Kappa Opioid Receptor Activation in the Nucleus Accumbens Inhibits Glutamate and GABA Release Through Different Mechanisms

2003 ◽  
Vol 89 (5) ◽  
pp. 2389-2395 ◽  
Author(s):  
Gregory O. Hjelmstad ◽  
Howard L. Fields
Keyword(s):  
Nucleus Accumbens ◽  
Drugs Of Abuse ◽  
Glutamate Release ◽  
Cell Voltage ◽  
Gaba Release ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Postsynaptic Currents ◽  
Mechanism Of Inhibition

Through their actions in the nucleus accumbens (NAc), kappa opioid (KOP) receptors and their endogenous ligand, dynorphin, modify behaviors associated with the administration of drugs of abuse and are regulated by exposure to such drugs. Despite their demonstrated behavioral significance, the synaptic actions of KOP receptor ligands in the NAc are not clearly understood. Using whole-cell voltage-clamp recordings of NAc medium spiny neurons, we have found that, in addition to suppressing glutamate release, the KOP receptor agonist U69593 also inhibits GABA release. Interestingly, the mechanism of inhibition of the release of glutamate differs from that controlling GABA. U69593 reduces the frequency of Ca2+-independent miniature excitatory postsynaptic currents, but not miniature inhibitory postsynaptic currents. Furthermore, while the U69593 inhibition of GABAergic transmission is blocked by the N-type Ca2+channel blocker ω-CgTx, the inhibition of excitatory glutamatergic transmission by U69593 is unaffected by N-type Ca2+ channel blockade. These results indicate that KOP receptor activation inhibits GABA release by reducing Ca2+ influx, but inhibits glutamate release at a step downstream of Ca2+entry.

scholarly journals EXPRESS: Functional bias of morphine and oliceridine under conditions of minor injury

2021 ◽  
pp. 174480692098844
Author(s):  
Chinwe Nwaneshiudu ◽  
Xiao-You Shi ◽  
Peyman Sahbaie ◽  
J. David Clark
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Opioid Receptor ◽  
Medial Prefrontal Cortex ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Opioid Antagonist ◽  
Opioid Agonist ◽  
Kappa Opioid ◽  
Mu Opioid

Recent reports suggest pain from surgical injury may influence the risks associated with exposure to opioids. In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin. In this focused group of studies, we examined the hypotheses that kappa-opioid receptor activation in the nucleus accumbens mediates attenuated drug- primed reinstatement after incisional surgery, and the G-protein biased mu-opioid agonist, oliceridine, leads to less priming of the dynorphin effect in comparison to morphine. To address these hypotheses, adult C57BL/6 male mice underwent intracranial cannulation for administration of the selective kappa-opioid antagonist norBNI directly into the nucleus accumbens. After recovery, they were conditioned with morphine or oliceridine after hind-paw incisional injury, then underwent extinction followed by opioid-primed reinstatement. Intra-accumbal administration of norBNI was carried out prior to testing. The nucleus accumbens and medial prefrontal cortex were extracted and analyzed for expression of prodynorphin. We observed that animals conditioned with morphine in the setting of incisional injury demonstrated blunted responses to opioid-primed reinstatement, and that the blunted responses were reversed with intra-accumbal norBNI administration. Persistently elevated levels of prodynorphin expression in the medial prefrontal cortex and nucleus accumbens were observed in the incised morphine-treated animals. However, both behavioral and molecular changes were absent in animals with incisional injury conditioned with oliceridine. These findings suggest a role for prodynorphin expression in the nucleus accumbens with exposure to morphine after surgery that may protect individuals from relapse not shared with biased mu- opioid receptor agonists.

Direct Actions of Cannabinoids on Synaptic Transmission in the Nucleus Accumbens: A Comparison With Opioids

2001 ◽  
Vol 85 (1) ◽  
pp. 72-83 ◽  
Author(s):  
Alexander F. Hoffman ◽  
Carl R. Lupica
Keyword(s):  
Nucleus Accumbens ◽  
Synaptic Transmission ◽  
Drugs Of Abuse ◽  
Glutamate Release ◽  
Brain Slices ◽  
Resting Membrane Potential ◽  
Projection Neurons ◽  
Whole Cell ◽  
Postsynaptic Currents ◽  
Abused Drugs

