Daiki Yamanaka

Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats.

AIMS The present study aimed to explore the preventive or therapeutic effect of peri-operative pregabalin treatment on the memory deficits and related hippocampal inflammation following surgery in aged rats. MAIN METHODS Aged rats underwent abdominal or sham surgery, and were then divided into 2 groups, either early or late pregabalin treatment. Fourteen days after surgery, the cognitive function was assessed using novel object recognition test, followed by measurement of hippocampal cytokines and voltage-dependent calcium channel α2δ subunit (CACNA2D1). The parabiotic experiments determined whether the humoral or neuronal pathway was involved in the neuroinflammation development following the abdominal surgery. The effects of pregabalin on LPS-induced cytokine release from hippocampal microglia were also evaluated. KEY FINDINGS Early pregabalin treatment, which was administered pre-operatively and continued for 3 or 7days after surgery, prevented memory deficits and decreased hippocampal pro-inflammatory cytokine levels. In contrast, no beneficial effects were observed when pregabalin was administered late in the post-operative period. The hippocampal levels of CACNA2D1 did not change under any experimental condition. The data from the cross-circulation (parabiosis) experiments indicated that abdominal surgery may induce neuroinflammation via a neural transmission pathway from the periphery to the brain. The ex vivo experiments further demonstrated that pregabalin had no effect on LPS-induced cytokines release from hippocampal microglia. SIGNIFICANCE Our findings highlight reveal that peri-operative pregabalin treatment during the early post-operative period can prevent neuroinflammation and memory deficits after surgery. It is likely this occurs through a peripheral and central neuro-immune interaction rather than through direct anti-inflammatory effects.

Effects and underlying mechanisms of endotoxemia on post-incisional pain in rats.

AIMS The aim of the present study was to investigate the effects and underlying mechanisms of endotoxin (lipopolysaccharide, LPS) on postoperative pain using a rat model of incisional pain. MAIN METHODS Animals were assigned to one of four groups using a 2×2 experimental design: a single intraperitoneal injection of 5mg/kg LPS versus vehicle, by plantar incision versus anesthesia alone. Spontaneous pain and mechanical paw withdrawal threshold (PWT) were evaluated using Rat Grimace Scale (RGS) and von Frey fibers, respectively. Analgesic effects of ketoprofen, morphine, and wound infiltration with ropivacaine, as well as the contribution of the Toll-like receptor (TLR) 4 pathway, were also evaluated. In vivo single fiber recordings were performed to assess the nociceptive afferent signals from the surgical site. KEY FINDINGS Systemic administration of LPS significantly increased the pain intensity at 2h after hind paw incision, but did not affect the PWT. The duration of post-incisional pain assessed by both scales did not significantly differ in the presence or absence of LPS. The analgesic efficiency of ketoprofen and morphine was reduced by LPS, while that of wound infiltration with ropivacaine was preserved. On the other hand, in vivo single fiber recording failed to demonstrate any significant effects of LPS on the activity of primary afferents due to mechanical stimuli. Pre-treatment with intrathecal LPS from Rhodobacter sphaeroides, a TLR-4 antagonist, almost completely inhibited LPS-induced exacerbated post-incisional pain, and decreased analgesic responsiveness. SIGNIFICANCE The present results suggested that LPS exacerbates post-incisional pain via the central TLR-4 pathway.

The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery

AIMS This study aimed to investigate the role of central insulin signaling, including glycogen synthase kinase 3β (GSK-3β), and its therapeutic potential for the prevention of postoperative neurocognitive deficits. MAIN METHODS In non-insulin experiment, aged rats were divided into a sham group and abdominal surgery group. In insulin experiment, sham and surgically treated rats were distributed into two groups: an intranasal denatured insulin-treated group and intranasal insulin-treated group. Insulin administration started the day of surgery and continued for 3days. Fourteen-days after surgery, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of pro-inflammatory cytokines, GSK-3β, and phosphorylated GSK-3β (pGSK-3β(ser9)). Under identical conditions, lipopolysaccharide (LPS)-induced cytokine release from isolated hippocampal microglia was also tested. KEY FINDINGS In non-insulin experiment, compared with non-surgical animals, the rats that underwent abdominal surgery showed memory deficits and increased hippocampal cytokine levels. The hippocampal ratio of pGSK-3β(ser9)/GSK-3β decreased after surgery, a ratio that was positively correlated with novel object recognition performance in the testing phase. Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery-induced hippocampal neuroinflammation and hyperactivation of GSK-3β, and prevent impairment in novel object recognition. Furthermore, ex vivo experiments indicated that intranasal insulin administration, as well as pretreatment with SB216763, a GSK-3β inhibitor, resulted in reduction of the surgery-related microglial hyper-reactivity to LPS. SIGNIFICANCE Our findings in aged rats suggest that surgical procedures could impair central insulin signaling including GSK-3β, which makes the individual more susceptible to hippocampal neuroinflammation and related cognitive disorders.

