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1.
Pharmacol Ther ; 210: 107519, 2020 06.
Article in English | MEDLINE | ID: mdl-32165137

ABSTRACT

The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are subject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the beginning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number of deaths by opioid overdose, is a tragic illustration of this. It is therefore legitimate to develop research into molecules likely to maintain or increase opioid efficacy while improving their tolerability. Several avenues are being explored including targeting of the mu opioid receptor (MOR) splice variants, developing biased agonists or targeting of other receptors such as heteromers with MOR. Ion channels acting as MOR effectors, are also targeted in order to offer compounds without MOR-dependent adverse effects. Another route is to develop opioid analgesics with peripheral action or limited central nervous system (CNS) access. Finally, endogenous opioids used as drugs or compounds that modify the metabolism of endogenous opioids (Dual ENKephalinase Inhibitors) are being developed. The aim of the present review is to present these various targets/strategies with reference to current indications for opioids, concerns about their widespread use, particularly in chronic non-cancer pains, and ways of limiting the risk of opioid abuse and misuse.


Subject(s)
Analgesics, Opioid/adverse effects , Analgesics/therapeutic use , Central Nervous System/drug effects , Drug Discovery , Opioid Peptides/therapeutic use , Opioid-Related Disorders/prevention & control , Pain/drug therapy , Receptors, Opioid, mu/agonists , Analgesics/adverse effects , Animals , Central Nervous System/metabolism , Central Nervous System/physiopathology , Humans , Ligands , Molecular Targeted Therapy , Opioid Epidemic , Opioid Peptides/adverse effects , Opioid Peptides/metabolism , Opioid-Related Disorders/diagnosis , Opioid-Related Disorders/epidemiology , Pain/metabolism , Pain/physiopathology , Pain Threshold/drug effects , Receptors, Opioid, mu/metabolism , Signal Transduction
2.
J Nutr Biochem ; 37: 39-46, 2016 11.
Article in English | MEDLINE | ID: mdl-27611101

ABSTRACT

Food-derived peptides, such as ß-casomorphin BCM7, have potential to cross the gastrointestinal tract and blood-brain barrier and are associated with neurological disorders and neurodevelopmental disorders. We previously established a novel mechanism through which BCM7 affects the antioxidant levels in neuronal cells leading to inflammatory consequences. In the current study, we elucidated the effects of casein-derived peptides on neuronal development by using the neurogenesis of neural stem cells (NSCs) as an experimental model. First, the transient changes in intracellular thiol metabolites during NSC differentiation (neurogenesis) were investigated. Next, the neurogenic effects of food-derived opioid peptides were measured, along with changes in intracellular thiol metabolites, redox status and global DNA methylation levels. We observed that the neurogenesis of NSCs was promoted by human BCM7 to a greater extent, followed by A2-derived BCM9 in contrast to bovine BCM7, which induced increased astrocyte formation. The effect was most apparent when human BCM7 was administered for 1day starting on 3days postplating, consistent with immunocytochemistry. Furthermore, neurogenic changes regulated by bovine BCM7 and morphine were associated with an increase in the glutathione/glutathione disulfide ratio and a decrease in the S-adenosylmethionine/S-adenosylhomocysteine ratio, indicative of changes in the redox and the methylation states. Finally, bovine BCM7 and morphine decreased DNA methylation in differentiating NSCs. In conclusion, these results suggest that food-derived opioid peptides and morphine regulated neurogenesis and differentiation of NSCs through changes in the redox state and epigenetic regulation.


Subject(s)
Caseins/metabolism , DNA Methylation , Endorphins/metabolism , Epigenesis, Genetic , Neural Stem Cells/metabolism , Neurogenesis , Opioid Peptides/metabolism , Peptide Fragments/metabolism , Analgesics, Opioid/pharmacology , Animals , Apoptosis/drug effects , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/immunology , Astrocytes/metabolism , Caseins/adverse effects , Caseins/chemistry , Cattle , Cell Proliferation/drug effects , Cells, Cultured , DNA Methylation/drug effects , Endorphins/adverse effects , Endorphins/chemistry , Epigenesis, Genetic/drug effects , Glutathione/chemistry , Glutathione/metabolism , Humans , Methylation , Morphine/pharmacology , Neural Stem Cells/cytology , Neural Stem Cells/drug effects , Neural Stem Cells/immunology , Neurogenesis/drug effects , Opioid Peptides/adverse effects , Opioid Peptides/chemistry , Oxidation-Reduction , Peptide Fragments/adverse effects , Peptide Fragments/chemistry , Protein Processing, Post-Translational , S-Adenosylhomocysteine/chemistry , S-Adenosylhomocysteine/metabolism , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism
3.
Braz. J. Psychiatry (São Paulo, 1999, Impr.) ; 38(3): 243-246, July-Sept. 2016.
Article in English | LILACS | ID: lil-792749

