Eiichi Inada

The macrophage-mediated effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuate tactile allodynia in the early phase of neuropathic pain development.

BACKGROUND: Neuroinflammation triggered by macrophage infiltration into sites of peripheral nerve injury may result in neuropathic pain. Peroxisome proliferator-activated receptor (PPAR)&ggr; signaling regulates the properties of macrophages. However, the macrophage-mediated effects of PPAR&ggr; signaling on neuropathic pain triggered by peripheral inflammation have not been investigated. METHODS: To evaluate the peripheral effects of PPAR&ggr; signaling on tactile allodynia, we administered the blood-brain barrier–impermeant PPAR&ggr; agonist, rosiglitazone, after partial sciatic nerve ligation (PSNL) as (1) systemic treatment during different phases of neuropathic pain development, (2) local injection to the PSNL site in the early phase, or (3) peritoneal macrophages pretreated with rosiglitazone transplanted into the PSNL site. In addition, the direct effect of rosiglitazone was evaluated in peritoneal macrophages activated with interferon-&ggr;. RESULTS: Systemic rosiglitazone treatment early in the course of progressive inflammation ameliorated tactile allodynia, macrophage infiltration, and production of proinflammatory mediators including cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease 9 at the PSNL site. Local injection of rosiglitazone and transplantation of rosiglitazone-treated peritoneal macrophages at the ligation site significantly improved tactile allodynia. In peritoneal macrophages, rosiglitazone down-regulated interferon-&ggr;–induced gene expression of cyclooxygenase-2 and inducible nitric oxide synthase and attenuated the chemotactic response to monocyte chemotactic protein-1. DISCUSSION: Rosiglitazone treatment in the early phase of neuropathic pain significantly alleviated the development of tactile allodynia by regulating macrophage infiltration and production of proinflammatory molecules at the inflamed site. Our results indicate that the activation of PPAR&ggr; signaling in macrophages during the early phase may suppress neuropathic pain development.

Replacement of Gabapentin with Pregabalin in Postherpetic Neuralgia Therapy

PURPOSE Although both gabapentin and pregabalin are first-line drugs for neuropathic pain including postherpetic neuralgia (PHN), no report has directly compared the magnitude of pain relief and the incidence of side effects of both drugs. By substituting gabapentin with pregabalin in postherpetic neuralgia therapy, we can compare the two drugs. METHODS In 32 PHN patients being administered gabapentin, without changing the frequency of dosing, the drug was substituted with pregabalin at one-sixth dosage of gabapentin. After 2 weeks, an interview was conducted about the visual analog scale (VAS) pain score, changes in the time of onset of action and duration of action after the substitution of drug and side effects (such as somnolence, dizziness, and peripheral edema). In addition, the dosage was increased while paying careful attention to the side effects (titration) in 22 patients who requested a dosage increase among those whom VAS pain score of ≥25 mm remained even after the substitution. RESULTS No significant changes were observed in VAS pain scores after the substitution of gabapentin with pregabalin. Regarding the time of onset of action and the duration of action after the substitution, the highest number of patients answered that no change occurred compared with the previous drug, followed by the patients who answered that the time of onset of action became quicker, and the duration of action became longer. The incidence of somnolence and dizziness showed no significant difference before and after the substitution, but peripheral edema showed a significant increase after the substitution. The level of side effects of both drugs was mild, and continued medication was possible. In the patient group where pregabalin dosage was increased, the VAS pain score decreased significantly compared with that before and after increase the dosage (P < 0.05). On the other hand, in nine out of 22 patients in the group where the dosage was increased, side effects appeared or were exacerbated. In two out of nine patients, it was necessary to reduce the dosage to the initial volume. CONCLUSION It was suggested that the analgesic action of pregabalin in PHN was six times that of gabapentin in terms of effectiveness in dosage conversion. Regarding the side effects, although the incidence of the peripheral edema was higher with pregabalin compared with gabapentin, this finding is not conclusive because the present study was conducted in a small number of subjects. Although pain reduction can be expected to increase with pregabalin dosage, it is necessary to increase the dosage gradually and carefully because of exacerbation of side effects.

