Mol Pain
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Aggressive breast cancer subtypes utilize system xc-, a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system xc- activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). ⋯ Treatment with DR-1-55 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1β, were also down-regulated at the mRNA level in response to DR-1-55 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system xc- blockers.
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Degranulation of meningeal mast cells leading to the sensitization of trigeminal vascular afferent processing is believed to be one of the mechanisms underlying the migraine pain pathway. Recent work suggests that Toll-like receptor 4 (TLR4) may be involved in signaling states of central sensitization. Using a murine model of light aversion produced by compound 48/80 (2 mg/kg, intraperitoneal) mast cell degranulation, employed as a surrogate marker for photophobia observed in migraineurs, we examined the role of TLR4 in migraine-like behavior and neuronal activation. ⋯ Assessing the downstream signaling pathway in mutant mice, we found that the TLR4-mediated, light aversion was dependent upon myeloid differentiation primary response gene 88 but not Toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β signaling. In separate groups, male mice sacrificed at 10 min following compound 48/80 revealed a significant increase in the incidence of evoked p-extracellular signal–regulated kinases (+) neurons in the nucleus caudalis of wild type but not Tlr4−/− mice or in mice pre-treated with sumatriptan. This study thus provides the first evidence for involvement of TLR4 signaling through MyD88 in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation in the mouse.
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The size and modular structure of versican and its gene suggest the existence of multiple splice variants. We have identified, cloned, and sequenced a previously unknown exon located within the noncoding gene sequence downstream of exon 8. This exon, which we have named exon 8β, specifies two stop-codons. mRNAs of the versican gene with exon 8β are predicted to be constitutively degraded by nonsense-mediated RNA decay. Here, we tested the hypothesis that these transcripts become expressed in a model of neuropathic pain.