Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

Squillace, Silvia; Spiegel, Sarah; Salvemini, Daniela

doi:10.1016/j.tips.2020.09.006

Cited by 31 publications

(37 citation statements)

References 121 publications

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“…Blocking ADK engages A 3 AR signalling and prevents the development of S1PR1-evoked hypersensitivity. Our ndings, which provide novel mechanistic insights into molecular signaling pathways engaged by S1PR1 in the spinal cord, in turn suggest that the bene cial effects of S1PR1 antagonists observed in neuropathic pain (Squillace et al 2020) may include their ability to restore A 3 AR signaling.…”

Section: Resultsmentioning

confidence: 66%

“…Since pain drugs often fail to achieve adequate relief in patients, and opioid treatments are associated with abuse and addiction, developing new pain medicines is crucial. Over the last several years, the sphingosine-1-phosphate (S1P) receptor subtype 1 (S1PR1) has emerged as an attractive molecular target for therapeutic intervention (Squillace et al 2020). Several studies found that alterations in sphingolipid metabolism in the spinal dorsal horn increase S1P production and contribute to hypersensitivity associated with cancer pain (Grenald et al 2017), opioid-induced hyperalgesia (Muscoli et al 2010;Doyle et al 2020a), neuropathic pain caused by chemotherapy (Stockstill et al 2019;Janes et al 2014), multiple sclerosis (Doolen et al 2018) or traumatic peripheral nerve injury (Chen et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies found that alterations in sphingolipid metabolism in the spinal dorsal horn increase S1P production and contribute to hypersensitivity associated with cancer pain (Grenald et al 2017), opioid-induced hyperalgesia (Muscoli et al 2010;Doyle et al 2020a), neuropathic pain caused by chemotherapy (Stockstill et al 2019;Janes et al 2014), multiple sclerosis (Doolen et al 2018) or traumatic peripheral nerve injury (Chen et al 2019). Blocking S1PR1 with functional or competitive S1PR1 antagonists prevents and reverses neuropathic pain states of various etiologies (Chen et al 2019;Squillace et al 2020). Moreover, studies in breast cancer patients showed that S1PR1 is a potential molecular driver of sensory peripheral neuropathy induced by chemotherapy (Chua et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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Role of Adenosine Kinase In Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

Lauro

Giancotti

Kolar

et al. 2021

Preprint

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Emerging evidence implicates the sphingosine-1-phosphate (S1P) receptor subtype 1 (S1PR1) in the development of neuropathic pain. Continued investigation of the signaling pathways downstream of S1PR1 are needed to support development of S1PR1 antagonists. In rodents, intrathecal (i.th.) injection of SEW2871, a selective S1PR1 agonist, activates the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, increases interleukin-1β (IL-1β) and causes behavioral hypersensitivity. I.th. injection of a IL-1β receptor antagonist blocks SEW2871-induced hypersensitivity, suggesting that IL-1β contributes to S1PR1’s actions. Interestingly, previous studies have suggested that IL-1β increases the expression/activity of adenosine kinase (ADK), a key regulator of adenosine signaling at its receptors (ARs). Increased ADK expression reduces adenosine signaling whereas inhibiting ADK restores the action of adenosine. Here, we show that SEW287-induced behavioral hypersensitivity is associated with increased expression of ADK in astrocytes of the dorsal horn of the spinal cord (DH-SC). Moreover, the ADK inhibitor, ABT702, blocks SEW2871-induced hypersensitivity. These findings link ADK activation to S1PR1. If SEW2871-induced pain is mediated by IL-1β, which in turn activates ADK and leads to mechano-allodynia, then blocking ADK should attenuate IL-1β effects. In support of this idea, recombinant rat (rrIL-1β)-induced allodynia was blocked by at least 90% with ABT702, functionally linking ADK to IL-1β. Moreover, the selective A3AR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1β-induced allodynia, implicating A3AR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-b and ADK activation.

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Section: Resultsmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Adenosine Kinase In Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

Lauro

Giancotti

Kolar

et al. 2021

Preprint

Self Cite

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“…FTY720/fingolimod, a functional S1PR1 antagonist, used clinically for nonpain conditions, is being utilized as nonnarcotic analgesics and may hopefully help reduce the abuse of opioids [ 101 ].…”

Section: Discussionmentioning

confidence: 99%

“…The lipophilic effect of FTY720 phosphate involves increasing the phosphorylation of Ser563 and transcription of hormone-sensitive lipase, fatty triglyceride lipase, and perilipin [99]. In addition, FTY720 can promote insulin resistance in mature adipocytes and reduce glucose uptake [100] FTY720/fingolimod, a functional S1PR1 antagonist, used clinically for nonpain conditions, is being utilized as nonnarcotic analgesics and may hopefully help reduce the abuse of opioids [101].…”

Section: 2mentioning

confidence: 99%

S1P Signaling Pathways in Pathogenesis of Type 2 Diabetes

Shen

et al. 2021

Journal of Diabetes Research

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The pathogenesis of type 2 diabetes mellitus (T2DM) is very complicated. The currently well-accepted etiology is the “Ominous Octet” theory proposed by Professor Defronzo. Since presently used drugs for T2DM have limitations and harmful side effects, studies regarding alternative treatments are being conducted. Analyzing the pharmacological mechanism of biomolecules in view of pathogenesis is an effective way to assess new drugs. Sphingosine 1 phosphate (S1P), an endogenous lipid substance in the human body, has attracted increasing attention in the T2DM research field. This article reviews recent study updates of S1P, summarizing its effects on T2DM with respect to pathogenesis, promoting β cell proliferation and inhibiting apoptosis, reducing insulin resistance, protecting the liver and pancreas from lipotoxic damage, improving intestinal incretin effects, lowering basal glucagon levels, etc. With increasing research, S1P may help treat and prevent T2DM in the future.

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Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

et al. 2021

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Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

Cited by 31 publications

References 121 publications

Role of Adenosine Kinase In Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

Role of Adenosine Kinase In Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

S1P Signaling Pathways in Pathogenesis of Type 2 Diabetes

Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

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