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G protein-coupled receptor (GPCR) signal transduction is a fundamental building block of cell biology, yet how different ligands such as peptide agonists and small molecules can act at the same receptor to produce different functional outcomes is not fully appreciated. A proliferation of biochemical, biophysical, and pharmacological studies led to an abundance of receptor active-state structures and candidate molecules selective for desired outcomes while avoiding side effects. With preponderance of data, however, also came contradictions and challenges in interpretations. This thesis returns to the basic step of ligand-receptor-effector interaction, and explores two fundamental questions: 1) can different agonists selectively couple the receptor to different cytoplasmic proteins in intact cells? and 2) in the agonist-selective receptor endocytosis pathway, how do GPCR kinases (GRKs) recognize different agonist-bound receptors? Using two engineered protein biosensors as discreet intracellular proteins, two agonists showed distinctly different profiles in recruiting the protein biosensors. This result provides a proof of concept of a potential answer to the first question, that in a ‘clean’ cellular environment without native signaling interference, agonists can indeed engage two different biosensors with selective preferences. Similarly for the second question, using an engineered GRK-free cellular background, a single GRK subtype was shown to produce agonist-selective functional outcome of receptor internalization. This GRK was also recruited to the receptor in an agonist-selective manner, supporting the hypothesis that selective functional outcomes begin upstream at selective receptor-GRK interactions. Furthermore, a single domain was shown to be the key selectivity determinant for GRK recruitment to the receptor and internalization function.

Zebrafish (Danio rerio) are becoming one of the most important model organisms in behavioural neuroscience. It has been shown repeatedly that different zebrafish strains show large behavioural differences. These divergent behavioural profiles may have a genetic basis, but environmental factors and previous experience are also known to greatly affect the behavioural phenotype of zebrafish. It could be expected that behavioural differences at the larval stage should be less affected by environmental factors and experience. In the present study, we screened larvae of zebrafish of the AB strain and offspring of wild-caught zebrafish for boldness, using an open field test. In order to follow the behavioural development, we studied larvae at the age of 5-, 7-, 12- and 30-days post fertilization (dpf). Behaviour, as well as behavioural development, clearly differed between the larvae of the different strains. Wild larvae showed larger total distance moved than AB larvae, both at light and dark conditions. These differences were already present at 12 dpf but became more pronounced with age. Wild larvae had a greater variance compared to AB larvae for most of the variables. We have previously shown that bold and shy adult zebrafish differ in the brain expression of dopamine and opioid receptors. The results of the current study show that wild larvae display significantly higher brain expression of drd2b than AB larvae at 30 dpf, a difference that could be related to differences in activity. We did not detect any differences in the expression of opioid receptors.

Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Arbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüft, Innsbruck, Univ., Diss., 2021

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, GABA(A)-benzodiazepine, and cannabinoid CB1), stimulant-induced dopamine release, presynaptic FDOPA influx, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT1A and 5-HT2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy.

We present the preparation of the new precursor 6-O-(2-tosyloxyethoxy)-6-O-desmethyl-3O-trityl-diprenorphine (TE-TDDPN) for a one-pot, two-step nucleophilic radiosynthesis of 6-O-(2[18F]fluoroethyl-6-O-desmethyl-diprenorphine ([18F]FE-DPN). The route to the precursor consists of a five-step synthesis starting from diprenorphine. We also provide alternative synthesis routes for the cold reference standard and the complete1H-and13C-NMR assignment of the prepared derivatives.

The obesity epidemic has increased type II diabetes mellitus (T2DM) across developed countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia-reperfusion (I-R) injury, and refractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opioid receptor stimulus may overcome diabetes mellitus-induced cardiac dysfunction via membrane/mitochondrial-dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I-R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochondrial function. T2DM induced 25% weight gain, hyperglycemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca2+ -induced swelling, and cell death were all evident. Morphine administration for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I-R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contractile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short-term, but high-dose morphine administration in diabetic patients undergoing or recovering from acute ischemic cardiovascular events.

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, GABA(A)-benzodiazepine, and cannabinoid CB1), stimulant-induced dopamine release, presynaptic FDOPA influx, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT1A and 5-HT2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy.

The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, behavioral addiction, and substance abuse. It is not always clear whether observed changes of tracer binding reflect altered release of endogenous opioids or altered opioid receptor expression. This issue may be resolved by studies in experimental animals that combine in vivo PET imaging with ex vivo immunohistochemistry. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). Yet, PET offers the unique opportunity of quantifying opioid receptor-mediated signaling in the living human brain. PET imaging has provided evidence for a link between opioid neurotransmission and peripheral immune activation.

Opioids are the mainstay for the management of moderate to severe pain. However, their acute use is associated with several side effects, ranging from nausea, itching, sedation, hypotension to respiratory depression, and death. Also, chronic use of these drugs can lead to the development of tolerance, dependence, and eventually addiction. The most serious side effect, lethality due to opioid-induced overdose, has reached the level of national emergency, i.e., the opioid crisis, which is now the forefront of medicine. In a detailed review (Novel Synthetic Opioids: The Pathologist's Point of View), Frisoni and colleagues have discussed the side effects of novel licit and illicit fentanyl derivatives, as well as the related compounds which are more potent and faster acting than morphine and other conventional opioids (Frisoni, et al., 2018). These drugs affect the central nervous system (CNS) and can promote the development of addiction due to the quick rush they induce because of their faster entry into the brain. These drugs also arrest the cardiovascular and pulmonary systems, increasing the chance of respiratory arrest, leading to opioid-induced overdose morbidity and mortality. The respiratory arrest induced by opioids can be potentiated by other CNS depressants, such as alcohol or benzodiazepines, and therefore may occur more frequently in polydrug users. Therefore, the use of these newer fentanyl derivatives as well as other fast acting opioids should be avoided or limited to specific cases and must be kept out of the reach of children and adolescents who are more vulnerable to become addicted or overdose themselves.

