mTORC1 pathway is involved in the kappa opioid receptor activation-induced increase in excessive alcohol drinking in mice

AbstractExcessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

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Combination of Clinically Utilized Kappa‐Opioid Receptor Agonist Nalfurafine With Low‐Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.14033 ◽

2019 ◽

Cited By ~ 2

Author(s):

Yan Zhou ◽

Mary Jeanne Kreek

Keyword(s):

Opioid Receptor ◽

Alcohol Drinking ◽

Receptor Agonist ◽

Low Dose ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Male And Female ◽

Opioid Receptor Agonist ◽

Excessive Alcohol ◽

Low Dose Naltrexone

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

Neuropharmacology ◽

10.1016/j.neuropharm.2021.108456 ◽

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

Journal of Clinical and Health Sciences ◽

10.24191/jchs.v3i2.7275 ◽

2018 ◽

Vol 3 (2) ◽

pp. 13 ◽

Cited By ~ 2

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.

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Signaling Events Initiated by Kappa Opioid Receptor Activation: Quantification and Immunocolocalization Using Phospho-Selective KOR, p38 MAPK, and KIR 3.1 Antibodies

Methods in Molecular Biology - Signal Transduction Immunohistochemistry ◽

10.1007/978-1-61779-024-9_11 ◽

2011 ◽

pp. 197-219 ◽

Cited By ~ 7

Author(s):

Julia C. Lemos ◽

Clarisse A. Roth ◽

Charles Chavkin

Keyword(s):

P38 Mapk ◽

Opioid Receptor ◽

Receptor Activation ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Signaling Events

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Dissociable Effects of Kappa-Opioid Receptor Activation on Impulsive Phenotypes in Wistar Rats

Neuropsychopharmacology ◽

10.1038/npp.2013.129 ◽

2013 ◽

Vol 38 (11) ◽

pp. 2278-2285 ◽

Cited By ~ 19

Author(s):

Brendan M Walker ◽

Jessica L Kissler

Keyword(s):

Opioid Receptor ◽

Wistar Rats ◽

Receptor Activation ◽

Kappa Opioid Receptor ◽

Kappa Opioid

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Alcohol Drinking Alters Stress Response to Predator Odor via Extended Amygdala Kappa Opioid Receptor Signaling in Male Mice

10.1101/773481 ◽

2019 ◽

Author(s):

Lara S. Hwa ◽

Sofia Neira ◽

Meghan E. Flanigan ◽

Christina M. Stanhope ◽

Melanie M. Pina ◽

...

Keyword(s):

Opioid Receptor ◽

Stress Responses ◽

Alcohol Drinking ◽

Kappa Opioid Receptor ◽

Predator Odor ◽

Stria Terminalis ◽

Receptor Signaling ◽

Kappa Opioid ◽

Bed Nucleus ◽

Heavy Alcohol

AbstractMaladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST compared to drinking or stress alone. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal from heavy drinking. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.Impact StatementHeavy alcohol drinking primes dynorphin / kappa opioid systems in the bed nucleus of the stria terminalis to alter stress responses in mice.

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