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Neuroinflammation, where inflammatory cytokines are produced in excess, contributes to the pathogenesis of delirium. Microglial cells play a central role in neuroinflammation by producing and releasing inflammatory cytokines in response to infection, tissue damage and neurodegeneration. Dexmedetomidine (DEX) is a sedative, which reduces the incidence of delirium. Thus, we hypothesized that DEX may alleviate delirium by exhibiting anti-inflammatory action on microglia. In the present study, we investigated the anti-inflammatory action of DEX on human microglial HMC3 cells. The results indicated that DEX partially suppressed the IL-6 and IL-8 production by lipopolysaccharide (LPS)-stimulated HMC3 cells as well as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. Furthermore, DEX substantially suppressed IL-6 and IL-8 production by unstimulated HMC3 cells as wells as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. These observations suggest that DEX exhibits anti-inflammatory action on not only LPS-stimulated but also unstimulated microglial cells via the suppression of inflammatory signaling and cytokine production.

This study aimed to investigate whether changes in psychosocial factors and pain severity were associated with reduction in disability due to pain among patients with chronic pain. We hypothesized that increased self-efficacy would reduce disability. This longitudinal observational study included 72 patients. Patients' psychological and physical variables were assessed before and after 3 months of treatment. Demographic and clinical information were collected, including the Pain Disability Assessment Scale (PDAS), the Pain Self-Efficacy Questionnaire (PSEQ), the Hospital Depression and Anxiety Scale, and the Numeric Rating Scale (NRS) to assess pain intensity. First, univariate regression analyses were conducted to clarify associations between change in PDAS and sex, age, pain duration, changes in psychosocial factors (self-efficacy, anxiety, and depression) and change in pain intensity. Second, multivariate regression was conducted using the variables identified in the univariate analyses (PSEQ and NRS) to detect the most relevant factor for reducing disability. Univariate regression analyses clarified that changes in PSEQ (β = -0.31; 95% CI: -0.54--0.08, p = 0.008) and NRS (β = 0.24; 95% confidence interval [CI]: 0.01-0.47, p = 0.04) were associated with reduction in PDAS. Multivariate regression analysis demonstrated that change in PSEQ (β = 0.26; 95% CI: -0.50--0.02; p = 0.01) was associated with a reduction in disability, independent of change in NRS. These findings suggest improved self-efficacy is associated with reduced disability in patients with chronic pain, independent of reduction in pain intensity. Focusing on improvement in self-efficacy may be an effective strategy in chronic pain treatment in addition to pain relief.

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G protein-biased delta-opioid receptor agonists, and in vivo studies have demonstrated that they exert several beneficial effects via the central nervous system. The most unique and attractive advantage of rubiscolin-6 over other oligopeptides is its oral availability. Therefore, it can be considered a promising candidate for the development of a novel and safe drug. In this review, we show the therapeutic potential of rubiscolin-6, mainly focusing on its effects when orally administered based on available evidence. Additionally, we present a hypothesis for the pharmacokinetics of rubiscolin-6, focusing on its absorption in the intestinal tract and ability to cross the blood–brain barrier.

As congenital cytomegalovirus (CMV) infections are the leading non-genetic cause of sensorineural hearing loss and significant neurological disabilities in children, the development of CMV vaccines should be given the highest public health priority. Although MF59-adjuvanted glycoprotein B (gB) vaccine (gB/MF59) is safe and immunogenic, its efficacy in terms of protection from natural infection was around 50 % in clinical trials. Although gB/MF59 induced high antibody titers, anti-gB antibodies contributed little to the neutralization of infection. Recent studies have found that non-neutralizing functions, including antibody-dependent phagocytosis of virions and virus-infected cells, are likely to play important roles in pathogenesis and vaccine design. Previously, we isolated human monoclonal antibodies (MAbs) that reacted with the trimeric form of gB ectodomain and found that preferential epitopes for neutralization were present on Domains (Doms) I and II of gB, while there were abundant non-neutralizing antibodies targeting Dom IV. In this study, we analyzed the phagocytosis activities of these MAbs and found the following: 1) MAbs effective for phagocytosis of the virions targeted Doms I and II, 2) the MAbs effective for phagocytosis of the virions and those of virus-infected cells were generally distinct, and 3) the antibody-dependent phagocytosis showed little correlation with neutralizing activities. Taking account of the frequency and levels of neutralization and phagocytosis, incorporation of the epitopes on Doms I and II into developing vaccines is considered desirable for the prevention of viremia.

