Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

Chan, Patrick; Lutfy, Kabirullah

doi:10.1016/bs.pmbts.2015.10.005

Cited by 25 publications

(9 citation statements)

References 134 publications

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“…In the presence of a specific adenylyl cyclase inhibitor, 9-CPA (100 µM), there was no significant change in the electrical coupling strength following application of propofol (Figures 5A-C), which suggests that activation of adenylyl cyclase is crucial in propofol-induced depression of electrical synaptic strength of TRN PV+ neurons. Activation of adenylyl cyclase is known to increase the intracellular levels of cAMP, which in turn causes an elevation of PKA (Bauman et al, 2006;Yan et al, 2011;Chan and Lutfy, 2016). So, we further examined whether inhibition of PKA mediates propofol-induced depression of electrical synaptic strength.…”

Section: Propofol-induced Depression Of Electrical Synaptic Strength mentioning

confidence: 99%

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Liu

Zhang

et al. 2020

Front. Neurosci.

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Electrical synapses between neurons exhibit a high degree of plasticity, which makes critical contributions to neuronal communication. The GABAergic parvalbuminexpressing (PV+) neurons in the thalamic reticular nucleus (TRN) interact with each other through electrical and chemical synapses. Plasticity of electrical synaptic transmission in TRN plays a key role in regulating thalamocortical and corticothalamic circuits and even the formation of consciousness. We here examined the effects of propofol, a commonly used general anesthetic agent, on the strength of electrical synapses between TRN PV+ neurons by fluorescence-guided patch-clamp recording and pharmacological methods. Results show that 100 µM propofol reduced the electrical synaptic strength between TRN PV+ neurons. Notably, the propofol-induced depression of electrical synaptic strength between TRN PV+ neurons was diminished by saclofen (10 µM, antagonist of GABA B receptors), but not blocked by gabazine (10 µM, antagonist of GABA A receptors). Application of baclofen (10 µM, agonist of GABA B receptors), similar to propofol, also reduced the electrical synaptic strength between TRN PV+ neurons. Moreover, the propofol-induced depression of electrical synaptic strength between TRN PV+ neurons was abolished by 9-CPA (100 µM, specific adenylyl cyclase inhibitor), and by KT5720 (1 µM, selective inhibitor of PKA). Our findings indicate that propofol acts on metabotropic GABA B receptors, resulting in a depression of electrical synaptic transmission of coupled TRN PV+ neurons, which is mediated by the adenylyl cyclase-cAMP-PKA signaling pathway. Our findings also imply that propofol may change the thalamocortical communication via inducing depression of electrical synaptic strength in the TRN.

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Section: Propofol-induced Depression Of Electrical Synaptic Strength mentioning

confidence: 99%

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Liu

Zhang

et al. 2020

Front. Neurosci.

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“…Heterologous sensitization of AC was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory G protein-coupled receptors (Sharma et al, 1975;Duman et al, 1988). Such an adaptive mechanism causes enhanced cAMP signaling and has been suggested to play a role in several pathologic processes, including chronic pain (Hucho and Levine, 2007), anxiety (Keil et al, 2016), and drug addiction (Chan and Lutfy, 2016). Research during the last 40 years has suggested Ga i / o -coupled receptors, G proteins, and AC isoform specific processes for heterologous sensitization (Watts et al, 1998;Ammer and Christ, 2002;Clark et al, 2004;Vortherms et al, 2006); however, fundamental underlying mechanisms of this phenomenon remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Small Interfering RNA Screening Reveals a Role for Cullin3–Really Interesting New Gene Ligase Signaling in Heterologous Sensitization of Adenylyl Cyclase

Ding

Ejendal

Soto-Velasquez

et al. 2019

J Pharmacol Exp Ther

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Heterologous sensitization of adenylyl cyclase (AC) is revealed as enhanced or exaggerated AC/cAMP signaling that occurs following persistent activation of Ga i/o -coupled receptors. This paradoxical phenomenon was discovered more than 40 years ago and was proposed as a cellular mechanism to explain the adaptive changes that occur following chronic exposure to drugs of abuse. However, the underlying molecular mechanisms of heterologous sensitization of AC remain largely unknown. In the present study, we performed a genome-wide cell-based RNA interference screen as an unbiased approach to identify genes associated with heterologous sensitization of AC. Following a series of validation and confirmation assays, three genes that form an E3 ligase complex, cullin3 (CUL3), neural precursorcell-expressed and developmentally downregulated 8 (NEDD8), and really interesting new gene (RING)-box protein 1 (RBX1), were identified as specific modulators of heterologous sensitization of AC. Furthermore, based on the downstream actions of these genes, we evaluated the activity of proteasome inhibitors as well as the specific NEDD8-activating enzyme inhibitor, MLN4924 (Pevonedistat), in AC sensitization. We demonstrate that MG-132 and bortezomib treatments could mimic the inhibitory effects observed with gene knockdown, and MLN4924 was potent and efficacious in blocking the development of heterologous sensitization of endogenous and recombinant AC isoforms, including AC1, AC2, AC5, and AC6. Together, by using genetic and pharmacological approaches, we identified, for the first time, cullin3-RING ligases and the protein degradation pathway as essential modulators for heterologous sensitization of AC. SIGNIFICANCE STATEMENTThrough a genome-wide cell-based RNA interference screening, we identified three genes that form an E3 ligase complex, cullin3, neural precursor-cell-expressed and developmentally downregulated 8 (NEDD8), and really interesting new gene-box protein 1, as specific modulators of heterologous sensitization of AC. The effect of cullin3, NEDD8, or really interesting new gene-box protein 1 small interfering RNAs on heterologous sensitization was recapitulated by proteasome inhibitors, MG132 and bortezomib, and the specific NEDD8-activating enzyme inhibitor, MLN4924. These results suggest a novel hypothesis in which protein degradation is involved in the sensitization of AC signaling that occurs following chronic activation of Ga i/o -coupled receptors.

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“…The activation of OR normally results in the inhibition of AC activity, but the prolonged exposure of cultured cells or mammalian organisms to morphine was shown to induce the hyper-sensitization or super-activation of AC activity instead [31][32][33][34][35][36]. This effect was considered a biochemical basis for the development of opioid tolerance and dependence.…”

Section: Opioid Receptors and Biochemical Mechanisms Of Homeostatic Amentioning

confidence: 99%

Expression of Opioid Receptors in Cells of the Immune System

Brejchova

Holáň

Svoboda

2020

IJMS

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The observation of the immunomodulatory effects of opioid drugs opened the discussion about possible mechanisms of action and led researchers to consider the presence of opioid receptors (OR) in cells of the immune system. To date, numerous studies analyzing the expression of OR subtypes in animal and human immune cells have been performed. Some of them confirmed the expression of OR at both the mRNA and protein level, while others did not detect the receptor mRNA either. Although this topic remains controversial, further studies are constantly being published. The most recent articles suggested that the expression level of OR in human peripheral blood lymphocytes could help to evaluate the success of methadone maintenance therapy in former opioid addicts, or could serve as a biomarker for chronic pain diagnosis. However, the applicability of these findings to clinical practice needs to be verified by further investigations.

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Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

Cited by 25 publications

References 134 publications

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Effects of Propofol on Electrical Synaptic Strength in Coupling Reticular Thalamic GABAergic Parvalbumin-Expressing Neurons

Genome-Wide Small Interfering RNA Screening Reveals a Role for Cullin3–Really Interesting New Gene Ligase Signaling in Heterologous Sensitization of Adenylyl Cyclase

Expression of Opioid Receptors in Cells of the Immune System

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