ABSTRACT

Autism spectrum disorders (ASDs) are characterized by deficits in the individual’s ability to socialize, communicate, and use the imagination, in addition to stereotyped behaviors. These disorders have a heterogenous phenotype, both in relation to symptoms and regarding severity. Organic problems related to the gastrointestinal tract are often associated with ASD, including dysbiosis, inflammatory bowel disease, exocrine pancreatic insufficiency, celiac disease, indigestion, malabsorption, food intolerance, and food allergies, leading to vitamin deficiencies and malnutrition. In an attempt to explain the pathophysiology involved in autism, a theory founded on opioid excess has been the focus of various investigations, since it partially explains the symptomatology of the disorder. Another hypothesis has been put forward whereby the probable triggers of ASDs would be related to the presence of bacteria in the bowel, oxidative stress, and intestinal permeability. The present update reviews these hypotheses.


Subject(s)
Humans , Opioid Peptides/adverse effects , Opioid Peptides/metabolism , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/metabolism , Gastrointestinal Diseases/metabolism , Sulfhydryl Compounds/metabolism , Oxidative Stress , Opioid Peptides/analysis , Gastrointestinal Tract/physiopathology , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Autism Spectrum Disorder/physiopathology , Gastrointestinal Microbiome , Gastrointestinal Diseases/physiopathology
4.
Rev. Soc. Esp. Dolor ; 23(4): 181-185, jul.-ago. 2016. tab
Article in Spanish | IBECS | ID: ibc-154044

ABSTRACT

Introducción: Desde el año 2000 vienen apareciendo en distintas publicaciones científicas los resultados de numerosos estudios experimentales realizados en animales, evaluando el impacto neurotóxico que sobre sus cerebros tenía la exposición a combinaciones de anestésicos de uso habitual. Se constata que la exposición en periodo de máxima sinaptogénesis conlleva una apoptosis neural diseminada. Comienzan entonces a preocuparse los anestesiólogos que trabajan con niños, pues quizás ese daño neuronal también pudiera acontecer a la población pediátrica. Así, son varios los estudios que están en marcha desde hace años valorando el desarrollo neurocognitivo de cohortes de niños que se sometieron a anestesias generales en edades tempranas de sus vidas. En este sentido, la necesidad de medir un daño cerebral agudo nos anima a utilizar marcadores que han demostrado su asociación con dicho deterioro cerebral en diferentes situaciones clínicas como la hipoxia perinatal, la parada cardiorrespiratoria o el traumatismo craneoencefálico. Objetivos: Planteamos este trabajo con el objetivo de determinar si la proteína S100B podría comportarse como un biomarcador de daño cerebral agudo postanestésico y si pudiéramos establecer asociación entre la elevación de este marcador en sangre y alguno de los fármacos anestésicos utilizados habitualmente. Metodología: Determinación sanguínea de la proteína S100B en 76 pacientes pediátricos intervenidos de hipertrofia amigdalar bajo anestesia general, antes y después de la cirugía Conclusión: Tras analizar los resultados podemos concluir que existe una elevación estadísticamente significativa entre los niveles de proteína S100B antes y después de la exposición anestésica. En segundo lugar, podemos establecer una correlación positiva, también con significación estadística, entre el fentanilo administrado y la elevación de dicha proteína al final del acto anestésico (AU)


