A new sigma ligand, (±)-PPCC, antagonizes kappa opioid receptor-mediated antinociceptive effect

Prezzavento, Orazio; Parenti, Carmela; Marrazzo, Agostino; Ronsisvalle, Simone; Vittorio, F; Aricò, Giuseppina; Scoto, G.M.; Ronsisvalle, Giuseppe

doi:10.1016/j.lfs.2007.11.032

Cited by 25 publications

(19 citation statements)

References 24 publications

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“…These results are consistent with previous findings that selective σ 1 agonists (such as PRE-084 or (+)-pentazocine) did not alter sensory thresholds when administered systemically16172133, supraspinally (e.g. ref.…”

Section: Discussionsupporting

confidence: 93%

“…Some studies showed that the administration of selective σ 1 agonists such as PRE-084 or (+)-pentazocine had the opposite effects to σ 1 antagonists, i.e., σ 1 agonism was able to induce or promote pain hypersensitivity23262728293031. Other studies, however, showed that the administration of these compounds did not alter sensory thresholds at all1617213233. Whether σ 1 agonists are pronociceptive is not a trivial question, since as noted above, several drugs that are marketed for clinical use, although not selective for σ 1 receptors, are able to bind this receptor and thereby act as nonselective σ 1 agonists.…”

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confidence: 99%

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Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

Entrena

Sánchez-Fernández

Nieto

et al. 2016

Sci Rep

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Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

Entrena

Sánchez-Fernández

Nieto

et al. 2016

Sci Rep

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“…SIGMAR1 agonists have been shown to exert therapeutic effects in depression and dementia [37,38] and an endogenous SIGMAR1 agonist, N,N-dimethyltryptamine (DMT), has recently been identified [36]. As more SIGMAR1 ligands are identified [39] and evaluated as therapeutic approaches for AD [40], our data suggest that the presence of the APOE 4 allele should be taken into account [41]. …”

Section: Discussionmentioning

confidence: 83%

Genetic Polymorphisms in Sigma-1 Receptor and Apolipoprotein E Interact to Influence the Severity of Alzheimers Disease

Huang

Zheng²,

Halliday³

et al. 2011

CAR

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Apolipoprotein E (APOE) ε4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE 4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE ε2 or ε3 allele often having better clinical outcomes compared to carriers with none or two ε2 or ε3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE ε4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non ε4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations.

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“…Further, the sigma-1 receptor antagonist, BD1047, blocked the transient pronociceptive effect provoked by DHEA, which is a sigma-1 agonist (Kibaly et al, 2008). Further, Ronsisvalle’s group synthesized a new sigma-1 receptor agonist (1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl]methyl]-1-(4-methylphenyl)cyclopropanecarboxylate and found that it antagonized kappa opioid receptor-mediated antinociceptive effects (Prezzavento et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

The pharmacology of sigma-1 receptors

Maurice

Su²

2009

Pharmacology & Therapeutics

574

518

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Originally considered an enigmatic protein, the sigma-1 receptor has recently been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery causes us to look back at the many proposed roles of this receptor, even before its molecular function was identified, in many diseases such as methamphetamine or cocaine addiction, amnesia, pain, depression, Alzheimer’s disease, stroke, retinal neuroprotection, HIV infection, and cancer. In this review, we examine the reports that have clearly shown an agonist-antagonist relationship regarding sigma-1 receptors in models of those diseases and also review the relatively known mechanisms of action of sigma-1 receptors in an attempt to spur the speculation of readers on how the sigma-1 receptor at the endoplasmic reticulum might relate to so many diseases. We found that the most prominent action of sigma-1 receptors in biological systems including cell lines, primary cultures, and animals is the regulation and modulation of voltage-regulated and ligand-gated ion channels, including Ca2+-, K+-, Na+, Cl-, and SK channels, and NMDA and IP3 receptors. We found that the final output of the action of sigma-1 receptor agonists is to inhibit all above-mentioned voltage-gated ion channels, while they potentiate ligand-gated channels. The inhibition or potentiation induced by agonists is blocked by sigma-1 receptor antagonists. Other mechanisms of action of sigma-1 receptors, and to some extent those of sigma-2 receptors, were also considered. We conclude that the sigma-1 and sigma-2 receptors represent potential fruitful targets for therapeutic developments in combating many human diseases.

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A new sigma ligand, (±)-PPCC, antagonizes kappa opioid receptor-mediated antinociceptive effect

Cited by 25 publications

References 24 publications

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

Genetic Polymorphisms in Sigma-1 Receptor and Apolipoprotein E Interact to Influence the Severity of Alzheimers Disease

The pharmacology of sigma-1 receptors

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