Involvement of acute neuroinflammation in postoperative delirium-like cognitive deficits in rats

PurposeThe purpose of this study was to investigate the age-, time-, and brain region-dependent postoperative neuroinflammatory trajectory, and its association with neurocognitive outcomes in rats.MethodsAdult and aged rats were randomly assigned to one of three groups: control, isoflurane anesthesia alone, and isoflurane anesthesia with abdominal surgery. On either postoperative day 2 (early phase) or 7 (late phase), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Freezing behavior was used as an index of fear memory. Following the cognitive testing, the levels of pro-inflammatory cytokines in several brain regions were measured using enzyme-linked immunosorbent assay (n = 8 in each group).ResultsIn the early postoperative period, surgery under isoflurane anesthesia induced acute neuroinflammation along with related trace and context memory dysfunction. Such acute neuroinflammatory responses were comparably observed in both adult and aged animals, whereas the aged rats were more likely to exhibit behavioral changes. On the other hand, in the late postoperative period, neither neuroinflammation in all tested brain regions nor concomitant memory decline were found in adult animals. Significant neuroinflammation was detected only in the hippocampus of aged rats, which was associated with context, but not trace memory dysfunction.ConclusionOur findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.

Peripheral nerve block with a high concentration of tetracaine dissolved in bupivacaine for intractable post-herpetic itch: a case report

BackgroundPost-herpetic itch (PHI) is a neuropathic itch syndrome following herpes zoster. It has been reported that PHI is occasionally sufficiently severe to compromise patients’ quality of life and frequently refractory to treatment. Here, we present a case of severe chronic PHI successfully treated with supraorbital nerve block using a high concentration of tetracaine dissolved in bupivacaine.Case presentationAn 82-year-old man presented with severe chronic itching in the ophthalmic branch of the left trigeminal nerve dermatome, following acute herpes zoster. The patient’s itching was unresponsive to usual medical treatments for PHI including antiepileptic drugs, topical capsaicin cream, and supraorbital nerve radiofrequency thermo-coagulation. Topical lidocaine cream could relieve the itching, but could not provide long-term relief of itching and thus failed to achieve a satisfactory result. After these conventional treatments, left supraorbital nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was conducted. Afterwards, the patient experienced long-lasting resolution of the itching with improvement of sleep disturbance. A transient, mild edema of the eyelids occurred, but there were no other complications.ConclusionsPeripheral nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was beneficial in relieving PHI in the ophthalmic division of the trigeminal nerve.

The role of hippocampal brain-derived neurotrophic factor in age-related differences in neuropathic pain behavior in rats

Aims: This study was aimed to explore the contribution of central brain‐derived neurotrophic factor (BDNF) in the neuropathic pain pathogenesis using an aged rodent model. Main methods: Adult and aged rats were randomly assigned to either a sciatic nerve ligation (SNL) group or a control skin sham surgery group. Sensory behavioral testing were performed on the day before surgery and on the 3rd, 7th, 14th, and 21st days after surgery, followed by measurement of BDNF protein levels in different brain regions. In another experiment, the hippocampal BDNF gene expression after SNL surgery was assessed at different time‐points. Furthermore, the analgesic effects of intranasal BDNF administration were tested in SNL animals. Key findings: Our behavioral results demonstrated that the hyperalgesia‐like behavior after painful nerve injury has a higher incidence in aged rats compared with in adult animals. In particular, the hippocampal BDNF levels were inversely correlated with the probability of hyperalgesia‐type behavior, in both brain‐region specific and age‐dependent manner. Time‐course analysis showed that the hippocampal levels of BDNF mRNA in aged and adult rats started to decrease 7 and 14 days after surgery, respectively. However, the decrease was more pronounced in aged animals. Moreover, the repeated intranasal BDNF treatment could restore the central BDNF signaling, counteracting the age‐related exacerbation of hyperalgesic behavior. Significance: Our findings imply that hippocampal BDNF may be related with the pathogenesis of elderly neuropathic pain. Pharmacological data further suggest that brain BDNF may be modifiable in aged neuropathic animals, and therefore, represent a promising target for intervention.

Does preoperative patient’s estimated acceptable pain affect the satisfaction with postoperative pain management?

BackgroundPatient satisfaction with postoperative pain management is an important quality indicator in patient health care, but its determinants are poorly understood. Here, we examined the contribution of the discrepancy between an individual’s estimated acceptable and actual postoperative pain scores to the overall satisfaction with pain treatment.FindingsA total of 93 surgical patients were included in this study. Preoperatively, the subjects were asked to rate their estimated acceptable postoperative pain using a numerical rating scale (NRS). One day after the surgery, the patients were again asked to give NRS ratings of the overall actual pain intensity they had experienced, as well as their satisfaction with the provided pain treatment. The median estimated acceptable and actual NRS values for postoperative pain were 4.0 (3.0–5.0) and 4.0 (2.0–5.0), respectively. Although there was no correlation between the degree of patient satisfaction and preoperative estimated acceptable pain intensity, there was a significant negative correlation between the degree of patient satisfaction and postoperative actual pain intensity. When the preoperative estimated acceptable NRS value was compared with the postoperative actual value for each individual, postoperative NRS was greater in 34 cases (36.6%), less in 43 cases (46.2%), and equal in 16 cases (17.2%). The degree of patient satisfaction was not significantly correlated with the magnitude of difference between preoperative estimated acceptable NRS and postoperative actual NRS.ConclusionsOur findings suggest that inquiring about the estimated acceptable pain before surgery may not help anesthesiologists to understand the patient’s goal of pain management for improving patient satisfaction.