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Journal of Medicinal Chemistry Sep 2023The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are...
The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are promising drug candidates for the treatment of neuropsychiatric disorders. Hitherto, the vast majority of selective drug leads that have been developed for KOR are small molecules. In this study, novel peptide probes were designed by using an endogenous dynorphin A sequence as a template for peptide stapling via late-stage cysteine functionalization. Leveraging this strategy, we developed a stable and potent KOR antagonist, CSD-CH-NH, with approximately 1000-fold improved selectivity for KOR over μ- and δ-opioid receptors. Its potent competitive KOR antagonism was verified in KOR-expressing cells, peripheral dorsal root ganglion neurons, and using the tail-flick and rotarod tests in mice. This work highlights the value of cysteine stapling to develop selective peptide probes to modulate central KOR function, as innovative peptide drug candidates for the treatment of KOR-related illnesses.
Topics: Animals; Mice; Narcotic Antagonists; Cysteine; Peptides; Dynorphins; Ganglia, Spinal; Receptors, Opioid, kappa
PubMed: 37632447
DOI: 10.1021/acs.jmedchem.3c00426 -
Handbook of Experimental Pharmacology 2022The opioid peptides and their receptors have been linked to multiple key biological processes in the nervous system. Here we review the functions of the kappa opioid... (Review)
Review
The opioid peptides and their receptors have been linked to multiple key biological processes in the nervous system. Here we review the functions of the kappa opioid receptor (KOR) and its endogenous agonists dynorphins (Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L, Proc Natl Acad Sci U S A 76:6666-6670, 1979) in modulating itch and pain (nociception). Specifically, we discuss their roles relative to recent findings that tell us more about the cells and circuits which are impacted by this opioid and its receptor and present reanalysis of single-cell sequencing data showing the expression profiles of these molecules. Since the KOR is relatively specifically activated by peptides derived from the prodynorphin gene and other opioid peptides that show lower affinities, this will be the only interactions we consider (Chavkin C, Goldstein A, Nature 291:591-593, 1981; Chavkin C, James IF, Goldstein A, Science 215:413-415, 1982), although it was noted that at higher doses peptides other than dynorphins might stimulate KOR (Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F, Nat Neurosci 9:1534-1540, 2006). This review has been organized based on anatomy with each section describing the effect of the kappa opioid system in a specific location but let us not forget that most of these circuits are interconnected and are therefore interdependent.
Topics: Analgesics, Opioid; Dynorphins; Humans; Molecular Biology; Pain; Receptors, Opioid, kappa
PubMed: 33145633
DOI: 10.1007/164_2020_397 -
Psychopharmacology Jun 2010The dynorphin/kappa opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well... (Review)
Review
BACKGROUND AND RATIONALE
The dynorphin/kappa opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well known to produce analgesia, and more recently, it has been implicated as a mediator of stress-induced responses including anxiety, depression, and reinstatement of drug seeking.
OBJECTIVE
Drugs selectively targeting specific KOR signaling pathways may prove potentially useful as therapeutic treatments for mood and addiction disorders.
RESULTS
KOR is a member of the seven transmembrane spanning (7TM) G-protein coupled receptor (GPCR) superfamily. KOR activation of pertussis toxin-sensitive G proteins leads to Galphai/o inhibition of adenylyl cyclase production of cAMP and releases Gbetagamma, which modulates the conductances of Ca(+2) and K(+) channels. In addition, KOR agonists activate kinase cascades including G-protein coupled Receptor Kinases (GRK) and members of the mitogen-activated protein kinase (MAPK) family: ERK1/2, p38 and JNK. Recent pharmacological data suggests that GPCRs exist as dynamic, multi-conformational protein complexes that can be directed by specific ligands towards distinct signaling pathways. Ligand-induced conformations of KOR that evoke beta-arrestin-dependent p38 MAPK activation result in aversion; whereas ligand-induced conformations that activate JNK without activating arrestin produce long-lasting inactivation of KOR signaling.
CONCLUSIONS
In this review, we discuss the current status of KOR signal transduction research and the data that support two novel hypotheses: (1) KOR selective partial agonists that do not efficiently activate p38 MAPK may be useful analgesics without producing the dysphoric or hallucinogenic effects of selective, highly efficacious KOR agonists and (2) KOR antagonists that do not activate JNK may be effective short-acting drugs that may promote stress-resilience.
