Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain

Yakhnitsa, Vadim; Ji, Guangchen; Hein, Matthew; Presto, Peyton; Griffin, Zack; Пономарева, О. А.; Navratilova, Edita; Porreca, Frank; Neugebauer, Volker

doi:10.3389/fphar.2022.903978

Cited by 21 publications

(31 citation statements)

References 89 publications

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“…The next part of the work is based on a study which found that blocking kappa opioid receptors in the amygdala leads to a decrease in the spike activity of pyramidal neurons [19]. A similar effect was observed when blocking CRF1 receptors, which, like kappa-opioid receptors, exert their effects through the beta-arrestin pathway and the activation of MAPK p38 [20].…”

Section: Resultsmentioning

confidence: 99%

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Kalitin,

Mukha,

Spasov

2024

Preprint

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This study focuses on RU-1205, a new kappa-opioid agonist exhibiting analgesic effect without causing dysphoric or aversive reactions. It is assumed that the absence of dysphoric or aversive effects can be attributed to functional selectivity or it might be due to an additional mechanism of action that involves blocking the p38 mitogen-activated protein kinase (MAPK). The aim of this study was the experimental identification of the mechanisms of action of RU-1205 associated with inhibition of MAPK p38 and functional selectivity at kappa-opioid receptors. Materials and methods: Rats weighing 260-280 g were implanted with chronic cortical and deep electrodes. LFP activity was recorded after intracerebroventricular administration of well-studied reference substances: the selective kappa-opioid agonist U-50488 at a dose of 100 μg; the MAPK p38 blocker SB203580 at a dose of 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning techniques were employed to reduce dimensionality and extract connectivity features using the principal component analysis method. Finally, signal classification was conducted using models based on Gaussian processes. By applying the patch-clamp technique in the whole-cell configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. The neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001-10 μM) and RU-1205 (10 μM); and (3) combinations of U-50488 (0.01-10 μM) and RU-1205 (100 μM). Results: The developed models were able to classify the compound RU-1205 as a "non-inhibitor" of MAPK p38 with a probability of 0.89. The results obtained were confirmed in patch clamp experiments on acute brain slices, where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons in the basolateral amygdala (p <0.05) and RU-1205 interacts with U-50488, suppressing its effect on the spike activity of neurons. Conclusions: The findings suggest that compound RU-1205 displays properties consistent with a functional kappa opioid receptor agonist and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of neuronal mechanisms of drug action and underscores the potential for further research in this area.

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Section: Resultsmentioning

confidence: 99%

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Kalitin,

Mukha,

Spasov

2024

Preprint

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“…In a spinal nerve ligation (SNL) model of pain, nor-BNI in the right CeA blocked conditioned place preference (CPP) driven by gabapentin (an FDA approved treatment for neuropathic pain), suggesting that CeA KOR signaling is necessary for pain-induced negative affect ( Navratilova et al, 2019 ). Further, intra-CeA KOR antagonism blocks anxiety-like behavior and ultasonic vocalizations in a rat functional pain model wherein morphine priming sensitizes stress-induced pain-like and affective behavior ( Yakhnitsa et al, 2022 ). Moreover, increased CeA Dyn signaling may shape pain-related behavior as intra-CeA KOR antagonism blocks defensive behaviors in response to noxious stimuli using Randall Selitto to measure the paw withdrawal threshold ( Phelps et al, 2019 ) or sensitivity to capsaicin left forepaw injection in a functional pain model involving morphine priming in rats exposed to a bright light stimulus ( Nation et al, 2018 ).…”

Section: Regulation Of Pain By Amygdala Dynorphin/kappa Opioid Recept...mentioning

confidence: 99%

“…Furthermore, electrically evoked IPSCs onto CeA neurons are only potentiated by nor-BNI in SNL rats but not sham controls ( Navratilova et al, 2019 ). Moreover, PBN-evoked polysynaptic inhibition or electrically-evoked IPSCs are potentiated by nor-BNI in the functional pain model described above ( Yakhnitsa et al, 2022 ). These studies suggest that heightened Dyn signaling may be contributing to CeA neuron disinhibition in pain states.…”

Section: Regulation Of Pain By Amygdala Dynorphin/kappa Opioid Recept...mentioning

confidence: 99%

Dynorphin/kappa opioid receptor system regulation on amygdaloid circuitry: Implications for neuropsychiatric disorders

Limoges

Yarur

Tejeda

2022

Front. Syst. Neurosci.

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Amygdaloid circuits are involved in a variety of emotional and motivation-related behaviors and are impacted by stress. The amygdala expresses several neuromodulatory systems, including opioid peptides and their receptors. The Dynorphin (Dyn)/kappa opioid receptor (KOR) system has been implicated in the processing of emotional and stress-related information and is expressed in brain areas involved in stress and motivation. Dysregulation of the Dyn/KOR system has also been implicated in various neuropsychiatric disorders. However, there is limited information about the role of the Dyn/KOR system in regulating amygdala circuitry. Here, we review the literature on the (1) basic anatomy of the amygdala, (2) functional regulation of synaptic transmission by the Dyn/KOR system, (3) anatomical architecture and function of the Dyn/KOR system in the amygdala, (4) regulation of amygdala-dependent behaviors by the Dyn/KOR system, and (5) future directions for the field. Future work investigating how the Dyn/KOR system shapes a wide range of amygdala-related behaviors will be required to increase our understanding of underlying circuitry modulation by the Dyn/KOR system. We anticipate that continued focus on the amygdala Dyn/KOR system will also elucidate novel ways to target the Dyn/KOR system to treat neuropsychiatric disorders.

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“…Furthermore, the optoinhibition of CRF containing neurons in CeA is sufficient to impair anxiety-like behaviour induced by pain (Hein et al, 2021;Mazzitelli et al, 2022). Interestingly, KOR blockade in CeA controls pain-related behaviour in a model of functional pain by restoring synaptic inhibition of CeA-CRF neurons, demonstrating that KOR and CRF systems are closely related in pain and its comorbidities (Yakhnitsa et al, 2022). However, most of these cited papers have obtained these results only in male rodents leaving females understudied.…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell

Lorente

Cuitavi

Rullo

et al. 2023

Preprint

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Background and purpouse Psychological disorders, such as anxiety and anhedonia are pain comorbidities, however how pain affects male and female individuals and through which mechanism is not well understood. Previous research show pain-induced alterations in the dynorphinergic pathway in the mesocorticolimbic system (MCLS) together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor involvement in these pain related behaviours. Experimental approach We used behavioural pharmacology and biochemical tools to characterize negative affective states induced by inflammatory pain in male and female rats, and the alterations in dynorphinergic and corticotropin systems in the MCLS. Key results. Female rats showed a persistent anxiety-like together with a reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations of in both dynorphin and corticotropin releasing factor in NAc and amygdala that suggest sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Conclusions and implications Our results show sex and time dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data pointing to the KOR/dyn recruitment in the NAc as key neurological substrate mediating these behaviours. This research encourages the study the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.

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Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain

Cited by 21 publications

References 89 publications

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods

Dynorphin/kappa opioid receptor system regulation on amygdaloid circuitry: Implications for neuropsychiatric disorders

Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell

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