Sigma-1 Receptor Antagonist BD1047 Reduces Allodynia and Spinal ERK Phosphorylation Following Chronic Compression of Dorsal Root Ganglion in Rats

Son, Ji Seon; Kwon, Young Bae

doi:10.4196/kjpp.2010.14.6.359

Cited by 30 publications

(17 citation statements)

References 19 publications

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“…Although SN79 treatment was found to mitigate METH-induced increases in STAT3 phosphorylation, it may be possible that modulation of ERK1/2 and JNK pathways are contributing to increases in SOCS3 (Baker et al 2008), thereby leading to the blockade of STAT3 phosphorylation seen in the current report. Supporting this hypothesis are previous studies showing the modulation of ERK1/2 and JNK signaling by various sigma receptor ligands (Cantarella et al 2007; Nishimura et al 2008; Son and Kwon 2010; Tan et al 2010; Tuerxun et al 2010), although their effects specifically within astrocytes on these signaling pathways are currently unknown.…”

Section: Discussionmentioning

confidence: 77%

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Robson

Turner

Naser

et al. 2014

Experimental Neurology

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Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.

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Section: Discussionmentioning

confidence: 77%

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Robson

Turner

Naser

et al. 2014

Experimental Neurology

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“…It has been reported that p38 MAPK plays an important role in a variety of chronic pain states. 45,46,48) Especially, Li et al showed that the expression of c-Fos and pp38 MAPK in the spinal cord dorsal horn were increased after an injection of formalin into the paw. 49) Recent study from Tan et al also reported that the activation of the Src/p38 MAPK signaling cascade in spinal microglia contributed to late stage persistent mechanical hyperalgesia evoked by formalin injection into the paw.…”

Section: Discussionmentioning

confidence: 97%

“…44) In particular, phosphorylated ERK (pERK) and p38 (pp38) MAPK in the spinal cord dorsal horn cells plays an important role in the induction and maintenance of pain hypersensitivity caused by partial sciatic nerve injury. 9, [44][45][46] Recently, Son and Kwon revealed that both allodynia induction and spinal pERK elevation were completely prevented during the time of BD1047 treatment (0-5 d after chronic compression on the DRG). 47) Furthermore, the Sig-1R knockout mice did not show any increase of pERK in the spinal cord after sciatic nerve injury, 9) suggesting that Sig-1Rs might be related to the mechanism of induction of ERK activation in the neuropathic condition.…”

Section: Discussionmentioning

confidence: 98%

Sigma-1 Receptor Antagonist, BD1047 Reduces Nociceptive Responses and Phosphorylation of p38 MAPK in Mice Orofacial Formalin Model

Roh

Yoon

2014

Biological & Pharmaceutical Bulletin

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Sigma-1 receptors (Sig-1Rs) play a role in different types of pain and in central sensitization mechanism in spinal cord. However, it is currently unexplored whether Sig-1Rs are involved in orofacial pain processing. Here we show whether a selective Sig-1R antagonist, BD1047 reduces nociceptive responses in the mouse orofacial formalin model and the number of Fos-immunoreactive (ir) cells in the trigeminal nucleus caudalis (TNC). In addition, it was examined whether the phosphorylation of extracellular signal-regulated kinase (pERK) or p38 (pp38) mitogen-activated protein kinases (MAPK), which are closely linked to pain signaling and sensitization, in TNC was modified by BD1047. The 5% formalin (10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with ipsilateral fore- or hind paw were counted for 45 min. BD1047 (1, 3 or 10 mg/kg) were intraperitoneally treated 30 min before formalin injection. High dose of BD1047 (10 mg/kg) produced significant anti-nociceptive effects in the first and the second phase. The number of Fos-ir cells in ipsilateral side of TNC was also reduced by BD1047 as compared to that in saline-treated animals. In addition, the number of pp38-ir cells in ipsilateral TNC was decreased in BD1047-treated animals, whereas the number of pERK-ir cells was not modified. Collectively, these results demonstrate that Sig-1Rs play a pivotal role in the orofacial pain processing, and the pp38 signaling pathway can be associated with Sig-1R's action in TNC.

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“…It has been reported that σ 1 receptor antagonists reduce the pain responses in the second phase of the formalin test, 23,25,27 the mechanical hypersensitivity induced by capsaicin, 22,24,27 and the neuropathic pain responses in various models. [27][28][29] There is an apparent discrepancy between the normal occurrence of capsaicin-induced referred hyperalgesia in σ 1 -KO mice and the inhibition of this hyperalgesia in WT mice treated with σ 1 receptor antagonists. This mismatch may be attributable to the development of compensatory mechanisms in σ 1 -KO mice versus WT animals, a general fact in genetic knockout experiments.…”

Section: Discussionmentioning

confidence: 99%

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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Sigma-1 Receptor Antagonist BD1047 Reduces Allodynia and Spinal ERK Phosphorylation Following Chronic Compression of Dorsal Root Ganglion in Rats

Cited by 30 publications

References 19 publications

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Sigma-1 Receptor Antagonist, BD1047 Reduces Nociceptive Responses and Phosphorylation of p38 MAPK in Mice Orofacial Formalin Model

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

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