Assessment of opioid knowledge and attitudes among senior medical students in Taiwan's pain education curriculum: A cross-sectional questionnaire survey.

INTRODUCTION: While the opioid crisis has been a significant concern in North America, Taiwan has not encountered a similar crisis. This study investigated medical students' perceptions of opioid therapy for chronic pain management in Taiwan. METHODS: A cross-sectional questionnaire survey was conducted among third- and fourth-year medical students who had completed an 18-hour pain medicine curriculum, in comparison with those who did not take the course in Mar 2022 and May 2023. The survey assessed their knowledge, attitude, and perceptions of the opioid crisis in the United States and Taiwan. RESULTS: In total, 135 (88.2%) of 153 senior medical students who had completed the curriculum responded to the survey. They exhibited a better understanding of opioids (P < 0.001) and held a more negative attitude toward opioid use (P = 0.011) compared with 105 students who did not take the course. Additionally, out of 240 respondents, 177 (73.8%) acknowledged the ongoing opioid crisis in the United States, while only 70 (29.2%) disagreed with the notion of an ongoing opioid crisis in Taiwan. Furthermore, 90% of all students expressed agreement with the need for further education on chronic pain management after graduation. CONCLUSION: Among senior medical students in Taiwan, those who completed an elective pain medicine curriculum demonstrated enhanced knowledge of opioids, a more cautious attitude toward opioid use, and a willingness to receive further education on chronic pain management. Over 70% of students remained uncertain or incorrectly believed that there was an opioid crisis in Taiwan.

Neuropsychological impairment in primary malignant brain tumor patients with awake craniotomy: a hospital-based registration study.

PURPOSE: Neuroplasticity is an ability to maintain neural circuit function when facing damages. It is one of the reasons that making brain tumors notorious. Therefore, we evaluated the characteristics of patients with primary brain tumors, compared neuropsychological deficits between patients who had awake craniotomy with left- or right-sided tumors, and analyzed the association between white matter tracts and neuropsychological deficits in patients with right-sided tumors. METHODS: Using the registration dataset of Chang Gung Memory Hospital between 2014 and 2020, this study included a total of 698 adult patients who received craniotomy for primary brain tumors (538 of conventional craniotomy; 160 of awake craniotomy). Neuropsychological assessments were arranged in patients as preoperative evaluation for awake craniotomies. RESULTS: A lower proportion of right-sided tumors was noted in patient who had awake craniotomy than those who had conventional craniotomy (33.8% and 51.5%, p < 0.001). In awake craniotomy, 88.7% of patients with left-sided tumors and 77.8% of patients with right-sided tumors had neuropsychological impairment. Patients with left-sided tumors had worse preoperative performance compared to those with right-sided tumors in global function (36.2% and 8.0%, p < 0.001), language domain (57.6% and 22.2%, p < 0.001), and attention (36.0% and 18.5%, p = 0.02). Furthermore, in those with right-sided low-grade gliomas, patients involving pathway of superior longitudinal fasciculus (SLF) I had a higher risk of deficits than those without involvement in verbal memory (p = 0.001, Odd ratio = 11.2, 95% CI = 1.8 ~ 71.4) and visual memory (p = 0.048, Odd ratio = 10.5, 95% CI = 1.0 ~ 111). CONCLUSION: In awake craniotomy, patients with left-sided brain tumors had worse cognitive function than those with right-sided tumors in terms of global function, language, and attention. 77% of patients with right-sided tumors had neuropsychological impairment. Therefore, a comprehensive neuropsychological evaluation and awake craniotomy are necessary for patients with brain tumors.

Case report: the management for a gestational hypertensive woman with influenza A virus pneumonia and peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is defined as an idiopathic cardiomyopathy occurring in the last month of pregnancy or the first 6 months postpartum without an identifiable cause. PPCM is suspected to be triggered by the generation of a cardiotoxic fragment of prolactin and the secretion of a potent antiangiogenic protein from the placental, but no single factor has been identified or defined as the underlying cause of the disease. Influenza virus can cause PPCM through immune-mediated response induced by proinflammatory cytokines from host immunity and endothelial cell dysfunction. We report a case in a parturient woman undergoing a cesarean delivery, who had influenza A pneumonia and PPCM. CASE PRESENTATION: A parturient woman at 40 weeks and 1 day of gestation who had experienced gestational hypertension accompanied by pulmonary edema developed hypotension after undergoing an emergency cesarean delivery. An elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was noted, and echocardiography revealed a left ventricular ejection fraction of 20%. She underwent a nasopharyngeal swab test, in which influenza A antigen was positive. She was diagnosed as having PPCM and received anti-viral treatment. After antiviral treatment, hemodynamic dysfunction stabilized. We present and discuss the details of this event. CONCLUSION: PPCM is a heart disease that is often overlooked by medical personnel. Rapid swab tests, serum creatine kinase measurement, and echocardiography are imperative diagnostic approaches for the timely recognition of virus-associated cardiomyopathy in peripartum women with influenza-like disease and worsening dyspnea, especially during the epidemic season. Prompt antiviral treatment should be considered, particularly after PPCM is diagnosed.

