Role of peripheral sigma‐1 receptors in ischaemic pain: Potential interactions with <scp>ASIC</scp> and P2X receptors

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

doi:10.1002/ejp.774

Cited by 19 publications

(15 citation statements)

References 42 publications

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“…It was recently reported that the local administration of PRE-084 synergistically enhanced the mechanical allodynia induced by low pH (which activates acid-sensing ion channels) and α-β-methylene-ATP (an agonist of P2-purinoreceptors)23. These findings together with our results indicate that σ 1 agonism is able to promote to the development of mechanical allodynia after priming of the nociceptive system by several agents.…”

Section: Discussionsupporting

confidence: 85%

“…It was previously reported that σ 1 receptor expression can increase in the spinal cord26 and in peripheral nervous tissues23 in chronic pain models, and this might influence the development of sensory hypersensitivity1323. Therefore, we also aimed to test whether chronic σ 1 activation by the selective σ 1 agonist PRE-084 is able to induce sensitization to mechanical stimuli per se or to promote mechanical hypersensitivity after the administration of capsaicin, and whether its effects are due to the altered expression of σ 1 receptors in key areas of the pain pathways in the central and peripheral nervous system.…”

mentioning

confidence: 98%

“…refs 8, 16 and 17), they are able to decrease the pain responses induced by chemical irritants such as formalin or capsaicin (e.g. refs 18, 19, 20) as well as the sensory gain (allodynia or hyperalgesia) occurring due to sensitization of the nociceptive system by capsaicin81621 or by pathological states such as neuropathy, inflammation or ischemic pain817222324.…”

mentioning

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%

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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: 85%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

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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“…In fact, it has been suggested the importance of the endoneurial microenvironment and the maintenance of adequate perfusion in the selection of agents and design of clinical trials in diabetic neuropathy (Cameron and Cotter, 1994). Other authors have also proposed that the blockade of peripheral σ1R induced analgesic effect in ischemic pain (Kwon et al., 2016). The dual effect of σ1R antagonists could be interesting and more research in relation to that is needed to identify new potential levels of intervention for different neuropathies.…”

Section: Discussionmentioning

confidence: 99%

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Paniagua

Girón

Goicoechea

et al. 2016

European Journal of Pain

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BackgroundE‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical and thermal response thresholds were tested on 7‐, 13‐, 14‐ and 15‐week‐old ZDF rats treated with saline or with E‐52862 acutely administered on week 13, followed by sub‐chronic administration (14 days). Axonal peripheral activity (skin–saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15‐week‐old ZDF rats treated with saline or E‐52862 and in LEAN rats.ResultsZucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single‐dose and sub‐chronic E‐52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E‐52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra‐threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E‐52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed.ConclusionsE‐52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.SignificanceBlockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients.What does this study add? This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats.The methodology includes behavioural evidences, electrophysiological data and vascular‐isolated models.

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Schwann cells as a target cell for the treatment of cancer pain

Zhang

Liu

2023

Glia

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Tumor erosion and metastasis can invade surrounding tissues, damage nerves, and sensitize the peripheral primary receptors, inducing pain, which can potentially worsen the suffering of patients with cancer. Reception and transmission of sensory signal receptors, abnormal activation of primary sensory neurons, and activation of glial cells are involved in cancer pain. Therefore, exploring promising therapeutic methods to suppress cancer pain is of great significance. Various studies have found that the use of functionally active cells is a potentially effective way to relieve pain. Schwann cells (SCs) act as small, biologically active pumps that secrete pain-relieving neuroactive substances. Moreover, SCs can regulate the progression of tumor cells, including proliferation and metastasis, through neuro-tumor crosstalk, which emphasizes the critical role of SCs in cancer and cancer pain. The mechanisms by which SCs repair injured nerves and exert analgesia include neuroprotection, neurotrophy, nerve regeneration, neuromodulation, immunomodulation, and enhancement of the nerve-injury microenvironment. These factors may ultimately restore the damaged or stimulated nerves and contribute to pain relief. Strategies for pain treatment using cell transplantation mainly focus on analgesia and nerve repair. Although these cells are in the initial stages of nerve repair and pain, they open new avenues for the treatment of cancer pain. Therefore, this paper discusses, for the first time, the possible mechanism of SCs and cancer pain, and new strategies and potential problems in cancer pain treatment.

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Role of peripheral sigma‐1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors

Abstract: Peripheral Sig-1Rs contribute to the induction of ischaemia-induced MA via facilitation of ASICs and P2X receptors. Thus, peripheral Sig-1Rs represent a novel therapeutic target for the treatment of ischaemic pain.

Cited by 19 publications

References 42 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

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Schwann cells as a target cell for the treatment of cancer pain

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