Sigma-1 receptors and animal studies centered on pain and analgesia

Davis, Mellar P.

doi:10.1517/17460441.2015.1051961

Cited by 24 publications

(16 citation statements)

References 182 publications

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“…Sigma receptor antagonists are emerging as potential therapeutics and adjuvants to treat nerve injury, neuroinflammation, and the modulation of nociception (Vidal-Torres et al, 2013; Davis, 2015). Although once thought to be a member of the opioid family (Martin et al, 1976) or a binding site on N-Methyl-D-aspartate (NMDA) receptors (Wong et al, 1988), subsequent cloning of the sigma-1 (S1R; Hanner et al, 1996) and sigma-2 receptors (S2R; Alon et al, 2017) is leading to a more defined role of this system in biological systems.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

et al. 2019

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Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10–45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09–1.82) and 2.31 (1.02–4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31–7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7–25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29–15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85–5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.

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Section: Introductionmentioning

confidence: 99%

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

et al. 2019

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“…The likely role of S1R in pain is also suggested by an unbiased expression screening of genes regulated by the sciatic nerve axotomy model of neuropathic pain, which demonstrated a 2 to 5-fold increase in the expression of S1R in the dorsal root ganglion (DRG) (Xiao et al, 2002). In fact, the S1R is emerging as a novel target in the therapeutic intervention for pain (Zamanillo et al, 2013; Davis, 2015; Gris et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody

et al. 2016

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Sigma-1 receptor (S1R) is a unique pluripotent modulator of living systems and has been reported to be associated with a number of neurological diseases including pathological pain. Intrathecal administration of S1R antagonists attenuate the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution, suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs. Since primary afferents are the major component in the pain pathway, we examined the mouse and rat DRGs for the presence of the S1R. At both mRNA and protein levels, qRT-PCR and Western confirmed that the DRG contains greater S1R expression in comparison to spinal cord, cortex, or lung but less than liver. Using a custom-made highly specific antibody, we demonstrated the presence of a strong S1R immuno-fluorescence in all rat and mouse DRG neurons co-localizing with the NSE marker, but not in neural processes or GFAP-positive glial satellite cells. In addition, S1R was absent in afferent terminals in the skin and in the dorsal horn of the spinal cord. Using immuno-electron microscopy, we showed that S1R is detected in the nuclear envelope and endoplasmic reticulum of DRG cells. In contrast to other cells, S1R is also located directly at the plasma membrane of the DRG neurons. The presence of S1R in the nuclear envelope of all DRG neurons suggests an exciting potential role of S1R as a regulator of neuronal nuclear activities and/or gene expression, which may provide insight towards new molecular targets for modulating nociception at the level of primary afferent neurons.

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“…In particular, stimulation of S1Rs dampened depression-like behavior in mice (4). Several studies have indicated that S1Rs also play a key role in nociception (5)(6)(7) and are known to interact with opioid receptors and modulate opioid activity (8,9). In particular, antinociceptive effects of S1R antagonists both when acting alone and in combination with opioids (to enhance opioid analgesia) have been reported at both central and peripheral sites (8,9).…”

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confidence: 99%

Biodistribution and Radiation Dosimetry of ¹⁸F-FTC-146 in Humans

et al. 2017

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The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[]thiazol-2(3H)-one (F-FTC-146). Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. All subjects tolerated the PET/MRI examination well, and no adverse reactions to F-FTC-146 were reported. High accumulation ofF-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). First-in-human studies with clinical-grade F-FTC-146 were successful. Injection ofF-FTC-146 is safe, and absorbed doses are acceptable. The potential of F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.

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Sigma-1 receptors and animal studies centered on pain and analgesia

Cited by 24 publications

References 182 publications

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody

Biodistribution and Radiation Dosimetry of ¹⁸F-FTC-146 in Humans

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Sigma-1 receptors and animal studies centered on pain and analgesia

Cited by 24 publications

References 182 publications

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody

Biodistribution and Radiation Dosimetry of 18F-FTC-146 in Humans

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Biodistribution and Radiation Dosimetry of ¹⁸F-FTC-146 in Humans