The Clinical Application of Pulsed Radiofrequency Induces Inflammatory Pain via MAPKs Activation: A Novel Hint for Pulsed Radiofrequency Treatment.

Pulsed radiofrequency (PRF) works by delivering short bursts of radiofrequency to a target nerve, thereby affecting nerve signal transduction to reduce pain. Although preliminary clinical investigations have shown that PRF treatment can be used safely as an alternative interventional treatment in patients with refractory pain conditions, unexpected damage to a normal nerve/ganglion is still one of the possible complications of using the PRF strategy. Noxious pain may also be triggered if PRF treatment accidentally damages an intact nerve. However, few studies in the literature have described the intracellular modifications that occur in neuronal cells after PRF stimulation. Therefore, in this study, we evaluated the effects of PRF on unimpaired nerve function and investigated the potential mechanisms of PRF-induced pain. Wistar rats were stimulated with 30-60 V of PRF for 6 min, and mechanical allodynia, cold hypersensitivity, cytokine and matrix metalloproteinase (MMP) production, and mitogen-activated protein kinase activity (p38 MAPK, ERK1/2, JNK/SAPK) were analyzed. The results indicated that PRF stimulation induced a significant algesic effect and nociceptive response. In addition, the protein array and Western blotting analyses showed that the clinical application of 60 V of PRF can induce the activation of MAPKs and the production of inflammatory cytokines and MMPs in the lumbar dorsal horn, which is necessary for nerve inflammation, and it can be suppressed by MAPK antagonist treatment. These results indicate that PRF stimulation may induce inflammation of the intact nerve, which in turn causes inflammatory pain. This conclusion can also serve as a reminder for PRF treatment of refractory pain.

Stage-dependent angiopoietin-Tie2 and nitric oxide signaling of erythrocytes in response to surgical trauma in head and neck cancer.

BACKGROUND: Angiopoietin-Tie2 and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis. This study aimed to investigate the angiopoietin-Tie2 and nitric oxide signaling of the erythrocyte membrane in response to surgical trauma in head and neck cancer. METHODS: We prospectively enrolled the patients with histology-proven head and neck squamous cell carcinoma undergoing surgical resection of primary tumors at the medical center between August and November 2019. We measured the preoperative and postoperative levels of angiopoietin-1, angiopoietin-2 in plasma using enzyme-linked immunosorbent assays, nitric oxide in plasma using nitrate/nitrite colorimetric assays, and Tie2 phosphorylation in erythrocyte membrane using Western blotting. RESULTS: The plasma angiopoietin-1 was downregulated from the median 971.3 pg/mL (interquartile range [IQR] 532.1-1569.3) to 417.9 (IQR 270.5-597.3) after tumor resection (p = 0.0020). Conversely, the plasma angiopoietin-2 was enhanced from 1173.6 pg/mL (IQR 977.7-1450.2) to 2353.7 (IQR 1352.4-2954.3) after surgery (p = 0.0021), with a concomitant increase in plasma nitric oxide level from 7.73 µM (IQR 5.39-10.06) to 10.50 (IQR 7.65-14.18) after surgical resection (p = 0.0093). Subgroup analyses further showed the angiopoietin-Tie2 and nitric oxide signaling was significant only in stage III and IV cancer. CONCLUSIONS: The dynamic change of angiopoietin-Tie2 signaling in the erythrocyte membrane along with the enhanced nitric oxide in plasma after tumor resection suggests erythrocytes play a significant role in modulating surgery-induced angiogenesis, which may provide a novel marker for cancer surveillance and control.

Glucose reduces the osmopressor response in connection with the tyrosine phosphorylation of focal adhesion kinase in red blood cells.

Glucose ingestion attenuates the water ingestion-induced increase in the total peripheral vascular resistance and orthostatic tolerance. We investigated the gastrointestinal physiology of glucose by examining the effect of glucose ingestion on the functional expression of focal adhesion kinase (FAK) in red blood cell (RBC) membrane. This study was performed in 24 young, healthy subjects. Blood samples were collected at 5 min before and 25 min and 50 min after an ingestion of 10% glucose water 500 mL, water 500 mL, or normal saline 500 mL. We determined glucose and osmolality in plasma, and phosphorylation of aquaporin 1 (AQP1), glucose transporter 1 (Glut1), and FAK in RBC membrane. Our results showed that glucose ingestion reduced the rise of peripheral vascular resistance after water ingestion and upregulated the serine phosphorylation of Glut1. It also lowered both the serine phosphorylation of FAK and tyrosine phosphorylation of AQP1, compared with the ingestion of either water or saline. In an ex vivo experiment, glucose activated the Glut1 receptor and subsequently reduced the expression of FAK compared with 0.8% saline alone. We concluded that glucose activates Glut1 and subsequently lowers the functional expression of FAK, a cytoskeleton protein of RBCs. The functional change in the RBC membrane proteins in connection with the attenuation of osmopressor response may elucidate the pathophysiology of glucose in postprandial hypotension.