Non-mesoporous Janus silica nanobowls (NBs) are unique in that they possess two different non-porous surfaces per particle for loading biological molecules and can thus be designed with multifunctional properties. Although silica NBs have been successfully employed for both targeted therapeutic and diagnostic applications, their ability to deliver DNA has not yet been fully explored. The purpose of this study was to design and develop an in vitro transfection agent that would exploit the distinct characteristics of the silica NB. In this work, we have demonstrated that such silica NBs can be used for in vitro (cell lines and primary neurons) and ex vivo transfections (dorsal root ganglia, DRG). We have shown that the NB system can be effectively used for supercoiled as well as linearized DNA loading and delivery in cells with dose-modulated protein expression efficiencies in a cell line dependent manner. NBs were shown to successfully internalize in vitro (cell lines and neurons), ex vivo (rat DRG) and in vivo (rat DRG and salivary gland) with high cell viability. This work also demonstrates the use of lipid encapsulation on the silica NBs to overcome vesicular entrapment following endocytosis, which is a well-known bottleneck to non-viral nano delivery systems. After the characterization and optimization of the lipid encapsulated silica NB system (LNB), four different gene delivery applications show its versatility. First, controlled release of linearized DNA was demonstrated with NBs in the presence of reducing agents and their relative protein expression efficiencies were compared with other constructs i.e. linearized and supercoiled. Second, the LNB system was used to transfect neurons and glia in the DRG of rats in vitro or ex vivo. Thirdly, the LNB system was used to co-deliver three different constructs simultaneously to functionally reconstruct the coupling of two membrane proteins relevant in opioid-dose response in the nervous system. G-protein coupled opi

Dopamine (DA)-replacement therapy utilizing L-DOPA is the mainstay of symptomatic treatment for Parkinson’s disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID), which occurs in the majority of patients. Endogenous opioid peptides, including enkephalins and dynorphins, are co-transmitters of dopamine, gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the direct and indirect striatal output pathways, which are disrupted in PD. Alterations in levels of expression of these peptides and their precursors have been implicated both in PD and in the subsequent development and expression of LID. Alterations in N-methyl-D-aspartate (NMDA) glutamate transmission have also been implicated in LID; the NMDA receptor antagonist amantadine is the only drug currently approved for the clinical treatment of LID.⁠ We utilized pharmacological techniques to investigate the role of altered opioid and NMDA neurotransmission occurring in the direct and indirect striatopallidal output pathways in preclinical models of PD and LID. In the first study presented (Chapter 2), we show that the antidyskinetic effects of the NMDA receptor antagonist MK-801 are preferential to the indirect pathway. Specifically, we show that MK-801 is capable of suppressing hyperkinetic abnormal involuntary movements (AIMs) induced by a selective D2R agonist, quinipirole but not those induced by a selective D1R agonist, SKF81297. Importantly, MK-801 is capable of suppressing AIMs induced by L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine), which is the most effective clinical treatment for PD, even though this agent likely activates both outflow pathways, and quinpirole, but not those induced by SKF81297. This finding of MK-801 also indicates that the contribution of NMDA receptor-mediated glutamatergic transmission to the expression of LID may be specific to the indirect striatopallidal output pathway. In Chapter 3, we have investigated the effec