The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. The medium spiny GABAergic projection neurons (MSNs) in the NAc receive innervation from intrinsic GABAergic interneurons and glutamatergic innervation from extrinsic sources. Both GABA and glutamate release onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to their rewarding properties. To investigate the actions of cannabinoids in the NAc, we performed whole cell recordings from MSNs located in the shell region in rat brain slices. The cannabinoid agonist WIN 55,212-2 (1 μM) had no effect on the resting membrane potential, input resistance, or whole cell conductance, suggesting no direct postsynaptic effects. Evoked glutamatergic excitatory postsynaptic currents (EPSCs) were inhibited to a much greater extent by [Tyr-d-Ala2, N-CH3-Phe4, Gly-ol-enkephalin] (DAMGO, ∼35%) than by WIN 55,212-2 (<20%), and an analysis of miniature EPSCs suggested that the effects of DAMGO were presynaptic, whereas those of WIN 55,212-2 were postsynaptic. However, electrically evoked GABAergic inhibitory postsynaptic currents (evIPSCs), were reduced by WIN 55,212-2 in every neuron tested (EC50 = 123 nM; 60% maximal inhibition), and the inhibition of IPSCs by WIN 55,212-2 was completely antagonized by the CB1 receptor antagonist SR141716A (1 μM). In contrast evIPSCs were inhibited in ∼50% of MSNs by the μ/δ opioid agonistd-Ala2-methionine2-enkephalinamide and were completely unaffected by a selective μ-opioid receptor agonist (DAMGO). WIN 55,212-2 also increased paired-pulse facilitation of the evIPSCs and did not alter the amplitudes of tetrodotoxin-resistant miniature IPSCs, suggesting a presynaptic action. Taken together, these data suggest that cannabinoids and opioids differentially modulate inhibitory and excitatory synaptic transmission in the NAc and that the abuse liability of marijuana may be related to the direct actions of cannabinoids in this structure.

scholarly journals Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function

2017 ◽  
Author(s):  
Jacques D. Nguyen ◽  
Dean Kirson ◽  
Michael Q. Steinman ◽  
Reesha Patel ◽  
Sophia Khom ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Drugs Of Abuse ◽  
Gaba Release ◽  
Kappa Opioid Receptor ◽  
Central Nucleus ◽  
Prescription Opioid ◽  
Control Group ◽  
Opioid Use ◽  
Self Administration ◽  
Kappa Opioid

ABSTRACTBackground:Prescription opioid addiction is a significant health problem characterized by compulsive drug seeking, withdrawal and chronic relapse. We investigated the neurobiological consequences of escalation of prescription opioid use using extended access to intravenous oxycodone self-administration in rats.Methods:Male Wistar rats acquired oxycodone self-administration (0.15 mg/kg/infusion, i.v.) in 1h or 12h access sessions. Electrophysiological and immunohistochemical studies investigated the effects of oxycodone self-administration on kappa opioid receptor (KOR) regulation of GABAergic signaling and dynorphin expression in the central nucleus of the amygdala (CeA).Results:Rats given 12h access to oxycodone for 5 sessions/week (LgA) escalated their responding more than rats given 1h oxycodone (ShA) or 12h saline access. Slowed escalation of responding was found in rats given 12h access for 7 sessions/week (LgA-7day) or rats pretreated with the KOR antagonist nor-binaltorphamine dihydrochloride (norBNI) before LgA (norBNI+LgA). The KOR agonist U-50488 decreased GABA release in CeA neurons of all groups except LgA. norBNI increased GABA release in control group neurons, suggesting tonic KOR activity. This activity was abolished in ShA, norBNI+LgA, and LgA-7day rat neurons, consistent with decreased CeA dynorphin immunoreactivity observed in LgA-7day rats. However, norBNI effects were reversed (decreased CeA GABA release) in LgA rat neurons.Conclusions:The experience of intermittent extended withdrawal periods accelerates the escalation of oxycodone self-administration and causes greater dysregulation of CeA KOR-mediated GABAergic signaling. A KOR agonist/antagonist switch effect seen with other drugs of abuse was absent, which suggests that oxycodone-induced neuroadaptations may be distinct from those resulting from other drugs of abuse.

scholarly journals Biosensors Monitor Ligand-Selective Effects at Kappa Opioid Receptors

2021 ◽  
Author(s):  
Lucie Oberhauser ◽  
Miriam Stoeber
Keyword(s):  
Subcellular Location ◽  
Receptor Activation ◽  
Cellular Level ◽  
Two Dimensions ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Downstream Signaling ◽  
Regulator Protein ◽  
Cellular Context ◽  
Selective Effects

AbstractThe kappa opioid receptor (KOR) has emerged as a promising therapeutic target for pain and itch treatment. There is growing interest in biased agonists that preferentially activate select signaling pathways downstream of KOR activation on the cellular level due to their therapeutic promise in retaining the analgesic and antipruritic effects and eliminating the sedative and dysphoric effects of KOR signaling on the physiological level. The concept of ligand-selective signaling includes that biased ligands promote KOR to selectively recruit one transducer or regulator protein over another, introducing bias into the signaling cascade at the very receptor-proximal level. Measuring agonist effects directly at the receptor has remained challenging and previous studies have focused on inferring agonist-selective KOR engagement with G protein relative to β-arrestin based on downstream signaling readouts. Here we discuss novel strategies to directly assess ligand-selective effects on receptor activation using KOR-interacting biosensors. The conformation-specific cytoplasmic biosensors are disconnected from the endogenous signaling machinery and provide a direct receptor-proxy readout of ligand effects in living cells. Receptor–biosensor interaction is ligand concentration dependent and can be used to determine relative ligand potency and efficacy. In addition, the biosensors reveal the existence of two dimensions of agonist bias in the cellular context: Firstly, agonists can selectively produce discrete protein-engaged KOR states and secondly, agonists can differ in the precise subcellular location at which they activate KOR. We discuss the value and the limitations of using orthogonal receptor-interacting biosensors in the quest to understand functional selectivity amongst KOR agonists in the cellular context.