Introduction: In the last decade many scietific publications bring out the results of experimental studies about the neurotoxic impact of an anesthetic expossure in animal´s brain. It is confirm that when this expossure occurs in a maximum synaptogenesis period of the animal´s live a widespread neuroapoptosis befall. From there on all the pediatrics anesthesiologist warried about if this damage could also affect the pediatric population. Nowadays there are several observational studies exploring the neurobehavioral conduct of many children who underwent general anesthesia early in their lives. Objetive: As a results of this we propose to use actual neuronal damage biomarkes, wich have demonstrated association between brain damage and perinatal hypoxia, or cardiac arrest or mild brain injury. When we planned this essay we intend to determine if S100B protein could work as an accute postanesthetic expossure neuronal damage biomarker, and if there would be any relationship between the biomarker elevation and any of the drugs commonly use for anesthesia. Metodology: In order to determinate the S100B protein serum level is, we obtained a blood sample before and after general anaesthesia expousure in 76 paediatric patient undergoing amigdalar hypertropy surgery. Conclusions: Once we analized our results we can coclude that an elevation of the blood levels of S100B protein occurs after anesthesia. We have also found a possitive correlation between the total amount of fentanyl administred and the higher level of this protein concentration at the end of the anesthetic expossure (AU)


Subject(s)
Humans , Male , Female , Child , Opioid Peptides/adverse effects , Opioid Peptides/toxicity , Analgesics, Opioid/adverse effects , Analgesics, Opioid/toxicity , Anesthesia, General , Neuronal Apoptosis-Inhibitory Protein/analysis , S100 Proteins/analysis , Biomarkers/analysis , Anesthesia, General/adverse effects , Cohort Studies , Fentanyl/adverse effects , Fentanyl/therapeutic use
5.
Braz J Psychiatry ; 38(3): 243-6, 2016.
Article in English | MEDLINE | ID: mdl-27304256

ABSTRACT

Autism spectrum disorders (ASDs) are characterized by deficits in the individual's ability to socialize, communicate, and use the imagination, in addition to stereotyped behaviors. These disorders have a heterogenous phenotype, both in relation to symptoms and regarding severity. Organic problems related to the gastrointestinal tract are often associated with ASD, including dysbiosis, inflammatory bowel disease, exocrine pancreatic insufficiency, celiac disease, indigestion, malabsorption, food intolerance, and food allergies, leading to vitamin deficiencies and malnutrition. In an attempt to explain the pathophysiology involved in autism, a theory founded on opioid excess has been the focus of various investigations, since it partially explains the symptomatology of the disorder. Another hypothesis has been put forward whereby the probable triggers of ASDs would be related to the presence of bacteria in the bowel, oxidative stress, and intestinal permeability. The present update reviews these hypotheses.


Subject(s)
Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/metabolism , Gastrointestinal Diseases/metabolism , Opioid Peptides/adverse effects , Opioid Peptides/metabolism , Autism Spectrum Disorder/physiopathology , Gastrointestinal Diseases/physiopathology , Gastrointestinal Microbiome , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/physiopathology , Humans , Opioid Peptides/analysis , Oxidative Stress , Sulfhydryl Compounds/metabolism
6.
PLoS One ; 10(8): e0134441, 2015.
Article in English | MEDLINE | ID: mdl-26305798

ABSTRACT

UNLABELLED: Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3­10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of "high-sensitizers" prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain. TRIAL REGISTRATION: EudraCT 2012-005663-27.


Subject(s)
Opioid Peptides/therapeutic use , Pain/drug therapy , Animals , Behavior , Disease Models, Animal , Heat-Shock Response , Humans , Hyperalgesia/drug therapy , Hyperalgesia/pathology , Male , Mice, Inbred C57BL , Opioid Peptides/adverse effects , Pain/complications , Pain Threshold , Young Adult
7.
Pharmacol Biochem Behav ; 134: 70-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25661529

ABSTRACT

Dohan proposed that an overload of dietary peptides, such as those derived from wheat gluten and milk casein, could be a factor relevant to the development or maintenance of schizophrenia (SZ) symptoms in at least a subset of vulnerable individuals. Rodent behavioral models may offer insight into the plausibility of Dohan's exorphin hypothesis by providing a means to directly study the effects of such peptides. Accordingly, a review of the literature on the behavioral effects of food-derived opioid-like peptides in rodents was undertaken. Studies using a variety of behavioral tests to examine the effects of several classes of food-derived opioid-like peptides were identified and reviewed. Peptides derived from casein (ß-casomorphins; BCMs, n=19), spinach (rubiscolins; RCs, n=4), and soy (soymorphins; SMs, n=1) were behaviorally active in various paradigms assessing nociception, spontaneous behavior, and memory. Surprisingly, only a single study evaluating a gluten-derived peptide (gliadorphin-7; GD-7, n=1) was identified and included in this review. In conclusion, food-derived peptides can affect rodent behavior, but more studies of GDs using diverse behavioral batteries are warranted. Assuming they occur in sufficient quantities during protein digestion and can access central opioid receptors (which entails crossing both the gastrointestinal and blood-brain barriers intact), these peptides may affect human behavior. Although BCMs and GDs may not be directly pathogenic in SZ, documented associations of casein and gluten sensitivity with SZ justify increased patient screening and dietary intervention where necessary.


