Selective Sigma-1 (&amp;#x3C3;1) Receptor Antagonists: Emerging Target for the Treatment of Neuropathic Pain

Dı́az, José Luis; Zamanillo, Daniel; Corbera, Jordi; Baeyens, José M.; Maldonado, Rafaël; Pericàs, Miquel À.; Vela, José Miguel; Torrens, Antoni

doi:10.2174/1871524910909030172

Cited by 84 publications

(80 citation statements)

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“…We now extend those results by showing that this s 1 antagonist as well as BD-1063 enhance opioid antinociception against a different type of nociceptive (mechanical) stimulus, and more importantly, that the enhanced antinociception is mediated peripherally (see below). Moreover, we show that opioid-induced mechanical antinociception is clearly potentiated in s 1 -KO mice, which contrasts with the previously reported absence of modulation of opioid thermal antinociception in s 1 -KO mice (Díaz et al, 2009;Vidal-Torres et al, 2013). These apparently contradictory results seem to be related to the type of sensory stimulation used, and may be attributable to the known differences in the neurochemical mechanisms of thermal and mechanical opioid antinociception (Kuraishi et al, 1985;Wegert et al, 1997).…”

Section: Modulation Of Peripheral M-opioidcontrasting

confidence: 99%

“…Hence, it is important to test whether the widely reported enhancement of morphine antinociception by s 1 inhibition (Chien and Pasternak 1993;Mei and Pasternak 2007;Díaz et al, 2009;Sánchez-Fernández et al, 2013) also occurs with other clinically relevant m opioids. It was recently reported that the systemic (subcutaneous) administration of S1RA enhanced antinociception against a thermal stimulus induced by morphine and other systemically administered centrally penetrant m-opioid analgesics (fentanyl, oxycodone, buprenorphine, and tramadol) (Vidal-Torres et al, 2013).…”

Section: Modulation Of Peripheral M-opioidmentioning

confidence: 99%

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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We evaluated the effects of s 1 -receptor inhibition on m-opioidinduced mechanical antinociception and constipation. s 1 -Knockout mice exhibited marked mechanical antinociception in response to several m-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral m-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective A peripheral role for s 1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, s 1 -receptor inhibition did not alter fentanyl-or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, s 1 -receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral m-opioid analgesia without affecting opioidinduced constipation.

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Section: Modulation Of Peripheral M-opioidcontrasting

confidence: 99%

Section: Modulation Of Peripheral M-opioidmentioning

confidence: 99%

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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“…The remaining response to capsaicin in σ 1 -KO and WT animals treated with the highest doses of σ 1 receptor antagonists indicates that mechanisms other than σ 1 receptor activation are also implicated in the acute visceral pain induced by capsaicin in both mouse types. It was previously reported that σ 1 receptor antagonists had no effect on acute pain induced by thermal or mechanical stimuli to the paw skin [22][23][24]39 but almost completely abolished the first phase of formalininduced pain 23,27 and, in the present study, partially reduced capsaicin-induced visceral pain-related behaviors. These data indicate that the analgesic actions of σ 1 receptor antagonists may depend on the type of pain (cutaneous, somatic, or visceral) and on the nociceptive stimulus applied (thermal, mechanical, or chemical).…”

Section: Discussionsupporting

confidence: 57%

σ1Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

2013

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Background: Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (σ 1 ) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored. Methods: The authors evaluated the role of σ 1 receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and σ 1 receptor knockout (σ 1 -KO) (n = 10 per group) mice, selective σ 1 receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen). Results: The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and σ 1 -KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in σ 1 -KO mice (mean ± SEM, 22 ± 2.9) was 48% of that observed in WT animals (46 ± 4.2). Subcutaneous administration of the σ 1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 ± 0.05 g) in WT mice. In contrast, these drugs produced no change in σ 1 -KO mice. Thus, the effects of these drugs are specifically mediated by σ 1 receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and σ 1 -KO mice, whereas ketoprofen had no effect in either mouse type. Conclusion: These results suggest that σ 1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value.

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“…The finding that S1R plays a role in HCV infection is of particular interest because, in addition to endogenous ligands, S1R activity can be modulated in vivo by a large number of drug-like ligands (70), some of which have been proven to be useful in the treatment of pain (71) and in experimental models for pathologies of the central nervous system (55). Although we have previously shown that putative S1R ligands inhibit HCV infection, most of these compounds selectively and efficiently inhibit viral entry (35), a process that is not altered by S1R downregulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

Friesland

Mingorance

Chung

et al. 2013

J Virol

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bHepatitis C virus (HCV) genome replication is thought to occur in a membranous cellular compartment derived from the endoplasmic reticulum (ER). The molecular mechanisms by which these membrane-associated replication complexes are formed during HCV infection are only starting to be unraveled, and both viral and cellular factors contribute to their formation. In this study, we describe the discovery of nonopioid sigma-1 receptor (S1R) as a cellular factor that mediates the early steps of viral RNA replication. S1R is a cholesterol-binding protein that resides in lipid-rich areas of the ER and in mitochondrion-associated ER membranes (MAMs). Several functions have been ascribed to this ER-resident chaperone, many of which are related to Ca 2؉ signaling at the MAMs and lipid storage and trafficking. Downregulation of S1R expression by RNA interference (RNAi) in Huh-7 cells leads to a proportional decrease in susceptibility to HCV infection, as shown by reduced HCV RNA accumulation and intra-and extracellular infectivity in single-cycle infection experiments. Similar RNAi studies in persistently infected cells indicate that S1R expression is not rate limiting for persistent HCV RNA replication, as marked reduction in S1R in these cells does not lead to any decrease in HCV RNA or viral protein expression. However, subgenomic replicon transfection experiments indicate that S1R expression is rate limiting for HCV RNA replication without impairing primary translation. Overall, our data indicate that the initial steps of HCV infection are regulated by S1R, a key component of MAMs, suggesting that these structures could serve as platforms for initial RNA replication during HCV infection. It is estimated that 170 million humans are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is associated with persistent liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (1). Recently, combination therapy, including pegylated alpha 2a interferon (IFN-␣2a), ribavirin, and specific HCV protease inhibitors, has been approved for the treatment of HCV-infected patients, with high cure rates compared with pegylated IFN-␣2a and ribavirin alone, the previous standard of care (2, 3). However, adverse effects and cost considerations limit the implementation of these new treatment regimens.HCV is an enveloped RNA virus with a single 9.6-kb positivestrand RNA genome that encodes a single open reading frame of approximately 3,000 amino acids flanked by 5= and 3= untranslated regions (UTR) that regulate translation and replication of the viral genome. The 5= UTR contains an internal ribosomal entry site (4) that cooperates with the 3= UTR regions for efficient viral polyprotein translation and RNA replication. Individual viral proteins are produced as a result of the sequential proteolysis of the HCV polyprotein by cellular and viral proteases, which produce structural proteins (core, E1, and E2) that are major components of the viral particles and p7 and NS2, which mediate infectious-particle assembly in...

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Selective Sigma-1 (σ1) Receptor Antagonists: Emerging Target for the Treatment of Neuropathic Pain

Cited by 84 publications

References 0 publications

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

σ1Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

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Selective Sigma-1 (&#x3C3;1) Receptor Antagonists: Emerging Target for the Treatment of Neuropathic Pain

Cited by 84 publications

References 0 publications

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

σ1Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

Contact Info

Product

Resources

About

Selective Sigma-1 (σ1) Receptor Antagonists: Emerging Target for the Treatment of Neuropathic Pain

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors