Shinn-Long Lin

Amitriptyline suppresses neuroinflammation-dependent interleukin-10-p38 mitogen-activated protein kinase-heme oxygenase-1 signaling pathway in chronic morphine-infused rats.

Background:This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats. Methods:Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 &mgr;g/h), morphine (15 &mgr;g/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 &mgr;g/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti–interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days. Results:Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti–IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti–IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti–IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine’s antinociception and antiinflammation in chronic morphine-infused rats. Conclusions:These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.

Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords

Co-infusion of ultra-low dose naloxone and morphine attenuates morphine tolerance through the prevention of mu opioid receptor-Gs protein coupling. We previously demonstrated that chronic intrathecal infusion of morphine leads to tolerance and spinal neuroinflammation. The aim of present study was to examine the possible mechanisms by which ultra-low dose naloxone modulates spinal neuroinflammation, particularly the role of anti-inflammatory cytokine interleukin 10 (IL-10). Morphine tolerance was induced in male Wistar rats by intrathecal infusion of morphine (15 microg/h) for 5 days, and co-infusion of naloxone (15 pg/h) was used to evaluate the impact on spinal cytokine expression. Recombinant rat IL-10 (rrIL-10) or anti-rat IL-10 antibody was injected to elucidate the effect of IL-10 on morphine tolerance. Our results showed that co-infusion of naloxone (15 pg/h) with morphine not only attenuated tolerance, shifting the AD(50) from 89.2 to 11.7 microg but also inhibited the increased expression of pro-inflammatory cytokine (TNF-alpha, IL-1beta, and IL-6) caused by chronic intrathecal morphine infusion. The increase of IL-10 protein and mRNA were 1.5- and 3-fold, respectively, compared to that in morphine-infused rat spinal cords. A combination of daily rrIL-10 (1 microg) injection with morphine infusion produced, in a less potent, preservative antinociception and inhibited pro-inflammatory cytokine production compared to ultra-low dose naloxone co-infusion, and the effect of ultra-low dose naloxone co-infusion was inhibited by daily intrathecal anti-rat IL-10 antibody injection. These results demonstrate that IL-10 contributes to the attenuation of pro-inflammatory cytokine expression caused by ultra-low dose naloxone/morphine co-infusion and thus the attenuation of morphine tolerance.

N-Methyl-d-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats

Chronic opioid therapy induces tolerance and hyperalgesia, which hinders the efficacy of opioid treatment. Previous studies have shown that inhibition of neuroinflammation and glutamatergic receptor activation prevents the development of morphine tolerance. The aim of the present study was to examine whether N-Methyl-D-aspartate receptors are involved in the regulation of chronic morphine-induced neuroinflammation in morphine-tolerant rats. Morphine tolerance was induced in male Wistar rats by intrathecal infusion of morphine (15 μg/h) for 5 days. Tail-flick latency was measured to estimate the antinociceptive effect of morphine. Morphine challenge (15 μg, intrathecally) on day 5 at 3h after discontinuation of morphine infusion produced a significant antinociceptive effect in saline-infused rats, but not in morphine-tolerant rats. Pretreatment with MK-801 (20 μg, intrathecally) 30 min before morphine challenge preserved its antinociceptive effect in morphine-tolerant rats. Morphine-tolerant rats expressed high levels of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α and the increase in interleukin-1β and interleukin-6, and tumor necrosis factor-α levels was prevented by MK-801 pre-treatment at both the protein and mRNA levels. The results show that a single dose of MK-801 reduces the increase in pro-inflammatory cytokines in the spinal cord, thus re-sensitizing neurons to the antinociceptive effect of morphine in morphine-tolerant rats. This study provides a piece of theoretical evidence that NMDA antagonist can be a therapeutic adjuvant in treating morphine tolerant patients for pain relief.

Minocycline and fluorocitrate suppress spinal nociceptive signaling in intrathecal IL‐1β–induced thermal hyperalgesic rats

We previously demonstrated that intrathecal IL‐1β caused thermal hyperalgesia in rats. This study was conducted to examine the effects and cellular mechanisms of glial inhibitors on IL‐1β–induced nociception in rats. The effects of minocycline (20 μg), fluorocitrate (1 nmol), and SB203580 (5 μg) on IL‐1β (100 ng) treatment in rats were measured by nociceptive behaviors, western blotting of p38 mitogen‐activated protein kinase (MAPK) and inducible nitric oxide synthase (iNOS) expression, cerebrospinal fluid nitric oxide (NO) levels, and immunohistochemical analyses. The results demonstrated that intrathecal IL‐1β activated microglia and astrocytes, but not neurons, in the dorsal horn of the lumbar spinal cord, as evidenced by morphological changes and increased immunoreactivity, phosphorylated p38 (P‐p38) MAPK, and iNOS expression; the activation of microglia and astrocytes peaked at 30 min and lasted for 6 h. The immunoreactivities of microglia and astrocytes were significantly increased at 30 min (6.6‐ and 2.7‐fold, respectively) and 6 h (3.3‐ and 4.0‐fold, respectively) following IL‐1β injection, as compared with saline controls at 30 min (all P < 0.01). IL‐1β induced P‐p38 MAPK and iNOS expression predominantly in microglia and less in astrocytes. Minocycline, fluorocitrate, or SB203580 pretreatment suppressed this IL‐1β–upregulated P‐p38 MAPK mainly in microglia and iNOS mainly in astrocytes; minocycline exhibited the most potent effect. Minocycline and fluorocitrate pretreatment abrogated IL‐1β–induced NO release and thermal hyperalgesia in rats. In conclusion, minocycline, fluorocitrate, and SB203580 effectively suppressed the IL‐1β–induced central sensitization and hyperalgesia in rats.

Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: role of the PSD-95/NR1/nNOS/PKCγ signaling pathway.

The tricyclic antidepressant amitriptyline binds with high affinity to N-methyl-d-aspartate receptors (NMDARs) and inhibits NMDAR-mediated events. Activation of the postsynaptic density protein-95 (PSD-95)/NMDAR-mediated downstream signaling cascade, including neuronal nitric oxide synthase (nNOS) and protein kinase gamma (PKCγ), has been shown to be involved in morphine tolerance. The present study examined the potential effect of amitriptyline on chronic morphine infusion-induced spinal PSD-95/NMDAR/nNOS/PKCγ signaling in morphine tolerance. Male Wistar rats were implanted with an intrathecal catheter and received an intrathecal infusion of saline or amitriptyline (15 μg/h), morphine+saline (tolerance induction, 15 μg/h), or morphine+amitriptyline for 5 days. Co-administration of amitriptyline with morphine not only preserved the antinociceptive effect of morphine, but also attenuated astrocyte activation in the rat spinal cord dorsal horn. On day 5 after drug infusion, increased expression and phosphorylation of spinal membrane NMDAR NR1 subunit and expression of PSD-95 were observed following chronic morphine infusion and these effects were attenuated by amitriptyline co-infusion. Upregulation of NMDAR-induced intracellular nNOS expression was also inhibited by amitriptyline co-infusion in chronic morphine-infused rats. Furthermore, amitriptyline co-infusion significantly inhibited morphine-induced PKCγ expression in both the cytosol and membrane of spinal neurons. These findings suggest that the attenuation of morphine tolerance caused by amitriptyline is due to downregulation of NMDAR NR1 subunit expression in the synaptosomal membrane accompanied by decreased expression of the scaffolding protein PSD-95. The effects of amitriptyline in attenuating astrocyte activation and reversing tolerance to morphine may be due, at least in part, to inhibition of the PSD-95/NMDAR NR1/nNOS/PKCγ signaling cascade.

Neurotoxicity associated with standard doses of piperacillin in an elderly patient with renal failure.

Piperacillin–tazobactam, a b-lactam–b-lactamase inhibitor combination, is a penicillin derivative with a broad spectrum of antibacterial activity against most Gram-positive and Gram-negative bacteria. Although tazobactam is non-toxic, piperacillin, like other b-lactam antibiotics, is neurotoxic to some extent if excessively accumulated. Neurotoxicity caused by excessive doses of b-lactam antibiotics is well-known [1], but its association with the renal failure package insert dose of piperacillin (4 g/day) has not been reported to date. Herein, we describe the development of acute unexplained encephalopathy in an 87-year-old man with advanced renal failure who had been treated for 3 days with piperacillin/tazobactam 2.25 g every 12 h. Withdrawal of piperacillin/tazobactam and initiation of high-flux hemodialysis rapidly reversed his encephalopathy. This is the first report of piperacillin-induced neurotoxicity caused by the minimum recommended dose in an elderly man with advanced renal failure.

Interference of patent blue dye with pulse oximetry readings, methemoglobin measurements, and blue urine in sentinel lymph node mapping: A case report and review of the literature

Patent blue (PB) dye has been successfully used worldwide in breast and cervix surgeries with few complications. Interference of oxyhemoglobin saturation reading by pulse oximetry (SpO(2)) and methemoglobinemia, from injection of PB dye, have rarely been reported in breast and cervix surgeries. We report here the first case of interference of SpO(2) reading, advent of methemoglobinemia, and blue urine from the use of PB dye, which occurred concurrently in a female undergoing bilateral modified radical mastectomy. The unexpected events might be a consequence of excessive administration of PB dye. We also reviewed the published discourses in literature on the adverse effects of PB dye.

The effect of anesthetic techniques on hemostatic function in arthroscopic surgery: evaluation by thromboelastography.

BACKGROUND Anesthetic techniques are known to affect blood hemostasis, which may be responsible for the pathogenesis of postoperative venous thromboembolism. The purpose of this study was to evaluate the effect of general and spinal anesthesias on blood hemostasis using thromboelastography. METHODS Forty patients undergoing arthroscopic knee surgery were enrolled for study and randomly allocated to one of two groups, to receive either general (GA; n = 20) or spinal anesthesia (SA; n = 20). In addition to thromboelastography, prothrombin and activated partial-thromboplastin time, and haematocrit and platelet count were also examined concurrently. Blood was sampled and examined before anesthesia to provide the baseline data (Time 1). Three more evaluations were performed at different time, i.e., twenty minutes after induction of anesthesia and just prior to skin incision (Time 2), thirty minutes after skin incision (Time 3), and three hours after surgery (Time 4). RESULTS There were no intra- or inter-group differences noted as comparing the measured parameters obtained prior to, during, or three hours after surgery. CONCLUSIONS From the present study, we do not find any individual anesthetic technique which would have effect on the hemostasis of patients who received diagnostic arthroscopic surgery.

Priming dose of intravenous rocuronium suppresses fentanyl-induced coughing

OBJECTIVES An intravenous bolus of fentanyl often induces a cough reflex. This study investigates whether priming with rocuronium can effectively attenuate fentanyl-induced coughing. METHODS The study involved 260 participants, aged between 18 and 80 years of age, who were undergoing various elective surgeries. They were randomly assigned to two groups. Patients in the study group (the rocuronium group) were treated with intravenous (IV) 0.06 mg/kg rocuronium, whereas those in the control group were treated with the same volume of normal saline. Fentanyl (1.5 μg/kg IV, given over 2 seconds) was administered 30 seconds after the injection of rocuronium or normal saline. We recorded the number of coughs for 1 minute after the fentanyl injection. RESULTS Patients in the rocuronium group showed a significantly lower incidence of coughing (8.5% vs. 23.1%, in the control group; p < 0.05) and a milder severity of cough in comparison with the patients in the control group. CONCLUSION Pretreatment with IV rocuronium (0.06 mg/kg) suppressed the cough reflex induced by fentanyl. Therefore, priming with rocuronium may be a clinically useful method for preventing fentanyl-induced cough.

Bilateral nephrocalcinosis in short bowel syndrome

A 25-year-old man presented with lethargy, poor appetite, generalized muscle weakness and tetanic spasms. One year earlier, he underwent an extensive small intestinal resection for midgut volvulus and developed short bowel syndrome. In the past 2 months, he noticed passing urinary gravel stones. He was malnourished, with a body mass index of 14.9 kg/m. He had extracellular volume depletion, pale conjunctivae and symmetrically diminished muscle tone of lower limbs. Plasma biochemistry showed the following: sodium 135 mmol/L, potassium 1.4 mmol/L, chloride 113 mmol/L, magnesium 0.6 mmol/L, ionized calcium 0.8 mmol/L, phosphate 0.7 mmol/L, urea 22.0 mmol/L, creatinine 237.5 lmol/L, albumin 30 g/L, bicarbonate 13 mmol/L and pH 7.3.Urinalysis showednumerouscalciumoxalatecrystals. An abdominal plain film showed several calcifications over both kidney areas (Fig. 1), and an X-ray computed tomography scan of the abdomen, obtained without i.v. contrast, disclosed bilateral nephrocalcinosis in a medullary distribution (Fig. 2). The 24-h urinary calcium excretion was 5.5 mmol/day, magnesium 0.8 mmol/day and oxalate 1320 lmol/day (normal 100–450 lmol/day). In addition to adequate i.v. administration of fluids and electrolytes, he was placed on a low-oxalate, low-fat diet and treated with calcium/potassium citrate, active vitamin D3 and antimotility agents. Dietary oxalate normally complexes with enteric calcium to form an insoluble salt and only less than 10% of oxalate is absorbed. Extensive small intestinal resection causes malabsorption of fats and bile salts that are able to bind enteric calcium, increase free oxalate and enhance colonic permeability to oxalate, leading to enteric hyperoxaluria. Other coexisting metabolic abnormalities in the short bowel syndrome including volume depletion, chronic metabolic acidosis, hypocitraturia and