Lidocaine attenuates the development of diabetic-induced tactile allodynia by inhibiting microglial activation.

BACKGROUND:Lidocaine is used clinically for tactile allodynia associated with diabetes-induced neuropathy. Although the analgesic effect of lidocaine through suppression of microglial activation has been implicated in the development of injury-induced neuropathic pain, its mechanism of action in diabetes-induced tactile allodynia has not yet been completely elucidated. METHODS:To evaluate the effects of lidocaine on microglial response in diabetic neuropathy, streptozotocin (STZ)-injected mice received a continuous infusion of lidocaine (vehicle, 2, or 10%) from day 14 to day 21 after STZ injection. On day 21, microglial accumulation and p38 mitogen-activated protein kinase activation in the dorsal horn were evaluated. In vitro, the effects of lidocaine on cell viability, chemotactic response to monocyte chemotactic protein-1, and induction of proinflammatory mediators were examined in interferon (IFN)-&ggr;–stimulated primary microglial cells. RESULTS:Continuous systemic administration of lidocaine in the early progression of tactile allodynia produced long-lasting analgesic effects in STZ-treated mice. Lidocaine significantly reduced accumulation and p38 phosphorylation of microglial cells in the dorsal horn. In vitro, lidocaine down-regulated IFN-&ggr;–induced gene induction of inducible oxide synthase and interleukin-1&bgr;. Pretreatment with lidocaine significantly reduced chemotactic response to monocyte chemotactic protein-1 of IFN-&ggr;–activated microglial cells. CONCLUSION:Lidocaine alleviates STZ-induced tactile allodynia, possibly by modulating the p38 pathway in spinal microglial cells. Inhibiting microglial activation by lidocaine treatment early in the course of diabetes-induced neuropathy represents a potential therapeutic strategy for tactile allodynia.

Changes in circadian rhythm for mRNA expression of melatonin 1A and 1B receptors in the hypothalamus under a neuropathic pain‐like state

Several clinical reports on neuropathic pain of various etiologies have shown that it significantly interferes with sleep. Inadequate sleep due to neuropathic pain may contribute to the stressful negative consequences of living with pain. It is generally recognized that melatonin (MT) system in the hypothalmus is crusial for circadian rhythm and sleep‐wake transition. However, little, if any, is known about whether neuropathic pain could affect the MT system associated with sleep disturbance. In this study, we investigated the possible changes in circadian rhythm for the expression of MT receptors, especially MT1A and MT1B receptors, in the hypothalamus of mice with sciatic nerve ligation. The samples for real‐time RT‐PCR assay were prepared at 8:00, 14:00, 20:00, and 2:00 on day 7 after sciatic nerve ligation or sham operation. The mRNA expression of MT1A and MT1B receptors at 2:00 in sciatic nerve‐ligated mice, which exhibited thermal hyperalgesia along with an increase in wakefulness and a decrease in nonrapid eye movement sleep, was significantly greater than those in sham‐operated mice, whereas the levels of both MT1A and MT1B receptors at 8:00 in sciatic nerve‐ligated mice were significantly lower than those in sham‐operated mice. These findings suggest that neuropathic pain‐like stimuli lead to sleep disturbance in parallel with changes in circadian rhythm for mRNA expression of MT 1A and 1B receptors in the hypothalamus of mice. Synapse 68:153–158, 2014.

Effect of olprinone, a phosphodiesterase III inhibitor, on hepatic ischemia-reperfusion injury in rats.