Cellular signaling by G protein-coupled receptors (GPCRs) governs a wide array of physiological functions throughout the body. The human δ-opioid receptor (hδOR) is a GPCR that modulates the sensation of pain and mood and has great potential for the treatment of pain and a variety of neurological disorders. A common single-nucleotide polymorphism (SNP) in the extracellular N-terminal tail of hδOR changes Phe to Cys at position 27. Using various biochemical and cell biological methods, the study demonstrates that several events during receptor biosynthesis and cell surface delivery are affected by the SNP. These events participate in the multifaceted regulation of the receptor and modulate receptor behavior at the cell surface. Two distinct pathways were shown to scrutinize the quality of the synthesized hδOR in the endoplasmic reticulum (ER) and target some for degradation in N-glycan-dependent and -independent ways. The hδORCys27 that matures inefficiently required N-glycan-mediated interactions with the lectin-chaperone calnexin to be expressed in a fully functional form at the cell surface, whereas the N-glycan-independent pathway was sufficient for hδORPhe27. For both variants, the N-glycan-independent quality control, which is likely to operate as a back-up pathway, led to a more rapid export from the ER and receptors at the cell surface that were less stable. Receptor dimerization emerged as an important regulatory step for receptor cell surface delivery. In co-transfected cells, interactions between the newly-synthesized variants led to the retention and subsequent ER-associated degradation of hδORPhe27. This dominant-negative attenuation of hδORPhe27 cell surface expression by hδORCys27 may have unpredictable consequences for opioid signaling in heterozygous individuals. Finally, the study shows that N-acetylgalactosamine (GalNAc)-type O-glycosylation catalyzed in the Golgi modulates hδOR expression at the cell surface by enhancing receptor stabilit, Tiivistelmä Solujenvälisellä viestinnällä on keskeinen tehtävä kehon kaikissa toiminnoissa. δ-opioidireseptori (δOR) on solusignalointiin erikoistuneen kalvoproteiiniperheen (G-proteiiniin kytketyt reseptorit) jäsen, joka ohjaa kivuntuntemusta ja mielialoja. Sitä pidetään mahdollisena lääkekehityksen kohteena paitsi kivunlievityksen, myös useiden neurologisten häiriöiden hoidossa. δOR ilmenee kahtena polymorfisena muotona sen solunulkoisessa osassa tapahtuneen aminohappomuutoksen vuoksi (Phe27Cys). Työssä tutkittiin reseptorin glykosylaatiota ja dimerisaatiota, jotka säätelevät sen prosessointia, käyttäytymistä ja toimintaa. Käyttäen useita biokemiallisia ja solubiologisia menetelmiä työssä osoitettiin polymorfian vaikuttavan useisiin prosessointivaiheisiin ja muokkaavan siten reseptorin viestintää. Proteiinien laadunvalvontakoneiston havaittiin säätelevän reseptorin siirtymistä endoplasmakalvostolta solun pinnalle kahdella eri mekanismilla ohjaten osan reseptoreista hajotukseen. Toisin kuin Phe27-variantin, tehottomasti kypsyvän Cys27-variantin laadunvalvonta on riippuvainen reseptoriin liittyvistä N-glykaaneista ja näihin sitoutuvasta kaitsijaproteiinista, kalneksiinista. Reseptorivariantit, joista N-glykaanit puuttuvat, siirtyvät nopeammin solukalvolle, mutta ne ovat epästabiileja ja häviävät nopeasti solun pinnalta. Vaihtoehtoinen N-glykaaneista riippumaton laadunvalvontamekanismi sallii myös inaktiivisen Cys27-variantin pääsyn solun pinnalle. Varianttien dimerisoitumisen osoitettiin säätelevän niiden kuljetusta soluissa. Cys27-variantin havaittiin sitoutuvan Phe27-varianttiin aikaisessa biosynteesivaiheessa ja ohjaavan osan siitä hajotukseen. Tällä voi olla suuri merkitys opioidiviestinnässä molempia alleeleja kantavilla henkilöillä. Työssä havaittiin myös GalNAc-transferaasi-2-entsyymin ohjaavan Golgin laitteessa tapahtuvaa reseptorin O-glykosylaatiota. Se glykosyloi reseptorin solunulkoisen osan seriinitähteitä (Ser6, Ser25, Ser29), stabiloiden siten solun pi

Aims: Eslicarbazepine acetate (ESL) is a novel dibenzazepine antiepileptic, that has demonstrated efficacy against trigeminal pain, both in preclinical and clinical studies. However, ESL's mechanism of antinociceptive action remains uncertain. Here, we aimed to examine the contribution of adrenergic/cholinergic/opioid receptors to the antinociceptive effects of ESL in a trigeminal pain model, as these neurotransmitter systems are known to have an important role in the modulation of trigeminal nociception. Main methods: ESL's effects in the orofacial formalin test were examined following peroral and local peripheral administration (subcutaneous, into the perinasal region). The involvement of adrenergic/cholinergic/opioid receptors was evaluated by intraperitoneally pretreating mice with an appropriate antagonist immediately after peroral application of ESL. We used antagonists of alpha(1)-adrenergic (prazosin), alpha(2)-adrenergic (yohimbine), beta(3)-adrenergic (non-selective, propranolol and beta(1)-selective, metoprolol), muscarinic (atropine), nicotinic (mecamylamine) and opioid receptors (naloxone). Additionally, the role of peripheral alpha(2)-adrenergic, beta(1)-adrenergic, muscarinic and opioid receptors was evaluated by co-injecting ESL with an antagonist into the perinasal area. Key findings: ESL dose-dependently reduced formalin-induced nociceptive behavior after systemic and local peripheral application. Systemic administration of yohimbine, propranolol, metoprolol, atropine and naloxone inhibited ESL's antinociceptive effects in a dose-related manner. Prazosin and mecamylamine did not produce inhibitory effects. Local application of yohimbine, atropine and naloxone into the perinasal area also produced a dose-related inhibition of ESL's efficacy, whereas metoprolol failed to inhibit the local antinociceptive effects of ESL. Significance: This study suggests that ESL's efficacy against trigeminal nociception is mediated by peripheral (and possibly central

Physiological responses to the opioid neuropeptide enkephalin often involve both mu and delta opioid receptors. To facilitate quantitative studies into opioid signaling, we previously developed a caged [Leu5]-enkephalin that responds to ultraviolet irradiation, but its residual activity at delta receptors confounds experiments that involve both receptors. To reduce residual activity, we evaluated side-chain, N-terminus, and backbone caging sites and further incorporated the dimethoxy-nitrobenzyl moiety to improve sensitivity to ultraviolet light-emitting diodes (LEDs). Residual activity was characterized using an in vitro functional assay, and the power dependence and kinetics of the uncaging response to 355 nm laser irradiation were assayed using electrophysiological recordings of mu opioid receptor-mediated potassium currents in brain slices of rat locus coeruleus. These experiments identified N-MNVOC-LE as an optimal compound. Using ultraviolet LED illumination to photoactivate N-MNVOC-LE in the CA1 region of hippocampus, we found that enkephalin engages both mu and delta opioid receptors to suppress inhibitory synaptic transmission.

