σ<sub>1</sub> Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor Binding

Kim, Felix J.; Kovalyshyn, Ivanka; Burgman, Maxim; Neilan, Claire L.; Chien, Chih‐Cheng; Pasternak, Gavril W.

doi:10.1124/mol.109.057083

Cited by 129 publications

(136 citation statements)

References 42 publications

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“…Naloxone methiodide does not bind to sigma-1 receptors (10), and conversely, the sigma-1 antagonists BD-1063 and S1RA do not bind to opioid receptors (9,17). However, sigma-1 receptors can form macromolecular complexes with opioid receptors to produce tonic inhibition of receptor functioning (12,13). Sigma-1 antagonism is well known to increase opioid agonistinduced signaling, resulting in the potentiation of opioid analgesia by sigma-1 antagonists (12,13).…”

Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

“…However, sigma-1 receptors can form macromolecular complexes with opioid receptors to produce tonic inhibition of receptor functioning (12,13). Sigma-1 antagonism is well known to increase opioid agonistinduced signaling, resulting in the potentiation of opioid analgesia by sigma-1 antagonists (12,13). Therefore, a possible explanation for the sensitivity of sigma-1-mediated antihyperalgesic effects to opioid antagonism is that naloxone methiodide antagonizes peripheral opioid receptors, thereby impeding the action of endogenous opioid agonists produced at the site of inflammation (whose action is maximized by sigma-1 antagonism), resulting in noncompetitive inhibition of the antihyperalgesic effects induced by sigma-1 antagonism.…”

Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

“…Moreover, these receptors in the dorsal root ganglion are selectively located in sensory neurons and not in glial cells (11). It is now known that sigma-1 receptors can form a macromolecular complex with opioid receptors, tonically inhibiting receptor functioning, and that sigma-1 antagonism can protect opioid receptors from the tonic inhibitory effects of sigma-1 receptors, thus enhancing opioid analgesia (12,13). However, although the ability of sigma-1 antagonism to potentiate the analgesic effects of opioid drugs is clear, the physiological and pathophysiological roles of sigma-1 receptors in opioid modulation remain unknown.…”

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confidence: 99%

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Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Tejada

Montilla-García

Cronin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence TyrGly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of β-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. β-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas.sigma-1 receptors | inflammatory pain | endogenous opioid peptides | immune cells

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Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

Section: Effects Of Sigma-1 Antagonists On Acute Inflammatory Hyperalmentioning

confidence: 99%

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confidence: 99%

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Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Tejada

Montilla-García

Cronin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).…”

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confidence: 99%

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Tsai

Chuang

Tsai

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.T he endoplasmic reticulum (ER) plays important roles in cellular functions, including synthesis of proteins and regulation of Ca 2+ signaling between the ER and plasma membrane (1) and between the ER and mitochondria (2-4). However, because the ER interacts with other organelles in the cell, other functions related to the ER remain to be uncovered.The sigma-1 receptor (Sig-1R) (5-8) is an ER chaperone molecule that resides at the ER-mitochondrion interface referred to as the mitochondria-associated ER membrane (MAM), where the Sig-1R ensures proper ER-mitochondrion Ca 2+ signaling for cellular survival (3, 9), as well as sustains the activity of an ER stress sensor IRE1 at the MAM (10). The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).Cocaine also causes the translocation of Sig-1Rs from the ER to the nucleus (16), where Sig-1Rs are shown to be present at the nuclear envelope (NE) (17). H...

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“…Presumably, as with sigma 1 , sigma 2 ligand binding may lead to conformational changes that influence other, associated protein systems. The sigma 1 receptor shows an allosteric-like effect on the functions of proteins as diverse as the androgen receptor (24) and G protein-coupled receptors (25). It also interacts with a wide range of other classes of signaling proteins, receptors, and channels.…”

mentioning

confidence: 99%

Cloning the sigma ₂ receptor: Wandering 40 years to find an identity

Kim

Pasternak

2017

Proc. Natl. Acad. Sci. U.S.A.

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σ₁ Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor Binding

Abstract: Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE (2)

Cited by 129 publications

References 42 publications

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Cloning the sigma ₂ receptor: Wandering 40 years to find an identity

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σ1 Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor Binding

Abstract: Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE (2)

Cited by 129 publications

References 42 publications

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Cloning the sigma 2 receptor: Wandering 40 years to find an identity

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σ₁ Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor Binding

Cloning the sigma ₂ receptor: Wandering 40 years to find an identity