I/R injury is the main cause for hepatic dysfunction and failure after liver transplantation and liver resection. Therefore, reduction of I/R injury is the most important goal to improve the outcome of these procedures. Olprinone is a newly developed selective phosphodiesterase III inhibitor, which has been reported to ameliorate renal I/R injury in rats. However, no clear evidence for the actions of olprinone on inflammatory response after hepatic I/R injury has been disclosed thus far. Our study was designed to evaluate the action of olprinone on the hepatic I/R injury in rats. Olprinone increased the cyclic adenosine monophosphate level in injured liver tissue and ameliorated the liver injury after hepatic I/R. Moreover, olprinone suppressed the activation of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-&kgr;B, cytokine production (TNF-&agr;, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), and intercellular adhesion molecule 1 expression in liver after hepatic I/R. These observations suggest that olprinone protects liver against I/R injury via the elevation of cyclic adenosine monophosphate level and suppression of intercellular adhesion molecule 1 expression and cytokine production (TNF-&agr;, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), possibly by interfering with the signaling pathways of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-&kgr;B in rats.

Effects of anesthesia with sevoflurane and propofol on the cytokine/chemokine production at the airway epithelium during esophagectomy.

Post-operative pulmonary complications such as pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are closely associated with morbidity and mortality after esophagectomy. One lung ventilation (OLV) is commonly used during esophagectomy. However, the effect of the anesthetic agents on the inflammatory response induced by OLV has yet to be evaluated, particularly during esophagectomy, which causes several complications in the lung. The aim of the present study was to determine the effects of anesthetic agents, such as sevoflurane or propofol, on the inflammatory reactions at the airway. Twenty patients undergoing esophagectomy were randomized to receive either sevoflurane (n=10) or propofol (n=10) as a main anesthetic agent. Epithelial lining fluid (ELF) was obtained from ventilated‑dependent lung (DL) and collapsed non-dependent lung (NDL) by a bronchoscopic microsampling method. The levels of inflammatory cytokines and chemokine [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-12p70] in the ELF were measured using multiplexed bead-based immunoassays before and after OLV. The results indicated that the levels of IL-6 in ELF were significantly increased in both the ventilated DL and collapsed NDL after OLV compared with the levels prior to OLV in the sevoflurane group. By contrast, there was no significant change in the IL-6 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. Similarly, IL-8 levels were markedly increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV in the sevoflurane group, whereas there was no significant change in IL-8 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. In contrast to the changes in IL-6 and IL-8 levels, levels of IL-10, an anti-inflammatory cytokine, were not obviously changed in both the ventilated DL and collapsed NDL before and after OLV in the sevoflurane group. However, IL-10 levels in the propofol group were increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV. Of note, the levels of TNF-α, IL-1β and IL-12p70 in ELF were below the detection limits. These observations suggested that propofol anesthesia more potently suppresses the surgical stress-induced inflammatory perturbation at the local milieu of the airway during esophagectomy compared with sevoflurane anesthesia.

Sevoflurane suppresses tumour necrosis factor-α-induced inflammatory responses in small airway epithelial cells after anoxia/reoxygenation

BACKGROUND Lung ischaemia-reperfusion (I/R) injury is correlated with poor clinical outcome. The inflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) are produced by pulmonary epithelial cells during lung transplantation and are considered to be involved in I/R injury. The volatile anaesthetic sevoflurane has been shown to exert a protective effect on I/R injury in various organs. We investigated the effect of sevoflurane on the inflammatory functions of pulmonary epithelial cells in vitro. METHODS Human normal small airway epithelial cells (SAEC) were incubated under anoxic conditions for 24 h with or without sevoflurane and then stimulated with tumour necrosis factor (TNF)-α under hyperoxic conditions for 5 h with or without sevoflurane. After incubation, IL-6, IL-8, and MCP-1 mRNA expression was analysed by quantitative real-time RT-PCR. The production of IL-6, IL-8, and MCP-1 was assayed by enzyme-linked immunosorbent assay, the effects of sevoflurane on inflammatory gene expression were examined by DNA microarray analysis, and the effects of sevoflurane on NF-κB-mediated inflammatory cytokine production were examined by immunoblotting. RESULTS Sevoflurane suppressed TNF-α-induced IL-6, IL-8, and MCP-1 gene expression and the production of IL-6 and IL-8 in SAEC under anoxia/reoxygenation conditions. DNA microarray analysis indicated that sevoflurane modulated NF-κB-related gene expression. Sevoflurane significantly inhibited TNF-α-induced translocation of p65 NF-κB into the nucleus. Sevoflurane enhanced TNF-α-induced gene expression of inhibitor κB (IκB) but not of NF-κB. CONCLUSIONS Sevoflurane suppressed the NF-κB-mediated production of pulmonary epithelial cell-derived inflammatory cytokines, including IL-6 and IL-8, which are capable of causing I/R injury.