In the present study, the role of inter-residue interactions in ligand binding and the ligand-receptor interactions were examined. Computational chemistry methods of ligand docking and molecular dynamics simulations were used to study the binding of beta-funaltrexamine (beta-FNA) and N-methyl-beta-funaltrexamine (N-methyl-beta-FNA) to mu- and kappa-opioid receptors and to the mu-receptor with Lys303(6.58) Glu mutation. It was found that inter-residue interactions Lys233(5.39)-Glu303(6.58) in the mutant receptor and Lys227(5.39) Asp223(5.35) in the.-receptor are more likely to prevent covalent bond formation between beta-FNA and the receptor than the ligand-receptor interactions. This emphasizes the importance of inter-residue interactions in ligand binding as well as the effects of point-mutations. (C) 2016 Institute of Chemistry, Slovak Academy of Sciences

Neurofibromatosis type 1 (NF1) is a monogenic dominant disorder caused by the mutations in the NF1 protein. In addition to developing tumors, NF1 patients suffer from prominent neuropsychiatric symptoms that include cognitive impairments, motor coordination problems, attention difficulties and pain. The focus of this proposal is on molecular mechanisms by which NF1 protein affects signal transduction in the key neuronal pathways and, as such, underlies development of neuropsychiatric problems. During the initial funding period we have achieved significant progress in many of the proposed directions and are on track to continue successful implementation of proposed studies during the next period. Specifically, we have generated all necessary animal models, tools and reagents and applied them to investigate impact of NF1 on: (1) cAMP signaling in brain tissues and cultured cells, and 2) Ras signaling in neurons, revealing its key role in transducing signals from opioid receptors. These findings will likely have an impact on understanding signaling disruptions in neurofibromatosis and development of innovative therapeutic strategies., The original document contains color images.

Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X(3) purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X(3)-mediated currents with IC50 similar to 10 nM in similar to 25 % of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X(3) currents. All effects of opioid were abolished by selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and mu-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X(3) receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X(3) receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.

Opioid peptides and their receptors have been localized to the inner ear of the rat and guinea pig mammalian models. The expression of mu opioid receptor (MOR) in the human and mouse cochlea is not yet known. We present MOR protein localization by immunohistochemistry and mRNA expression by in situ hybridization in the human and mouse spiral ganglia (SG) and organ of Corti. In the human most of the (SG) neurons were immunoreactive; a subset was non-immunoreactive. In situ hybridization revealed a similar labeling pattern across the neurons of the SG. A similar distribution MOR pattern was demonstrated in the mouse SG. In the mouse organ of Corti MOR was expressed in inner and outer hair cells. Fibers underneath the inner hair cells were also MOR immunoreactive. These results are consistent with a role of MOR in neuromodulation of the auditory periphery. The present results show that the expression of MORs is well-conserved across multiple mammalian species, indicative of an important role in auditory processing.

Using drugs such as alcohol and morphine among others can be addictive in some individuals, and progress into a substance abuse disorder. The mesolimbic dopaminergic system (MD-system) is involved in the reward process during the development of drug addiction. The MD-system is critical for survival and affects different behaviors in both man and animal. Neurochemical pathways drive for instance physical activity, food intake, love and reproduction and are part of the natural reward process involved partly in the release of dopamine (DA) into frontal lobes. Within the MD-system opioid receptors throughout the brain are affected by drug intake, and activation of these receptors modulate DA-release in brain regions involved in reward-behavior. The aim of this study was to evaluate gene expression of MOR and DOR within the endogenous opioid system (EO-system) in relation to voluntary physical activity, a natural reinforcer. Further on investigations of the drug alcohol was compared to the natural reinforcer sucrose using voluntary consumption. For both experiments qRT-PCR was used to measure mRNA levels of MOR and DOR from brain areas of interest. We found a small significant up regulation in NAc, PFC and VTA but for DOR in VTA a down regulation in gene expression of physical exercising mice. Additionally these two different genes OPRM1- and the OPRD1- gene are down regulated in VTA and NAc due to alcohol- and sugar-intake. This implicate that the natural reward system and their ORs point in the direction of earlier findings; the opioid receptors have a key role in regulate alcohol intake and the natural rewarding stimuli as food intake.

Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma-aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate's antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of systemic and local peripheral topiramate on carrageenan-induced hyperalgesia and (ii) the effects of systemic and local peripheral bicuculline (selective GABAA receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective 2-adrenergic receptor antagonist) on topiramate-induced antihyperalgesia. Systemic topiramate (40160mg/kg; p.o.) produced a significant dose-dependent reduction in the paw inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of systemic topiramate was significantly decreased by systemic bicuculline (0.51mg/kg; i.p.), naloxone (25mg/kg; i.p.), and yohimbine (13mg/kg; i.p.). Local peripheral topiramate (0.030.34mg/paw; i.pl.) also produced significant dose-dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.050.2mg/paw; i.pl.) but not by local peripheral bicuculline (0.15mg/paw; i.pl.) or naloxone (0.1mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABAA and opioid receptors and by peripheral and most probably central 2-adrenergic receptors. These findings contribute to better understanding of topiramate's action in pain states involving inflammation.