Subject(s)
Behavior, Animal/drug effects , Food Analysis , Opioid Peptides/pharmacology , Schizophrenia/chemically induced , Animals , Mice , Opioid Peptides/adverse effects , Opioid Peptides/analysis , Rats
8.
J Health Popul Nutr ; 33: 24, 2015 Nov 24.
Article in English | MEDLINE | ID: mdl-26825414

ABSTRACT

Gluten-containing cereals are a main food staple present in the daily human diet, including wheat, barley, and rye. Gluten intake is associated with the development of celiac disease (CD) and related disorders such as diabetes mellitus type I, depression, and schizophrenia. However, until now, there is no consent about the possible deleterious effects of gluten intake because of often failing symptoms even in persons with proven CD. Asymptomatic CD (ACD) is present in the majority of affected patients and is characterized by the absence of classical gluten-intolerance signs, such as diarrhea, bloating, and abdominal pain. Nevertheless, these individuals very often develop diseases that can be related with gluten intake. Gluten can be degraded into several morphine-like substances, named gluten exorphins. These compounds have proven opioid effects and could mask the deleterious effects of gluten protein on gastrointestinal lining and function. Here we describe a putative mechanism, explaining how gluten could "mask" its own toxicity by exorphins that are produced through gluten protein digestion.


Subject(s)
Asymptomatic Diseases , Celiac Disease/physiopathology , Edible Grain/adverse effects , Glutens/adverse effects , Models, Biological , Opioid Peptides/adverse effects , Peptides/adverse effects , Animals , Celiac Disease/immunology , Celiac Disease/metabolism , Digestion , Edible Grain/metabolism , Gastrointestinal Tract/immunology , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/physiopathology , Gastrointestinal Transit , Glutens/metabolism , Humans , Opioid Peptides/metabolism , Peptides/metabolism , Proteolysis , Severity of Illness Index
9.
Ross Fiziol Zh Im I M Sechenova ; 98(8): 970-9, 2012 Aug.
Article in Russian | MEDLINE | ID: mdl-23155621

ABSTRACT

The effects of repeated opilong injections in a dose of 50 microg/kg/day on subsequent learning of Wistar rats have been studied. The substance caused significant anxiolytic and analgesic effects, as the majority of animals could be learned (90% against 40% in control group) despite of painful stimulus preceding to education. Opilong in a small dose displaced a relation of excitatory-inhibit processes to significant prevalence of excitation although the substance was already absent in an organism for a long time. Raised peripheral sensitivity in all rats, provoked by opilong, correlated with CNS hyper excitability, expressed in stressful, neurotic psychoemotional reactions and in the form of active avoidance. The biochemical blood analysis in opilong-induced rats demonstrated the attributes of prethrombosis in the form of fibrinolysis depression and hypercoagulation. A view is expressed, that the neuromediator brain systems can be the basic point of opilong action, that are responsible for the excitatory-inhibit conditions of CNS functioning referred on maintenance of conditioned field stability.


Subject(s)
Analgesics, Opioid , Central Nervous System , Fibrinolysis/drug effects , Learning/drug effects , Opioid Peptides , Thrombophilia/congenital , Analgesics, Opioid/adverse effects , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/pharmacology , Animals , Central Nervous System/metabolism , Central Nervous System/physiopathology , Dose-Response Relationship, Drug , Male , Opioid Peptides/adverse effects , Opioid Peptides/pharmacokinetics , Opioid Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Thrombophilia/metabolism , Thrombophilia/physiopathology
10.
Med Hypotheses ; 79(6): 754-6, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23062774

ABSTRACT

Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.


