Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in sensory neurons and functions as a nociceptive channel. TRPV1 is activated by capsaicin, acidic pH, and noxious heat. Compounds inhibiting TRPV1 have been explored to develop analgesic drugs. In this study, the effect of linalyl acetate (LA), a lavender essential oil component that exerts analgesic effects, on TRPV1 was investigated by measuring intracellular Ca2+ concentration ([Ca2+]i) and whole-cell membrane currents. The analgesic effects of LA on TRPV1-mediated pain were also examined. LA inhibited [Ca2+]i responses to capsaicin, acidic pH, and heat in mouse sensory neurons. Unlike the transient LA-inhibition on capsaicin- and heat-responses, its inhibition on acid-responses persisted even after the LA removal. In TRPV1-expressing HEK293 cells, LA reversibly suppressed [Ca2+]i responses to capsaicin and heat, but persistently inhibited those to acids. Similarly, LA reversibly attenuated current responses to capsaicin but durably suppressed those to acids. LA sustainingly inhibited the responses to spermine, an endogenous TRPV1 agonist, and reduced pain-related behaviors induced by spermine and noxious heat. These results indicate that LA inhibits TRPV1 in a mode-independent manner, with long-lasting inhibition of acid-induced TRPV1 activation. These inhibitory actions of LA on TRPV1 may be related to its analgesic effects.

Tramadol and duloxetine, reuptake inhibitors of serotonin and noradrenaline, are widely used analgesics. Cytoplasmic serotonin in human platelets reportedly regulates the activity of low-molecular-weight GTP-binding proteins via serotonylation, leading to the modulation of platelet functions. We recently showed that the combination of thrombopoietin and collagen in the low doses synergistically induces human platelet activation via Rac and Rho/Rho-kinase. In the present study, we investigated the effects of tramadol and duloxetine on the synergistic effect, and the mechanism. Tramadol reduced the platelet aggregation and the release of PDGF-AB by the combination of thrombopoietin and collagen in the low doses. The aggregation and the release were also inhibited by duloxetine. Not reboxetine, a specific inhibitor of noradrenaline transporter, but fluvoxamine and sertraline, specific inhibitors of serotonin transporter suppressed the aggregation and the release. Tramadol, duloxetine, fluvoxamine and sertraline but not reboxetine attenuated the levels of GTP-Rac and GTP-Rho, and phospho-cofilin induced by the combination. Taken together, our results strongly suggest that tramadol and duloxetine, not as noradrenaline reuptake inhibitor but as serotonin reuptake inhibitor, suppress the activation of Rac and Rho/Rho-kinase elicited by the combination of subthreshold thrombopoietin and collagen, leading to the attenuation of human platelet activation.

Polymicrobial sepsis is associated with a poor prognosis due to severe type-1 innate inflammation triggered by immune cells, such as dendritic cells and macrophages. This immune response frequently leads to damage in the heart. Although interleukin (IL)-13 is thought to play a protective role in organ inflammation, its function in polymicrobial sepsis remains unclear. We aimed to investigate the role of IL-13 in modulating myocardial injury during cecal ligation and puncture (CLP)-induced sepsis using a murine model. Cardiac troponin I (cTnI), a biomarker for myocardial damage, was measured in both IL-13-deficient (KO) and wild type (WT) mice subjected to CLP. Contrary to the conventional view of IL-13 as a protective cytokine, IL-13-competent mice exhibited significantly higher serum cTnI levels than IL-13-deficient mice, indicating exacerbated myocardial injury. Elevated cardiac tumor necrosis factor-alpha (TNF-α) levels and IL-1β in WT CLP mice corroborated this finding, suggesting IL-13’s role in enhancing the inflammatory response. In vitro assays with bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharide and Group A Streptococcus revealed a dose-dependent suppression of TNF-α and IL-6 production by recombinant IL-13. These findings indicate a complex role of IL-13 in sepsis, modulating inflammation but potentially increasing myocardial stress.

Previous clinical data have shown that perioperative β-blocker administration can improve lung cancer prognosis, possibly by blocking autonomic nervous system responses. This study aimed to investigate the anticancer mechanisms of the β-blockers propranolol and landiolol for human lung adenocarcinoma cells treated with noradrenaline. A549 human lung adenocarcinoma cells were exposed to each of the following alone or in combination for 2 h: medium only for naïve control; noradrenaline at a dose of 10 μmol/L; propranolol at 10 nmol/L; and landiolol at 1000 nmol/L. Cell proliferation was examined using a cell counting kit-8 assay and immunofluorescent staining of Ki67. qRT-PCR array was performed for Harvey rat sarcoma viral oncogene homolog (HRAS), transforming growth factor-beta receptor II (TGFBR2), and vascular endothelial growth factor A (VEGFA). Noradrenaline (N) showed enhanced cell proliferation compared to control, with higher Ki67 expression on immunostaining, higher HRAS and VEGFA expressions, and lower TGFBR2 expression in qRT-PCR, whereas N-propranolol and N-landiolol showed no significant changes. The present data indicated that perioperative administration of β-blockers might improve the post- operative prognosis of lung cancer via blockage of the adrenergic response.