Kappa Opioid Receptor Inhibition of Glutamatergic Transmission in the Nucleus Accumbens Shell

2001 ◽  
Vol 85 (3) ◽  
pp. 1153-1158 ◽  
Author(s):  
Gregory O. Hjelmstad ◽  
Howard L. Fields
Keyword(s):  
Nucleus Accumbens ◽  
Synaptic Transmission ◽  
Opioid Receptor ◽  
Receptor Activation ◽  
Kappa Opioid Receptor ◽  
Excitatory Synaptic Transmission ◽  
Nucleus Accumbens Shell ◽  
Receptor Agonists ◽  
Κ Receptor

Microinjection of κ-opioid receptor agonists into the nucleus accumbens produces conditioned place aversion. While attention has focused primarily on the inhibition of dopamine release by κ-receptor agonists as the synaptic mechanism underlying this effect, recent anatomical studies have raised the possibility that regulation of noncatecholaminergic transmission also contribute. We have investigated the effects of κ-receptor activation on fast excitatory synaptic transmission in an in vitro slice preparation using whole cell voltage-clamp or extracellular field recordings in the shell region of the nucleus accumbens. The κ-receptor agonist U69593 produces a pronounced, dose-dependent inhibition of glutamatergic excitatory postsynaptic currents (EPSCs) that can be reversed by 100 nM nor-BNI. Furthermore, U69593 causes an increase in the paired-pulse ratio as well as a decrease in the frequency of spontaneous miniature events, suggesting a presynaptic site of action. Despite anatomical evidence for κ-receptor localization on dendritic spines of nucleus accumbens neurons, no electrophysiological evidence of a postsynaptic effect was found. This presynaptic inhibition of excitatory synaptic transmission in the nucleus accumbens shell provides a novel mechanism that may contribute to the κ-receptor–mediated aversion observed in intact animals.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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.

GABAB receptors presynaptically modulate excitatory synaptic transmission in the rat supraoptic nucleus in vitro

1996 ◽  
Vol 76 (2) ◽  
pp. 1166-1179 ◽  
Author(s):  
S. B. Kombian ◽  
J. A. Zidichouski ◽  
Q. J. Pittman
Keyword(s):  
Synaptic Transmission ◽  
Receptor Agonist ◽  
Supraoptic Nucleus ◽  
Gabab Receptor ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Excitatory Synaptic Transmission ◽  
Gabab Receptors ◽  
Dependent Manner

1. The effect of gamma-aminobutyric acid-B (GABAB)-receptor activation on excitatory synaptic transmission in the rat supraoptic nucleus (SON) was examined using the nystatin perforated-patch whole cell recording technique in coronal hypothalamic slices. 2. Stimulation of the hypothalamic region dorso-medial to the SON elicited glutamate and GABAA-receptor-mediated synaptic responses in electrophysiologically identified magnocellular neurosecretory cells. 3. Bath application of the GABAB-receptor agonist, +/- -baclofen reversibly reduced pharmacologically isolated, glutamate-mediated excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. At the concentrations used, baclofen altered neither the postsynaptic conductances of these cells nor their response to bath applied alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). 4. The baclofen-induced synaptic depression was accompanied by an increase in paired pulse facilitation (PPF). This increase in PPF, as well as the synaptic depression, was blocked by the GABAB-receptor antagonists CGP36742 and saclofen. 5. In addition to blocking the actions of baclofen in this nucleus, CGP36742 caused an increase in the evoked EPSC amplitude without altering postsynaptic cell conductances or responses induced by bath-applied AMPA. Contrary to the action of CGP36742, saclofen caused a baclofen-like depression of the evoked EPSC, suggesting that it may act as a partial GABAB receptor agonist. 6. These results indicate that the activation of presynaptic GABAB receptors reduces fast excitatory synaptic transmission in the SON. They further suggest that presynaptic GABAB receptors may be tonically activated in vitro. Thus GABAB receptors may influence the level of activity and excitation of SON neurons and hence modulate the secretion of the regulatory neuropeptides vasopressin and oxytocin.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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
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