Subject(s)
Drug Tolerance , Hyperalgesia/prevention & control , Opioid Peptides/adverse effects , Toll-Like Receptor 4/antagonists & inhibitors , Humans , Hyperalgesia/chemically induced , Immunity, Innate , Models, Theoretical
11.
J Biol Chem ; 287(13): 10403-10413, 2012 Mar 23.
Article in English | MEDLINE | ID: mdl-22311985

ABSTRACT

4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is a molecule of physiologically unknown function, although it is predominantly expressed in the brain, spinal cord, liver, and kidney. We identified NIPSNAP1 as a protein that interacts with the neuropeptide nocistatin (NST) from synaptosomal membranes of mouse spinal cord using high-performance affinity latex beads. NST, which is produced from the same precursor protein as an opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ), has opposite effects on pain transmission evoked by N/OFQ. The calculated full-length pre-protein of NIPSNAP1 was 33 kDa, whereas the N-terminal truncated form of NIPSNAP1 (29 kDa) was ubiquitously expressed in the neuronal tissues, especially in synaptic membrane and mitochondria of brain. The 29-kDa NIPSNAP1 was distributed on the cell surface, and NST interacted with the 29-kDa but not the 33-kDa NIPSNAP1. Although intrathecal injection of N/OFQ induced tactile allodynia in both wild-type and NIPSNAP1-deficient mice, the inhibition of N/OFQ-evoked tactile allodynia by NST seen in wild-type mice was completely lacking in the deficient mice. These results suggest that NIPSNAP1 is an interacting molecule of NST and plays a crucial role in pain transmission.


Subject(s)
Analgesics, Opioid/pharmacology , Brain/metabolism , Nerve Tissue Proteins/metabolism , Opioid Peptides/pharmacology , Pain/metabolism , Proteins/metabolism , Spinal Cord/metabolism , Synaptic Transmission/drug effects , Analgesics, Opioid/adverse effects , Animals , Brain/pathology , COS Cells , Chlorocebus aethiops , Humans , Hyperalgesia/chemically induced , Hyperalgesia/genetics , Hyperalgesia/metabolism , Hyperalgesia/pathology , Intercellular Signaling Peptides and Proteins , Membrane Proteins , Mice , Mitochondria/genetics , Mitochondria/metabolism , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/genetics , Opioid Peptides/adverse effects , Pain/genetics , Proteins/agonists , Proteins/genetics , Spinal Cord/pathology , Synaptic Membranes/genetics , Synaptic Membranes/metabolism , Synaptic Transmission/genetics
14.
Peptides ; 32(2): 421-7, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21126548

ABSTRACT

Dermorphin (Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) is a heptapeptide isolated from amphibian skin. With a very high affinity and selectivity for µ-opioid receptors, dermorphin shows an extremely potent antinociceptive effect. The structure-activity relationship studies of dermorphin analogs clearly suggest that the N-terminal tetrapeptide is the minimal sequence for agonistic activity at µ-opioid receptors, and that the replacement of the d-Ala(2) residue with d-Arg(2) makes the tetrapeptides resistant to enzymatic metabolism. At present, only a handful of dermorphin N-terminal tetrapeptide analogs containing d-Arg(2) have been developed. The analogs show potent antinociceptive activity that is greater than that of morphine with various injection routes, and retain high affinity and selectivity for µ-opioid receptors. Interestingly, some analogs show pharmacological profiles that are distinct from the traditional µ-opioid receptor agonists morphine and [d-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO). These analogs stimulate the release of dynorphins through the activation of µ-opioid receptors. The activation of κ-opioid receptors by dynorphins is suggested to reduce the side effects of µ-opioid receptor agonists, e.g., dependence or antinociceptive tolerance. The dermorphin N-terminal tetrapeptide analogs containing d-Arg(2) may provide a new target molecule for developing novel analgesics that have fewer side effects.


Subject(s)
Analgesics, Opioid/pharmacology , Morphine/pharmacology , Oligopeptides/pharmacology , Opioid Peptides/chemistry , Opioid Peptides/pharmacology , Analgesics, Opioid/adverse effects , Analgesics, Opioid/chemistry , Animals , Humans , Morphine/adverse effects , Oligopeptides/adverse effects , Oligopeptides/chemistry , Opioid Peptides/adverse effects
15.
Hippocampus ; 20(8): 911-6, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20087887