Endogenous opioids play an important role in regulating reinstatement of extinguished drug seeking. Ten experiments investigated the neuroanatomical locus for opioid regulation of renewal, alcohol-primed reinstatement, and re-acquisition of extinguished beer seeking response. Rats were trained to nose poke for alcoholic beer in a particular context. This response was extinguished in either an alternate context or in the same context. Recovery of responding was produced in one of three ways. In renewal, rats were returned to the acquisition context. In primed reinstatement, rats were allowed to consume a small amount of beer at the commencement of test. In reacquisition, rats were allowed to respond once more for alcoholic beer. Within each of these experiments three different challenges to opioid neurotransmission were applied: a systemic injection of the general opioid receptor antagonist, naloxone, an infusion of the µ-opioid receptor antagonist CTAP into the accumbens shell, or a similar infusion into the ventral pallidum. Systemic naloxone attenuated renewal, primed reinstatement, and reacquisition. Intra-pallidal infusions of CTAP also attenuated all three forms of relapse; however intra-accumbal infusions reduced context-induced reinstatement only. In order to characterise the role of the ventral pallidum in reinstatement, active projections to this region during renewal were examined. The retrograde neuronal tracer Cholera Toxin-b subunit was injected into the pallidum of rats prior to training and testing for renewal. Retrograde-labelled neurons and c-Fos protein immunoreactivity within the accumbens shell and elsewhere in the brain were examined. Active projections specific to renewal were not found in the accumbens shell, however they were seen in the accumbens core, rostral basolateral amygdala, and the paraventricular thalamus. These findings are consistent with the hypothesis that opioid receptors mediate the hedonic impact of ethanol and ethanol associ

Opioid receptors, including the mu and delta opioid receptors (MOR and DOR) are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers compared to DOR homomers. Here we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.

We previously demonstrated that intrathecal treatment with substance P metabolite substance P1-7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1-7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1-7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1-7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1-7. The antinociceptive effect of substance P1-7 amide was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the mu-, delta- or kappa-opioid receptor, respectively. In addition, the antinociceptive effect induced by substance P1-7 amide was partly reversed by the sigma(1) receptor agonist (+)-pentazocine, suggesting a possible involvement of the sigma(1) receptor for the action of this peptide. These results suggest that the actions of substance P1-7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the sigma(1) receptor system.

The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants' hedonic value. NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals' obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether the NAcc dopamine response to palatable food depends on obesity susceptibility. We investigated the effect of unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D(1) and D(2) gene expression in OP and OR rats subjected to HFHS withdrawal (bland chow for 18 days). Effects of restricted access to HFHS by pair-feeding were also studied. Using reverse transcriptase PCR (RT-PCR), we found that NAcc D(1) mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect was also observed after 18 days of HFHS withdrawal. Furthermore, restricted HFHS led to downregulation of D(1) as well as of D(2) mRNA levels compared to chow-fed controls. A difference in the expression of mu opioid receptor in the NAcc was also detected between the OP and OR rats during access to palatable food but not after withdrawal. We conclude that exposure to HFHS diets has lasting consequences for the NAcc dopamine system, perhaps modifying the motivation to search for food reward. The fact that the NAcc D(1) expression changes in OP animals after long-term exposure to palatable food and that this effect extends well into the reward discontinuation phase, implicates the D(1) receptor in the propensity to overeat and, in effect, gain weight in obesity prone individuals.

BACKGROUND AND PURPOSE Levetiracetam, a novel antiepileptic drug, has recently been shown to have antinociceptive effects in various animal models of pain. The purpose of this study was to investigate the antihyperalgesic effect of levetiracetam and its mechanism of action, by examining the involvement of GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic) and adrenergic systems in its effect, in a rat model of inflammatory pain. EXPERIMENTAL APPROACH Rats were intraplantarly injected with the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of levetiracetam on carrageenan-induced hyperalgesia; and (ii) the effects of bicuculline (selective GABA(A) receptor antagonist), naloxone (non-selective opioid receptor antagonist), methysergide (non-selective 5-HT receptor antagonist) and yohimbine (selective alpha(2)-adrenoceptor antagonist) on the antihyperalgesic action of levetiracetam. RESULTS Levetiracetam (10-200 mg center dot kg-1; p.o.) significantly reduced, in a dose-dependent manner, the inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of levetiracetam was significantly decreased after administration of bicuculline (0.5-2 mg center dot kg-1; i.p.), naloxone (1-3 mg center dot kg-1; i.p.), methysergide (0.25-1 mg center dot kg-1; i.p.) and yohimbine (1-3 mg center dot kg-1; i.p.). CONCLUSIONS AND IMPLICATIONS These results show that levetiracetam produced antihyperalgesia which is at least in part mediated by GABA(A), opioid, 5-HT and alpha(2)-adrenergic receptors, in an inflammatory model of pain. The efficacy of levetiracetam in this animal model of inflammatory pain suggests that it could be a potentially important agent for treating inflammatory pain conditions in humans.

