Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Grenald, Shaness A.; Doyle, Tim; Zhang, Hong; Slosky, Lauren M.; Chen, Zhoumou; Largent-Milnes, Tally M.; Spiegel, Sarah; Vanderah, Todd W.; Salvemini, Daniela

doi:10.1097/j.pain.0000000000000965

Cited by 60 publications

(39 citation statements)

References 56 publications

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“…Recent studies have linked aberrant S1P signaling to a variety of diseases, including asthma (Chiba et al, 2010;Tränkner et al, 2014 Janes et al, 2014;Grenald et al, 2017). However, the cellular and molecular targets of S1P in these disorders are largely unknown.…”

Section: Discussionmentioning

confidence: 99%

S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

et al. 2018

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Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here, we find that S1P triggers itch and pain in male mice in a concentration-dependent manner, with low levels triggering acute itch alone and high levels triggering both pain and itch. Ca imaging and electrophysiological experiments revealed that S1P signals via S1P receptor 3 (S1PR3) and TRPA1 in a subset of pruriceptors and via S1PR3 and TRPV1 in a subset of heat nociceptors. Consistent with these findings, S1P-evoked itch behaviors are selectively lost in mice lacking TRPA1, whereas S1P-evoked acute pain and heat hypersensitivity are selectively lost in mice lacking TRPV1. We conclude that S1P acts via different cellular and molecular mechanisms to trigger itch and pain. Our discovery elucidates the diverse roles that S1P signaling plays in somatosensation and provides insight into how itch and pain are discriminated in the periphery. Itch and pain are major health problems with few effective treatments. Here, we show that the proinflammatory lipid sphingosine 1-phosphate (S1P) and its receptor, S1P receptor 3 (S1PR3), trigger itch and pain behaviors via distinct molecular and cellular mechanisms. Our results provide a detailed understanding of the roles that S1P and S1PR3 play in somatosensation, highlighting their potential as targets for analgesics and antipruritics, and provide new insight into the mechanistic underpinnings of itch versus pain discrimination in the periphery.

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Section: Discussionmentioning

confidence: 99%

S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

et al. 2018

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“…FTY720 is phosphorylated by SphK and binds to four of the S1P receptors and modulates receptor activities . S1PR antagonists including FTY720 have been demonstrated to inhibit bone cancer pain and chemotherapy‐induced painful neuropathy in murine models . It is likely that mast cells contribute to these S1P‐dependent painful conditions; however, this remains to be proven.…”

Section: Mast Cell Products That Contribute To Painmentioning

confidence: 99%

Mast cell‐neural interactions contribute to pain and itch

Gupta

Harvima

2018

Immunological Reviews

206

189

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Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer.

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“…Emerging evidence implicates S1PR1 activation in the development of chemotherapy (9, 10) and bone cancer-induced pain (11). Moreover, intrathecal administration of a highly selective S1PR1 agonist, SEW2871 (12), caused the development of mechanohypersensitivity in naïve animals (9).…”

mentioning

confidence: 99%

Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

Chen

Doyle

Luongo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

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Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Cited by 60 publications

References 56 publications

S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

Mast cell‐neural interactions contribute to pain and itch

Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

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