ABSTRACT

Nociceptin/orphanin-FQ (N/OFQ) peptide and its receptor (NOP: N/OFQ opioid peptide receptor) are highly expressed in the hippocampus, but their functional role remains poorly understood. We recently showed that hippocampal N/OFQ inhibits learning and memory abilities in mice. Here, we investigated whether the endogenous peptide also regulated emotional responses at the level of the hippocampus. Bilateral infusions of the selective NOP receptor antagonist, UFP-101 (1-3 nmol/side), into the dorsal hippocampus produced antidepressant-like effects in the mouse forced swim and tail suspension tests comparable with those obtained with the prototypical antidepressant, fluoxetine (10-30 mg/kg, intraperitoneal). In the light-dark test, neither UFP-101 (1-3 nmol/side) nor N/OFQ peptide (1-3 nmol/side) modified anxiety measures when injected at behaviorally active doses in the dorsal hippocampus. These findings show a clear dissociation in the involvement of hippocampal N/OFQ system in anxiety- and despair-related behaviors. We conclude that the dorsal hippocampus is a brain region in which there is an important N/OFQ modulation of mnemonic processes and adaptive emotional responses associated to despair states.


Subject(s)
Depression/pathology , Hippocampus/metabolism , Opioid Peptides/metabolism , Analysis of Variance , Animals , Behavior, Animal/drug effects , Dark Adaptation/drug effects , Depression/chemically induced , Depression/physiopathology , Disease Models, Animal , Hindlimb Suspension/psychology , Hippocampus/drug effects , Imidazoles/adverse effects , Male , Mice , Mice, Inbred C57BL , Opioid Peptides/adverse effects , Opioid Peptides/antagonists & inhibitors , Spiro Compounds/adverse effects , Swimming/psychology , Nociceptin
16.
Peptides ; 30(12): 2432-79, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19793543

ABSTRACT

This paper is the 31st consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2008 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 neurologic 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).


Subject(s)
Behavior/physiology , Opioid Peptides/metabolism , Animals , Behavior, Animal/physiology , Female , Humans , Male , Opioid Peptides/adverse effects , Opioid Peptides/agonists , Opioid Peptides/antagonists & inhibitors , Receptors, Opioid/agonists , Receptors, Opioid/metabolism , Receptors, Opioid/physiology
17.
Anesthesiology ; 111(3): 616-24, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19672186

ABSTRACT

BACKGROUND: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). METHODS: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. RESULTS: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CONCLUSION: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.


Subject(s)
Analgesics, Opioid/pharmacology , Opioid Peptides/pharmacology , Oxycodone/pharmacology , Pain/drug therapy , Receptors, Opioid, kappa/agonists , Adult , Analgesics, Opioid/adverse effects , Cross-Over Studies , Double-Blind Method , Electric Stimulation , Esophagus/drug effects , Esophagus/physiology , Hot Temperature , Humans , Male , Monitoring, Physiologic , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Opioid Peptides/adverse effects , Pain Measurement/drug effects , Skin Physiological Phenomena/drug effects , Young Adult
18.
J Pain ; 10(5): 509-16, 2009 May.
Article in English | MEDLINE | ID: mdl-19231294

ABSTRACT

UNLABELLED: Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide for the NOP receptors. Depending on the doses, intrathecal administration of N/OFQ has dual actions (ie, hyperalgesia and antinociception) in rodents. However, the pharmacological profile of intrathecal N/OFQ is not fully known in primates. The aim of this study was to investigate behavioral effects of intrathecal N/OFQ over a wide dose range and to compare its effects with ligands known to produce hyperalgesia or antinociception in monkeys. Intrathecal N/OFQ from 1 fmol to 1 nmol did not produce any hyperalgesic or scratching responses. In contrast, intrathecal substance P 100 nmol produced hyperalgesia, and intrathecal DAMGO 10 nmol produced antinociception. At the dose range between 10 nmol and 1 micromol, intrathecal N/OFQ dose-dependently produced thermal antinociception against a noxious stimulus in 2 intensities. More importantly, N/OFQ in combined with intrathecal morphine dose-dependently potentiated morphine-induced antinociception without inhibiting morphine-induced itch/scratching. Taken together, this study is the first to provide a unique functional profile of intrathecal N/OFQ over a wide dose range in primates. Intrathecal N/OFQ produces thermal antinociception without anti-morphine actions or scratching responses, indicating that N/OFQ or NOP receptor agonists represent a promising target as spinal analgesics. PERSPECTIVE: Intrathecal administration of N/OFQ only produced thermal antinociception, not hyperalgesia, in monkeys. In addition, intrathecal N/OFQ does not have anti-morphine actions or itch/scratching responses. This study strongly supports the therapeutic potential of N/OFQ or NOP receptor agonists as spinal analgesics for clinical trials.