Topics: Adenylyl Cyclases; Animals; Cyclic AMP; Dynorphins; Enzyme Activation; G-Protein-Coupled Receptor Kinases; Humans; Ligands; Mitogen-Activated Protein Kinases; Receptors, Opioid, kappa; Signal Transduction; Stress, Physiological
PubMed: 20401607
DOI: 10.1007/s00213-010-1806-y -
Brain Research Feb 2010Drug addiction is one of the top three health concerns in the United States in terms of economic and health care costs. Despite this, there are very few effective... (Review)
Review
Drug addiction is one of the top three health concerns in the United States in terms of economic and health care costs. Despite this, there are very few effective treatment options available. Therefore, understanding the causes and molecular mechanisms underlying the transition from casual drug use to compulsive drug addiction could aid in the development of treatment options. Studies in humans and animal models indicate that stress can lead to both vulnerability to develop addiction, and increased drug taking and relapse in addicted individuals. Exposure to stress or drugs of abuse results in long-term adaptations in the brain that are likely to involve persistent alterations in gene expression or activation of transcription factors, such as the cAMP Response Element Binding (CREB) protein. The signaling pathways controlled by CREB have been strongly implicated in drug addiction and stress. Many potential CREB target genes have been identified based on the presence of a CRE element in promoter DNA sequences. These include, but are not limited to CRF, BDNF, and dynorphin. These genes have been associated with initiation or reinstatement of drug reward and are altered in one direction or the other following stress. While many reviews have examined the interactions between stress and addiction, the goal of this review was to focus on specific molecules that play key roles in both stress and addiction and are therefore posed to mediate the interaction between the two. Focus on these molecules could provide us with new targets for pharmacological treatments for addiction.
Topics: Animals; Brain Chemistry; Brain-Derived Neurotrophic Factor; Corticotropin-Releasing Hormone; Cyclic AMP Response Element-Binding Protein; Dynorphins; Gene Expression Regulation; Humans; Neuronal Plasticity; Stress, Psychological; Substance-Related Disorders
PubMed: 19900417
DOI: 10.1016/j.brainres.2009.11.002 -
Human Reproduction Update 2014The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction.... (Review)
Review
BACKGROUND
The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction. The related discovery of the kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further strengthened our understanding of the modulation of GnRH secretion by endocrine, metabolic and environmental inputs. In this review, we summarize current understanding of the physiological roles of these novel neuropeptides, and discuss the clinical relevance of these discoveries and their potential translational applications.
METHODS
A systematic literature search was performed using PUBMED for all English language articles up to January 2014. In addition, the reference lists of all relevant original research articles and reviews were examined. This review focuses mainly on published human studies but also draws on relevant animal data.
RESULTS
Kisspeptin is a principal regulator of the secretion of gonadotrophins, and through this key role it is critical for the onset of puberty, the regulation of sex steroid-mediated feedback and the control of adult fertility. Although there is some sexual dimorphism, both neuroanatomically and functionally, these functions are apparent in both men and women. Kisspeptin acts upstream of GnRH and, following paracrine stimulatory and inhibitory inputs from neurokinin B and dynorphin (KNDy neuropeptides), signals directly to GnRH neurones to control pulsatile GnRH release. When administered to humans in different isoforms, routes and doses, kisspeptin robustly stimulates LH secretion and LH pulse frequency. Manipulation of the KNDy system is currently the focus of translational research with the possibility of future clinical application to regulate LH pulsatility, increasing gonadal sex steroid secretion in reproductive disorders characterized by decreased LH pulsatility, including hypothalamic amenorrhoea and hypogonadotropic hypogonadism. Conversely there may be scope to reduce the activity of the KNDy system to reduce LH secretion where hypersecretion of LH adds to the phenotype, such as in polycystic ovary syndrome.
CONCLUSIONS
Kisspeptin is a recently discovered neuromodulator that controls GnRH secretion mediating endocrine and metabolic inputs to the regulation of human reproduction. Manipulation of kisspeptin signalling has the potential for novel therapies in patients with pathologically low or high LH pulsatility.
Topics: Amenorrhea; Animals; Dynorphins; Feedback, Physiological; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Infertility; Kisspeptins; Luteinizing Hormone; Male; Neurokinin B; Neurons; Reproduction; Sex Characteristics; Sex Factors; Sexual Development; Signal Transduction
PubMed: 24615662
DOI: 10.1093/humupd/dmu009 -
Neuropsychopharmacology : Official... Dec 2021Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component...
Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In C57BL/6 male mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant-delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdyn neurons using Channelrhodopsin-2 disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.