The studies proposed in this project will test the hypotheses that in the non-human primate (1) the functions and behavioral effects of the NOP receptor are independent of classical opioid receptors, (2) activation of the NOP receptor produces strong antinociception without abuse liability, and (3) NOP receptor agonists possess a promising therapeutic profile as analgesics compared to mu opioids following repeated administration in primates. Several key findings have been obtained and some have been published. First, intrathecal administration of N/OFQ only produced antinociception in primates. The functional profiles of spinal NOP receptors are different between primates and rodents. Second, intrathecal administration of N/OFQ produced antinociception without eliciting itch/scratching responses, indicating that NOP receptor agonists represent a therapeutic target as spinal analgesics. Third, NOP receptor agonists produced antinociceptive effects comparable to clinically used mu opioids such as morphine and alfentanil in three different primate pain models, indicating that the analgesic effectiveness of NOP receptor agonists may be similar to that of mu opioid analgesics in humans. Finally, unlike mu opioids, NOP receptor agonists did not produce reinforcing effects, respiratory depressant, sedation, or itch/pruritic side effects, indicating that NOP receptor agonists may be a new generation of novel analgesics without abuse liability.

Improved procedures for the glycosylation of serine and threonine utilizing Schiff base activation are reported. The procedures are less expensive and more efficient alternatives to previously published methods. The Schiff bases exhibited ring-chain tautomerism in CDCl₃ as shown by ¹H NMR. Acting as glycosyl acceptors, the Schiff bases reacted at RT with simple sugar peracetate donors with BF₃•OEt₂ promotion to provide the corresponding protected amino acid glycosides in good yields. With microwave irradiation, the reactions were complete in 2-5 minutes. Glycosylation with the dipeptide Schiff base shows the potential of this method in the preparation of peptide building blocks. To investigate this reaction further, direct glycosylation of sugar acetates with FMOC-Ser-OH/OBZl under BF₃•OEt₂ promotion in a microwave provided glycosides in high yield. In addition to the expected glycoside products acetylated side products resulting from acetate migration were isolated, suggesting that activation of the anomeric sugar acetates with a Lewis acid such BF₃•OEt₂ led to an oxocarbenium ion, which rearranged to a 1,2-dioxocarbenium ion because of the acetate participating group at C-2. Solvent participation was also illustrated with acetate migration being more pronounced when CH₃CN was used as a solvent and resulted in less product yield and higher amounts of the acetylated product. The acyl transfer products in these reactions where sugar acetates serve as glycosyl donors is reported for the first time, which also implies that ortho-ester like intermediates are important in the reaction mechanism. Keeping the message segment constant in the sequence H-Tyr-DThr-Gly-Phe-Leu- Ser-CO-NH₂ and modification of the address segment with different carbohydrate moieties had little effect on selectivity for binding at the μ, δ, or κ-opiod receptors. However, substitution of D-threonine with D-serine or the less polar D-alanine in the message segment resulted in a loss of κ-receptor af

The mechanisms of the analgesic action of carbamazepine and oxcarbazepine, in particular the role of opioid receptors, have not been established precisely. The systemic effects of naloxone, an opioid receptor antagonist, on the antihyperalgesic effects of carbamazepine and oxcarbazepine were examined in the model of inflammatory hyperalgesia induced by the intraplantar (i.pl.) administration of concanavaline A (Con A, 0.8 mg/paw) into the rat hind paw. Naloxone (3 mg/kg; i.p.) did not alter the antihyperalgesic effects of either carbamazepine or axcarbazepine. These results indicate that the opioid system of pain modulation does not play a significant role in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

The development of the prototype synthetic δ-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe-Phe-OH); Tic: tetrahydroisoquinoline-3- carboxylic acid] and TIPPψ (H-Tyr-ψTic-Phe-Phe-OH) by Schiller and co-workers was followed by extensive structure-activity relationship studies, leading to the emergence of numerous analogs that are of pharmacological interest. Eight novel diastereomeric compounds in this peptide family were designed, prepared, and tested biologically to gain structure-activity relationship information. The new multisubstituted tetrapeptide analogs contain both a 2′,6′-dimethyltyrosine residue at the N-terminus and β-methyl-cyclohexylalanine at the third position as replacements for the original first tyrosine and the third phenylalanine, respectively. These derivatives wear either free acidic (-COOH) or amidated (-CONH2) C-terminal. The potency and δ- versus μ-opioid receptor selectivity were evaluated by in vitro radioreceptor-binding assays, while the intrinsic G-protein-activating efficacy of these analogs was tested in [ 35S]GTPγS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing μ- or δ-opioid receptors. The analogs showed δ-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed μ-agonist/δ-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. These results constitute further examples of the influence of β-methyl substitution and C-terminal amidation on potency, selectivity, and signal transduction properties of TIPP-related peptides as well as they represent valuable pharmacological tools for opioid research. Copyright © 2005 S. Karger AG., SCOPUS: ar.j, info:eu-repo/semantics/published

1. Morphine and opiate narcotics are potent analgesics that have a high propensity to induce tolerance and physical dependence following their repeated administration. 2. The molecular basis of opiate dependence has not been completely elucidated, although the participation of opioid receptors is a prerequisite. Cellular dependence on opioids is believed to result from the chronic stimulation of opioid-regulated signalling networks. 3. As G-protein-coupled receptors, the opioid receptors must rely on heterotrimeric G-proteins for signal transduction. Recent advances in our understanding of G-protein signalling have unveiled novel signalling molecules and mechanisms, some of which may be intricately involved in the manifestation of opiate dependence. 4. In the present review, we will attempt to trace chronic opioid signals along elaborate G-protein-regulated pathways.