Preoperative plasma brain natriuretic peptide level is an independent predictor of postoperative atrial fibrillation following off-pump coronary artery bypass surgery

PurposeAtrial fibrillation (AF) is a frequent complication after coronary artery bypass surgery. Postoperative AF can lead to thromboembolic events, prolonged hospital stay, and increased costs. Recent reports have shown that an elevated plasma brain natriuretic peptide (BNP) level is associated with AF. The purpose of this prospective study was to test the hypothesis that preoperative BNP level is a predictor of postoperative AF following off-pump coronary artery bypass surgery (OPCAB).MethodsOne hundred and fifty patients without a history of AF undergoing elective isolated OPCAB were enrolled. Plasma BNP level was measured preoperatively. Heart rate and rhythm were continuously monitored during the first 72 h after surgery.ResultsTwenty-six patients (17.3%) exhibited postoperative AF. This proportion is similar to those reported in earlier studies. Univariate analysis demonstrated that age (odds ratio [OR], 1.060; 95% confidence interval [CI], 1.008 to 1.114; P = 0.023), previous myocardial infarction (MI; OR, 2.628; 95% CI, 1.031 to 6.697; P = 0.043), and BNP level (OR, 7.336; 95% CI, 2.401 to 22.409 / log BNP level; P < 0.001) were accurate predictors of postoperative AF. Stepwise multivariate regression analysis indicated age (OR, 1.059; 95% CI, 1.002 to 1.120; P = 0.043) and BNP level (OR, 6.272; 95% CI, 1.980 to 19.861/log BNP level; P = 0.002) as the only independent predictors of postoperative AF.ConclusionPreoperative BNP level is an independent predictor of postoperative AF following OPCAB. Our findings permit us to stratify the risk of AF and to plan prophylactic strategies in high-risk patients.

Effects of sivelestat on bronchial inflammatory responses after esophagectomy.

Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

Changes in the circadian rhythm of mRNA expression for µ-opioid receptors in the periaqueductal gray under a neuropathic pain-like state

Variation in the production of opioid receptors over a 24‐h period is considered to contribute to circadian alterations in neuropathic pain. In this study, we investigated the possible changes in the circadian rhythm of mRNA expression for µ‐opioid receptor (MOR), κ‐opioid receptor (KOR), and adrenaline α2a receptor (α2a) in the periaqueductal gray, frontal cortex, thalamus, and spinal cord following sciatic nerve ligation in mice. In sham‐operated mice, the latencies of hind paw‐withdrawal in response to thermal stimuli at 14:00 and 20:00 were significantly greater than that at 8:00 and the latency at 2:00 was significantly less than those at 14:00 and 20:00, indicating a “rest” period‐dominant circadian rhythm for thermal pain‐thresholds. In sciatic nerve‐ligated mice, the latencies of hind paw‐withdrawal in response to thermal stimuli at 14:00 and 20:00 were significantly less than that at 8:00, and the latency at 2:00 was significantly greater than those at 14:00 and 20:00. A correlative tendency between the time‐variation of pain latency and the time‐variation of MOR mRNA expression was observed in the periaqueductal gray of sham‐operated and sciatic nerve‐ligated mice. In contrast, neither mouse showed a strong circadian rhythm for the expressions of KOR and α2a mRNAs in any region. The present data suggest that changes in MOR mRNA expression in the periaqueductal gray may be synchronized with the circadian rhythm for the pain threshold for noxious thermal stimuli. In contrast, neuropathic pain in mice exhibited a negative circadian pattern for the expression of MOR, KOR, and α2a receptors in the frontal cortex, thalamus, and spinal cord. Synapse 67:216–223, 2013.