Sigma-1 receptor-mediated increase in spinal p38 MAPK phosphorylation leads to the induction of mechanical allodynia in mice and neuropathic rats

Moon, Ji Young; Roh, Dae Hyun; Yoon, Seo Yeon; Kang, Sung-Soo; Choi, Sheu Ran; Kwon, Soon Gu; Choi, Hoon; Han, Ho Jae; Beitz, Alvin J.; Lee, Jang Hern

doi:10.1016/j.expneurol.2013.01.004

Cited by 33 publications

(32 citation statements)

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“…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. 50) In addition, our previous study revealed that the increase in spinal pp38 MAPK is closely associated with the induction of Sig-1R mediated mechanical allodynia in normal mice and neuropathic pain rats. 51) Because p38 MAPK activation is regulated by elevated concentrations of intracellular Ca 2+ and the activation of Ca 2+ dependent enzymes, 52,53) and Sig-1R sense endoplasmic reticulum Ca 2+ concentration, 12,54) it is reasonable that changes in p38 MAPK phosphorylation in TNC might be regulated by Sig-1Rs, which may ultimately contribute to orofacial formalin-induced pain signaling.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…Therefore, these findings together suggest that σ 1 agonism alone is not enough to induce pain. However, it was previously reported that the intrathecal administration of σ 1 agonists is sufficient to clearly trigger mechanical allodynia13283031. One explanation for the proalgesic effects of spinal σ 1 agonism is that the procedure for intrathecal catheterization might prime the nociceptive system, thus facilitating the pronociceptive effect of σ 1 agonism.…”

Section: Discussionmentioning

confidence: 99%

“…However, the effects of σ 1 agonists are controversial. 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.…”

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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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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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“…phosphorylation) of intracellular p38 mitogen-activated protein kinases (MAPK) mediates the action of Sig-1R, which ultimately leads to the mechanical allodynia, but not thermal hyperalgesia in sciatic nerve injured mice. 35,36) In addition, we showed that the anti-nociceptive effect of BD1047 in orofacial region was also associated with the suppression of phosphorylated p38 MAPK, but not extracellular signal-regulated kinase (ERK) pathway. 18) Thus it is possible that the modulation of intracellular nociceptive signaling (e.g.…”

Section: Discussionmentioning

confidence: 97%

“…[11][12][13] Our previous studies have shown that pharmacological blockade of Sig1Rs using BD1047 treatment suppressed nociceptive signaling under acute or chronic pain condition using the hind paw formalin-induced pain test 16,21) or the sciatic nerve injury-induced pain animal models. 17,35) In addition, we have recently reported that i.p. treatment of BD1047 dose-dependently reduced orofacial nociceptive responses and the expression of c-Fos protein, a nociceptive marker in the TNC in the mouse orofacial formalin model.…”

Section: Discussionmentioning

confidence: 99%

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination

Yoon

Kang

Kim

et al. 2015

Biological & Pharmaceutical Bulletin

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Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced antinociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore-or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.Key words alpha-2 adrenoceptor; clonidine; sigma-1 receptor; orofacial pain; formalin testThe orofacial region is one of the most densely innervated, by the trigeminal nerve, areas of the body, which focuses some of the most common acute pains, i.e., those accompanying the pathological states of the teeth and the related structures.1) It is also the site of frequent chronic post-herpetic neuralgia, migraine, and referred pains. However, only few analgesic trials have been undergone in trigeminal region, and a lot of difficulties in the management of acute and chronic orofacial pain conditions stem from a lack of recognition and understanding of pain mechanisms. 2,3) In this regard, the management of orofacial disorders is one of the most challenging in the pharmacology field in relation to analgesics.It is well established that an alpha-2 adrenoceptor agonist, clonidine significantly attenuates nociception and hyperalgesia in acute and chronic pain animal models.4,5) Alpha-2 adrenoceptor agonists are thought to produce analgesia primarily by actions in the spinal cord, both by reducing the release of glutamate and substance P from central afferent terminals 6,7) and by hyperpolarizing dor...

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Sigma-1 receptor-mediated increase in spinal p38 MAPK phosphorylation leads to the induction of mechanical allodynia in mice and neuropathic rats

Cited by 33 publications

References 50 publications

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

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

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

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination

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