In this thesis, two newly discovered endogenous opioid peptide families, the hemorphins and endomorphins, are investigated with emphasis on modulation of pain and inflammation. In addition, the presence of hemorphins in human biological fluids as well as the in vitro and in vivo processing ofLVV-hemorphin-7 in blood and brain is investigated. Using various chromatographic techniques in combination with radioimmunoassay, several hemorphin-like peptides were detected in cerebrospinal fluid from patients with cerebrovascular bleedings, but only in negligible amounts in control CSF. Results from in vitro experiments in human plasma showed that LVV-hemorphin-7 was metabolized mainly from the N-terminal end, as determined by RP-HPLC and micro-electrospray mass spectromety. In vivo microdialysis was used to study the processing of LVV-hemorphin-7 in rat striatum and blood. The results demonstrated that the decapeptide was metabolized to form C-terminal fragments, consistent with the results in vitro, however an N-terminal fragment and several internal fragments were also detected. The modulatory effects of hemorphin-7 and endomorhin-1 (EM-l) on a peripheral inflammatory response were investigated in a blister model in the rat hind paw. The results showed that hemorphin-7 (20µM) and EM-1 (100µM) inhibited the vascular response to electrical stimulation of the sciatic nerve at 20V, 5Hz, 2ms by 54% and 58%, respectively. When exogenously perfused over blisters induced acutely in naive skin, both peptides were shown to attenuate both plasmaextravasation and vasodilatation responses to substance P in a naloxone-revesible manner, suggesting an involvement of opioid receptor(s) in these responses. While hemorphin-7 was shown to modulate the peripheral inflammatory response, in acute injury conditions only, EM-l was able to attenuate this response in acute, as well as recurrent and chronic injury conditions. The results presented support the proposition that different endogenous i

The role of central opioid receptor types in the modulation of humoral immune response was not investigated so far. Therefore, the aim of the present work was to investigate the possible role of these receptors in immunomodulation. For this purpose, male Wistar rats were intracerebroventricularly (icv) injected with opioid receptor specific antagonists. Control groups of rats were treated icv with physiological saline. Primary humoral immune response was determined by the "plaque-forming cell assay" (PFC response). ICI 174864, a selective d opioid receptor antagonist, administered icv at doses of 0.1; 1; 10; 20 and 50 mg/kg bw caused a statistically significant immunosuppression. b-funaltrexamine (b-FNA), specific m opioid receptor antagonist, applied icv produced a significant immunosuppression only at lower doses of 0.01 and 0.1 mg/kg. Nor-binaltorphimine (nor-BNI), a selective k opioid receptor antagonist administered icv, produced significant immunopotentiation at all applied doses (0.1; 1; 10 and 50 mg/kg bw) except for the lowest dose 0.01 mg/kg bw. Quaternary naltrexone (QNTx), which is a m opioid antagonist at lower doses, but a nonselective opioid antagonist at higher doses, caused statistically significant potentiation on PFC response only when it was given icv at doses of 1 and 10 mg/kg bw. The results indicated differential involvment of central opioid receptor subtypes in immunomodulation., Uloga samostalno intracerebroventrikularno (icv) primenjenih antagonista opioidnih receptora na humoralni imuni odgovor do danas nije proučavana. Stoga je cilj ovog rada bio da rasvetli efekte ovih supstancija u imunomodulaciji. U tu svrhu koristili smo Vistar pacove, težine 200-250 g, koji su čuvani pod standarnim uslovima. Suptancije su icv aplikovane i sve grupe imale su kontrolne grupe koje su bile tretirane ekvimolarnim fiziološkim rastvorom. Imuni odgovor je odredjivan merenjem broja hemolitičkih plaka (PFC) odgovor. ICI 174864, selektivni delta opioidni antagonist, icv aplikovan u dozama od 0,1;1;10;20 i 50 mg/kg tt prouzrokovao je statistički značajnu imunosupresiju. Beta-funaltreksamin (beta-FNA), specifični mi opioidni antagonist icv aplikovan izazvao je statistički značajnu imunosupresiju, kada je bio primenjen u dozama 0,01 i 0,1 mg/kg tt. Nor-binaltorfimin (nor-BNI), selektivni kapa opioidni antagonist icv primenjen, prouzrokovao je statistički značajnu imunopotencijaciju u svim aplikovanim dozama (0,1; 1; 10 i 50 mg/kg tt), izuzev u najnižoj dozi (0,01 mg/kg tt). Kvaternerni naltrekson (QNTx) koji se ponaša kao mi opioidni antagonist u nižim dozama, a delta opioidni antagonist u višim dozama, ne prelazi krvno moždanu barijeru icv aplikovan izazvao je statistički značajnu potencijaciju PFC odgovora, ali samo kada je primenjen u dozama od 1 i 10 mg/kg tt.

The cloning of the opioid receptors allows the investigation of receptor domains involved in the peptidic and nonpeptidic ligand interaction and activation of the opioid receptors. Receptor chimera studies and mutational analysis of the primary sequences of rite opioid receptors have provided insights into the structural domains required for the ligand recognition and receptor activation. In the current review, we examine the current reports on the possible involvement of extracellular domains and transmembrane domains in the high-affinity binding of peptidic and nonpeptidic ligands to the opioid receptor. The structural requirement for the receptors' selectivity toward different ligands is discussed. The receptor domains involved in the activation and subsequent cellular regulation of the receptors' activities as determined hy mutational analysis will also be discussed Finally, the validity of the conclusions based on single amino acid mutations is examined. (C) 2000 John Wiley & Sons, Inc.