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.

Purpose This study aimed to investigate whether smoking is an independent risk factor for central sensitization syndrome (CSS) in individuals with pain as measured by the Central Sensitization Inventory (CSI). Methods In 2020, we conducted an Internet survey targeting 2000 ordinary residents of Japan (aged 20–69 years) who had pain symptoms from October to November 2020. A multiple regression analysis was performed on the association between smoking status (nonsmokers and current smokers; Brinkman index) and CSI values. Moreover, compared to nonsmokers, the relative risk (RR) of the CSI cut-off score of 40 points or higher among current smokers was calculated using a modified Poisson regression model. Covariates included age, sex, body mass index, marital status, equivalized income, exercise habits, history of hypertension, history of hyperlipidemia, history of diabetes, pain chronicity, and Pain Catastrophizing Scale score. Results This study analyzed 1,822 individuals (1,041 men and 781 women). Among those experiencing pain, current smoking was associated with the increase in CSI values ( β  = 0.07). The Brinkman index was also significantly associated with the increase in CSI values ( β  = 0.06). Current smoking also increased the risk of being over the CSI cut-off score, with a relative risk (RR) of 1.29 (95% confidence intervals, 1.04–1.60). Younger age, being women, experiencing chronic pain, and higher pain catastrophizing thinking were also significantly associated with increased CSS severity, independent of smoking status. Conclusion Smoking is an independent risk factor for CSS. This indicates that smoking may be an important factor in the management of central pain disorders.

Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC50 values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists.

Insomnia is a major comorbid symptom of chronic pain and is likely to affect caregiver burden. This cross-sectional study investigated the association between insomnia in chronic pain patients and family caregiver burden. Participants were 60 patients with chronic pain of ≥3 months duration. Demographic and clinical information were collected using the Athens Insomnia Scale (AIS), the Pain Disability Assessment Scale (PDAS), the Hospital Anxiety and Depression Scale (HADS), and a pain intensity numerical rating scale (NRS). Family members who accompanied chronic pain patients to hospital completed the Zarit Burden Interview (ZBI). Univariate regression analysis and multiple regression analysis were conducted to clarify the associations between ZBI scores and total/subscale AIS scores. Covariates were age; sex; pain duration; and scores on the PDAS, HADS anxiety subscale, HADS depression subscale, and NRS. Insomnia was independently associated with ZBI scores [β: 0.27, 95% confidence interval (CI): 0.07-0.52, p = 0.001]. Scores on the AIS subscale of physical and mental functioning during the day were significantly associated with ZBI scores (β: 0.32, 95% CI: 0.05-0.59, p = 0.007). In conclusion, the findings suggest that in chronic pain patients, comorbid insomnia and physical and mental daytime functioning is associated with family caregiver burden independently of pain duration, pain-related disability, and pain intensity.

The neuropeptide substance P (SP) is an important mediator of neurogenic inflammation within the central and peripheral nervous systems. SP has been shown to induce the expression of pro-inflammatory cytokines implicated in the pathogenesis of several disorders of the human brain via the neurokinin-1 receptor (NK-1R). Ketamine, an intravenous anesthetic agent, functions as a competitive antagonist of the excitatory neurotransmission N-methyl-D-aspartate (NMDA) receptor, and also antagonizes the NK-1R by interfering with the binding of SP. In the present study, we investigated the anti-inflammatory effects of ketamine on the SP-induced activation of a human astrocytoma cell line, U373MG, which expresses high levels of NK-1R. The results from our experiments indicated that ketamine suppressed the production of interleukin (IL)-6 and IL-8 by the U373MG cells. Furthermore, ketamine inhibited the SP-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). Taken together, these observations suggest that ketamine may suppress the SP-induced activation (IL-6 and IL-8 production) of U373MG cells by inhibiting the phosphorylation of signaling molecules (namely ERK1/2, p38 MAPK and NF-κB), thereby exerting anti-inflammatory effects. Thus, ketamine may modulate SP-induced inflammatory responses by NK-1R-expressing cells through the suppression of signaling molecules (such as ERK1/2, p38 MAPK and NF-κB).

A 56‐year‐old woman presented with a 2 months history of patulous eustachian tube. She had sudden weight loss after developing a cold, after which she had been experiencing disabling autophony and a sensation of blockage in the ear. She underwent stellate ganglion block in 8 months; her symptoms resolved subsequently. We concluded that successful management of PET can be obtained with SGB; this treatment was not previously used for this disorder.