scholarly journals Kisspeptin-8 Induces Anxiety-Like Behavior and Hypolocomotion by Activating the HPA Axis and Increasing GABA Release in the Nucleus Accumbens in Rats

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 112
Author(s):  
Katalin Eszter Ibos ◽  
Éva Bodnár ◽  
Zsolt Bagosi ◽  
Zsolt Bozsó ◽  
Gábor Tóth ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Ex Vivo ◽  
Gaba Release ◽  
Receptor Activation ◽  
Ambulatory Activity ◽  
Corticosterone Concentration ◽  
Reproductive Axis ◽  
Neuropeptide Ff ◽  
Serum Lh ◽  
Anxiogenic Effect

Kisspeptins (Kp) are RF-amide neuropeptide regulators of the reproductive axis that also influence anxiety, locomotion, and metabolism. We aimed to investigate the effects of intracerebroventricular Kp-8 (an N-terminally truncated octapeptide) treatment in Wistar rats. Elevated plus maze (EPM), computerized open field (OF), and marble burying (MB) tests were performed for the assessment of behavior. Serum LH and corticosterone levels were determined to assess kisspeptin1 receptor (Kiss1r) activation and hypothalamic-pituitary-adrenal axis (HPA) stimulation, respectively. GABA release from the nucleus accumbens (NAc) and dopamine release from the ventral tegmental area (VTA) and NAc were measured via ex vivo superfusion. Kp-8 decreased open arm time and entries in EPM, and also raised corticosterone concentration, pointing to an anxiogenic effect. Moreover, the decrease in arm entries in EPM, the delayed increase in immobility accompanied by reduced ambulatory activity in OF, and the reduction in interactions with marbles show that Kp-8 suppressed exploratory and spontaneous locomotion. The increase in GABA release from the NAc might be in the background of hypolocomotion by inhibiting the VTA-NAc dopaminergic circuitry. As Kp-8 raised LH concentration, it could activate Kiss1r and stimulate the reproductive axis. As Kiss1r is associated with hyperlocomotion, it is more likely that neuropeptide FF receptor activation is involved in the suppression of locomotor activity.

scholarly journals Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors

2021 ◽  
Vol 185 ◽  
pp. 108456
Author(s):  
Matthew Hein ◽  
Guangchen Ji ◽  
Dalton Tidwell ◽  
Preston D'Souza ◽  
Takaki Kiritoshi ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Crf Neurons

scholarly journals Analgesic Activity of the Kappa Opioid Receptor Agonist RU-1205 in Rats

2018 ◽  
Vol 3 (2) ◽  
pp. 13 ◽  
Author(s):  
AA Spasov ◽  
OY Grechko ◽  
DM Shtareva ◽  
AI Raschenko ◽  
Natalia Eliseeva ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Analgesic Activity ◽  
Analgesic Effect ◽  
Physical Dependence ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test

Introduction: Opioid analgesics are the most efficient and widely used drugs for the management of moderate to severe pain. However, side effects associated with mu receptor activation, such as respiratory depression, tolerance and physical dependence severely limit their clinical application. Currently, the kappa-opioid system is the most attractive in terms of the clinical problem of pain, because kappa-agonists do not cause euphoria and physical dependence. The purpose of this study was to evaluate the antinociceptive effect of the novel compound - RU-1205. Methods: The analgesic activity of RU-1205 was studied on nociceptive models that characterize the central and peripheral pathways of pain sensitivity (hot plate test, electrically induced vocalisation, formalin test, writhing test). Results: RU-1205 exhibited highly potent antinociceptive effects in rodent models of acute pain with ED50 values of 0.002 - 0.49 mg /kg. Pretreatment with the κ-opioid receptor antagonist norBinaltorphimine significantly attenuated the analgesic activity of investigated substance in a hot plate test. Conclusions: It was established that the compound shows a significant dose-dependent central and peripheral analgesic effect. It was assumed kappa-opioidergic mechanism of analgesic effect of RU-1205.

scholarly journals Kappa-opioid receptor-dependent changes in dopamine and affective behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

2020 ◽  
Author(s):  
Breanne E. Pirino ◽  
Mary B. Spodnick ◽  
Andrew T. Gargiulo ◽  
Genevieve R. Curtis ◽  
Jessica R. Barson ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Opioid Receptor ◽  
Dopamine Release ◽  
Neural Circuit ◽  
Ex Vivo ◽  
Kappa Opioid Receptor ◽  
Affective Behavior ◽  
Kappa Opioid ◽  
Affective Behaviors ◽  
The Impact

ABSTRACTNeural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

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