The effect of opioid receptor agonists and antagonists on the electrically evoked release of endogenous serotonin (5-hydroxytryptamine, 5-HT) was studied in superfused slices of the rat ventral lumbar spinal cord. Met-ENK (1 x 10(-8)M-1 x 10(-6)M) and DPDPE (1 x 10(-8)M-1 x 10(-6)M) reduced the evoked 5-Ht release in a concentration dependent fashion. DAMGO (1 x 10(-8)-1 x 10(-6)) and (-)-trans-(1S,2S)-U-50488 (1 x 10(-6)M) had no effect on the 5-HT release. The inhibitory effect of met-ENK was completely abolished by ICI-174,864, but neither by naloxonazine nor nor-binaltorphimine. Following i.c.v. treatment with 5,7-dihydroxytryptamine (5,7-DHT), the tissue concentration of 5-HT was reduced by 97%, whereas the concentration of noradrenaline was reduced by only 5%. The tissue concentration of met-ENK, as measured by radioimmunoassay, was not significantly altered. The results suggest that met-ENK is present in the rat ventral spinal cord mainly in non-serotonergic nerve terminals and exerts an inhibitory action on 5-HT release via delta opioid receptors.

The guanine nucleotide analogue, 5′‐p‐fluorosul‐phonylbenzoyl guanosine (FSBG), can react covalently with GTP‐binding proteins (G proteins). In rat brain membranes, FSBG causes a time‐dependent loss of β,γ‐imido[8‐3H]guanosine 5′‐triphosphate binding sites. Using 1 mM FSBG, the guanyl nucleotide modulation of opioid agonist binding is abolished, whereas the guanyl nucleotide sensitivity of neurotensin binding is retained. The action of FSBG can be prevented by the presence of opioid agonists, but not the antagonist naloxone. Iodoacetamide treatment of membranes in the presence of agonist, but not antagonist, can attenuate the action of FSBG in blocking guanyl nucleotide modulation of opioid agonist binding. These results suggest that FSBG covalently modifies essential thiol groups, whose exposure to the reagent is modified by agonist occupancy of the receptor, on a species of G protein linked to opioid receptors, but not on a species of G protein linked to neurotensin receptors. Thus, FSBG may have selectivity for the forms of Gi or Go, proteins associated with opioid receptors. Copyright © 1990, Wiley Blackwell. All rights reserved

Pub. in Proceedings of the Western Pharmacology Society, v27 p429-433 1984.

Opioid receptors solubilized in Mg2+-digitonin (2%, wt/vol) from Mg2+-pretreated rat brain membranes maintain, in addition to high-affinity opioid agonist binding, the modulation by guanine nucleotides. One of the modes of expression of the latter property is an attenuation of agonist binding by guanine nucleotides in the presence of Na+. To investigate the molecular basis of this modulation and to identify the G protein(s) involved, the soluble receptors were [32P]ADP-ribosylated by means of Bordetella pertussis toxin and subjected to molecular size exclusion chromatography. In addition, soluble extracts were chromatographed on lectin and hydrophobic affinity columns. The binding of 35S- and 3H-labelled analogues of GTP was also monitored in the species separated. The oligomeric G protein-coupled opioid receptors and the guanine nucleotide/pertussis toxin-sensitive species showed similar chromatographic properties in all three systems. This indicates that the biochemically functional G protein-opioid receptor complex formed in Mg2+-pretreated membranes in the absence of an agonist is stable in digitonin solution and to chromatographic separation. Further analysis showed that the guanine nucleotide modulation of opioid receptors is via the pertussis toxin substrates with Mr of 41,000 and 39,000, which are identified as Gi and Goα subunits, respectively.

Intracerebroventricular administration of the synthetic dipeptide derivative Lys-Trp (Nps) (LTN) elicits a potent and naloxone-sensitive antinociceptive effect in mice and in rats using heat and electrical current respectively as the noxious stimuli. LTN does not induce analgesia by directly acting on opioid receptors but the peptidase inhibiting activity of the new compound may account in part for the behavioral effect. LTN produces also a marked decrease in the met-enkephalin content of the periaqueductal gray suggesting a possible enkephalin releasing property. Structure-activity studies with different analogs of LTN indicate that replacement of Lys by other basic amino acids results also in compounds with a potent antinociceptive effect whereas replacement by neutral or acidic amino acids leads to a complete loss of activity.

© 2017, Pleiades Publishing, Ltd.Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABAB and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The preand postsynaptic effects of activation of these receptors are also discussed.

© 2017, Pleiades Publishing, Ltd.Long-term potentiation and depression of synaptic transmission have been considered as cellular mechanisms of memory in studies conducted in recent decades. These studies were predominantly focused on mechanisms underlying plasticity at excitatory synapses. Nevertheless, normal central nervous system functioning requires maintenance of a balance between inhibition and excitation, suggesting existence of similar modulation of glutamatergic and GABAergic synapses. Here we review the involvement of G-protein-coupled receptors in the generation of long-term changes in synaptic transmission of inhibitory synapses. We considered the role of endocannabinoid and glutamate systems, GABAB and opioid receptors in the induction of long-term potentiation and long-term depression in inhibitory synapses. The preand postsynaptic effects of activation of these receptors are also discussed.