagnosis and treatment. In this review, we critically appraise the role of kisspeptin in the HPG axis, including its signaling pathways, negative and positive feedback mechanisms, and its control on female and male reproduction.
Topics: Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Male; Receptors, Kisspeptin-1; Reproduction; Semen
PubMed: 35837314
DOI: 10.3389/fendo.2022.925206 -
Neuropharmacology Jun 2020Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and... (Review)
Review
Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions. This article is part of the special issue on Neuropeptides.
Topics: Affect; Amygdala; Animals; Chronic Pain; Corticotropin-Releasing Hormone; Emotions; Humans; Neuropeptides; Neurophysins; Oxytocin; Protein Precursors; Vasopressins
PubMed: 32188569
DOI: 10.1016/j.neuropharm.2020.108052 -
Pharmacological Reviews Jan 2021Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication,... (Review)
Review
Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
Topics: Drug Development; Humans; Motivation; Reinforcement, Psychology; Reward; Substance-Related Disorders
PubMed: 33318153
DOI: 10.1124/pharmrev.120.000083 -
Cell Dec 2014Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ...
Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM(+) neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM(+) excitatory and Dyn(+) inhibitory neurons, form a microcircuit that transmits and gates mechanical pain. PAPERCLIP:
Topics: Animals; Dynorphins; Mechanoreceptors; Mice; Neurons; Pain; Pain Perception; Somatostatin; Spinal Cord
PubMed: 25467445
DOI: 10.1016/j.cell.2014.11.003 -
Nature Reviews. Endocrinology Aug 2020Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that... (Review)
Review
Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that ultimately affect the release of kisspeptin, which modulates gonadotropin-releasing hormone (GnRH) release from GnRH neurons to control the reproductive axis. The presence of sufficient energy reserves is critical to achieve successful reproduction. Consequently, metabolic factors impose a very tight control over kisspeptin synthesis and release. This Review offers a synoptic overview of the different steps in which kisspeptin neurons are subjected to metabolic regulation, from early developmental stages to adulthood. We cover an ample array of known mechanisms that underlie the metabolic regulation of KISS1 expression and kisspeptin release. Furthermore, the novel role of kisspeptin neurons as active players within the neuronal circuits that govern energy balance is discussed, offering evidence of a bidirectional role of these neurons as a nexus between metabolism and reproduction.
Topics: Animals; Dynorphins; Energy Metabolism; Female; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurons; Ovary; Puberty; Reproduction
PubMed: 32427949
DOI: 10.1038/s41574-020-0363-7 -
Neuron Dec 2022Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid...
Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DR), but not from NAc neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DR neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.
Topics: Humans; Mice; Animals; Dynorphins; Serotonin; Analgesics, Opioid; Dopamine; Receptors, Opioid, kappa; Narcotics; Nucleus Accumbens
PubMed: 36202097
DOI: 10.1016/j.neuron.2022.09.024