Subject(s)
Analgesics , Opioid Peptides/therapeutic use , Receptors, Opioid/agonists , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/adverse effects , Analgesics, Opioid/pharmacology , Animals , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/adverse effects , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Female , Hyperalgesia/psychology , Injections, Spinal , Macaca mulatta , Male , Morphine/adverse effects , Morphine/pharmacology , Opioid Peptides/administration & dosage , Opioid Peptides/adverse effects , Pain Measurement/drug effects , Pruritus/chemically induced , Substance P/administration & dosage , Substance P/adverse effects , Substance P/pharmacology , Nociceptin
19.
Behav Neurosci ; 121(6): 1224-33, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18085876

ABSTRACT

Gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) provide innervation to cortical and subcortical regions of the brain. To solidify the importance of these VTA GABA neurons in behavioral function, we employed the neurotoxin dermorphin-saporin (DS) to selectively lesion VTA GABA neurons prior to assessing spontaneous motor activity. Rats were bilaterally microinfused with DS (1.0 or 2.0 pmol/200 nl/side) or blank-saporin control (BS, 200 nl/side) into the VTA. Seven days later, DS-treated rats exhibited significantly elevated motility in comparison with BS-treated rats; this elevated motility normalized by Day 14 following pretreatment with 1.0 pmol of DS but was sustained on Day 14 after pretreatment with 2.0 pmol of DS. A selective loss of VTA GABA neurons on Day 14 was demonstrated through reduced expression of mRNA for glutamic acid decarboxylase-67 and micro-opioid receptor, but not tyrosine hydroxylase (a dopamine neuron marker), in the VTA. Thus, a dose- and time-related selective loss of VTA GABA neurons was accomplished using this novel neurotoxin. This loss of GABA VTA neurons was associated with hypermotility, further supporting their important regulatory role in the generation of behavior.


Subject(s)
Motor Activity/physiology , Neurons/physiology , Ventral Tegmental Area/cytology , Ventral Tegmental Area/physiology , gamma-Aminobutyric Acid/metabolism , Analysis of Variance , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Male , Motor Activity/drug effects , Neurons/drug effects , Neurotoxins/adverse effects , Opioid Peptides/adverse effects , Rats , Rats, Sprague-Dawley , Ribosome Inactivating Proteins, Type 1/adverse effects , Saporins , Time Factors , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/drug effects
20.
Eur J Pharmacol ; 563(1-3): 209-12, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17362918

ABSTRACT

The respiratory effects of stimulation of mu-opioid receptors were studied in spontaneously breathing anaesthetized rats that were either neurally intact or subjected to bilateral supranodosal vagotomy. An intravenous dermorphin bolus of 0.5 mg/kg evoked the apnea followed by breathing of reduced rate and compensatory augmentation of tidal volume, which resulted in an invariable minute ventilation. Cardiovascular effects consisted of hypotension and temporary fall in heart rate. In rats initially treated by supranodosal vagotomy, dermorphin did not evoke any respiratory and cardiovascular effects. These results indicate that vagal pathway and the nodose ganglia are involved in dermorphin-induced respiratory depression.


Subject(s)
Analgesics, Opioid/adverse effects , Apnea/chemically induced , Nodose Ganglion/drug effects , Opioid Peptides/adverse effects , Receptors, Opioid, mu/agonists , Respiration/drug effects , Vagus Nerve/drug effects , Analgesics, Opioid/administration & dosage , Animals , Apnea/physiopathology , Blood Pressure/drug effects , Depression, Chemical , Heart Rate/drug effects , Injections, Intravenous , Male , Neural Pathways/drug effects , Nodose Ganglion/metabolism , Opioid Peptides/administration & dosage , Pulmonary Ventilation/drug effects , Rats , Rats, Wistar , Receptors, Opioid, mu/metabolism , Respiratory Mechanics/drug effects , Respiratory Muscles/innervation , Time Factors , Vagotomy/methods , Vagus Nerve/metabolism , Vagus Nerve/surgery
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