Topics: Analgesics, Opioid; Animals; Cognition; Dynorphins; Male; Mice; Mice, Inbred C57BL; Naltrexone; Prefrontal Cortex; Receptors, Opioid, kappa
PubMed: 34545197
DOI: 10.1038/s41386-021-01168-2 -
International Journal of Molecular... Feb 2021Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from...
Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.
Topics: Alcohol Drinking; Alcoholism; Amygdala; Animals; Behavior, Animal; Dynorphins; Ethanol; Male; Neurotransmitter Agents; Opioid Peptides; Peptide Fragments; Rats; Rats, Wistar; Receptors, Opioid
PubMed: 33671048
DOI: 10.3390/ijms22052448 -
Molecular Pain 2023Dynorphin A (1-17) (DynA17) has been identified as a key regulator of both sensory and affective dimensions of chronic pain. Following nerve injury, increases in DynA17...
Dynorphin A (1-17) (DynA17) has been identified as a key regulator of both sensory and affective dimensions of chronic pain. Following nerve injury, increases in DynA17 have been reported in the spinal and supraspinal areas involved in chronic pain. Blocking these increases provides therapeutic benefits in preclinical chronic pain models. Although heavily characterized at the behavioral level, how DynA17 mediates its effects at the cellular physiological level has not been investigated. In this report, we begin to decipher how DynA17 mediates its direct effects on mouse dorsal root ganglion (DRG) cells and how intrathecal administration modifies a key node in the pain axis, the periaqueductal gray These findings build on the plethora of literature defining DynA17 as a critical neuropeptide in the pathophysiology of chronic pain syndromes.
Topics: Mice; Animals; Dynorphins; Chronic Pain; Neuropeptides; Ganglia, Spinal
PubMed: 37351900
DOI: 10.1177/17448069231186592 -
Frontiers in Endocrinology 2021Increasing evidence accumulated during the past two decades has demonstrated that the then-novel kisspeptin, which was discovered in 2001, the known neuropeptides... (Review)
Review
Increasing evidence accumulated during the past two decades has demonstrated that the then-novel kisspeptin, which was discovered in 2001, the known neuropeptides neurokinin B and dynorphin A, which were discovered in 1983 and 1979, respectively, and their G-protein-coupled receptors, serve as key molecules that control reproduction in mammals. The present review provides a brief historical background and a summary of our recent understanding of the roles of hypothalamic neurons expressing kisspeptin, neurokinin B, and dynorphin A, referred to as KNDy neurons, in the central mechanism underlying gonadotropin-releasing hormone (GnRH) pulse generation and subsequent tonic gonadotropin release that controls mammalian reproduction.
Topics: Animals; Dynorphins; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Kisspeptins; Mammals; Neurokinin B; Neurons; Reproduction
PubMed: 34566891
DOI: 10.3389/fendo.2021.724632 -
Journal of Neurochemistry Sep 2004Rats exposed to learned helplessness (LH), an animal model of depression, showed a recovery following an intracerebroventricular injection of nor-binaltorphimine... (Comparative Study)
Comparative Study
Rats exposed to learned helplessness (LH), an animal model of depression, showed a recovery following an intracerebroventricular injection of nor-binaltorphimine dihydrochloride (norBNI; a kappa-opioid antagonist). To investigate the potential role of dynorphin A and dynorphin B, we examined the effects of different stress/depression models on dynorphin A and dynorphin B immunoreactivity in hippocampus and nucleus accumbens (NAc). Immobilization stress (3 h) caused an increase in levels of dynorphin A and dynorphin B immunoreactivity in the hippocampus and the NAc. Forced swim stress also temporally increased dynorphin A levels in the hippocampus. Furthermore, exposure to LH produced a similar increase in dynorphin A and dynorphin B in the hippocampus and NAc. Infusions of norBNI into the dentate gyrus or CA3 regions of hippocampus and into the shell or core regions of NAc produced antidepressant-like effects in the LH paradigm. The degrees of norBNI's effects were stronger in the CA3 region and NAc shell and less effective in the dentate gyrus of hippocampus and NAc core. These results indicate that both dynorphin A and dynorphin B contribute to the effects of stress, and suggest that blockade of kappa-opioid receptors may have therapeutic potential for the treatment of depression.
Topics: Animals; Behavior, Animal; Cell Count; Disease Models, Animal; Dose-Response Relationship, Drug; Dynorphins; Endorphins; Escape Reaction; Helplessness, Learned; Immobilization; Immunohistochemistry; Limbic System; Male; Naltrexone; Rats; Rats, Sprague-Dawley; Stress, Physiological
PubMed: 15312181
DOI: 10.1111/j.1471-4159.2004.02589.x