Ultrasound-Guided Pulsed Radiofrequency Stimulation of Posterior Tibial Nerve: A Potential Novel Intervention for Recalcitrant Plantar Fasciitis.

OBJECTIVE: To evaluate the therapeutic benefit of ultrasound-guided pulsed radiofrequency (PRF) stimulation at the posterior tibial nerve (PTN) in patients with recalcitrant plantar fasciitis (PF). DESIGN: A prospective, randomized, double-blinded, placebo-controlled trial (12-wk follow-up). SETTING: Outpatient local medical center settings. PARTICIPANTS: Patients (N=36) with recalcitrant PF underwent randomization, and all were included in the final data analysis. INTERVENTIONS: Patients in the PRF group were treated with 1 dose of ultrasound-guided PRF stimulation at the PTN, and those in the control group received 1 dose of 2% lidocaine, 0.5mL, injected at the PTN under ultrasound guidance. MAIN OUTCOME MEASURES: The visual analog scale (first-step and overall pain), American Orthopedic Foot-Ankle Society (AOFAS) ankle-hindfoot scale, and ultrasonographic thickness of the plantar fascia were evaluated at 1, 4, 8, and 12 weeks after treatment. RESULTS: Thirty-six patients (20 feet per group) completed the study. The PRF group had a significantly larger improvement in first-step pain, overall pain, and AOFAS score (all P<.001), as well as plantar fascia thickness (P<.05), compared with those of the control group at all observed time points. CONCLUSIONS: This study shows that ultrasound-guided PRF stimulation at the PTN is effective for treating recalcitrant PF. This simple, reproducible method could be a novel strategy for managing recalcitrant PF.

Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency.

BACKGROUND: The application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI). METHODS: Neuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3-0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups. RESULTS: The three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery. CONCLUSIONS: Immediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.

Long-Term Anti-Allodynic Effect of Immediate Pulsed Radiofrequency Modulation through Down-Regulation of Insulin-Like Growth Factor 2 in a Neuropathic Pain Model.

Pulsed radiofrequency (PRF) is effective in the treatment of neuropathic pain in clinical practice. Its application to sites proximal to nerve injury can inhibit the activity of extra-cellular signal-regulated kinase (ERK) for up to 28 days. The spared nerve injury (SNI)+ immPRF group (immediate exposure to PRF for 6 min after SNI) exhibited a greater anti-allodynic effect compared with the control group (SNI alone) or the SNI + postPRF group (application of PRF for 6 min on the 14th day after SNI). Insulin-like growth factor 2 (IGF2) was selected using microarray assays and according to web-based gene ontology annotations in the SNI + immPRF group. An increase in IGF2 and activation of ERK1/2 were attenuated by the immPRF treatment compared with an SNI control group. Using immunofluorescent staining, we detected co-localized phosphorylated ERK1/2 and IGF2 in the dorsal horn regions of rats from the SNI group, where the IGF2 protein predominantly arose in CD11b- or NeuN-positive cells, whereas IGF2 immunoreactivity was not detected in the SNI + immPRF group. Taken together, these results suggest that PRF treatment immediately after nerve injury significantly inhibited the development of neuropathic pain with a lasting effect, most likely through IGF2 down-regulation and the inhibition of ERK1/2 activity primarily in microglial cells.

Intrathecal glutamate release during hindlimb tourniquet inflation and femoral artery occlusion in rats.

BACKGROUND/PURPOSE: A tourniquet is commonly used in limb surgery. Tourniquet inflation after a period of time may produce painful sensation. While the mechanisms of tourniquet-induced pain are still unknown, two components, pressure and ischemia, have been proposed. In this study, in vivo microdialysis was used to detect changes in intrathecal glutamate, an excitatory amino acid highly relevant to pain transmission, following hindlimb tourniquet application and femoral artery occlusion in the rat. METHODS: Male Wistar rats were used. For the tourniquet study, 6 rats of the study group received 30 minutes right hindlimb tourniquet inflation and another 6 rats as the control group received only tourniquet application without inflation. In the femoral artery occlusion study, 6 rats of the study group received 30 minutes right femoral artery occlusion and another 6 rats as the control group received only sham operation without femoral artery occlusion. Cerebrospinal fluid dialysates were collected prior to, during, and after tourniquet application or femoral artery occlusion. Glutamate was measured by HPLC. RESULTS: A significant increase in intrathecal glutamate release was found during the tourniquet inflation period, and it returned to baseline after tourniquet deflation. No change of glutamate release was noted during femoral artery occlusion or after femoral artery reperfusion. CONCLUSION: The intrathecal glutamate release was increased by the hindlimb tourniquet inflation, but not influenced by femoral artery occlusion in the rat.

Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.

BACKGROUND/PURPOSE: As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. METHODS: Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 µg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 µl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 µl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 µg in 5 µl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective). RESULTS: Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. CONCLUSION: This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management.

The effects of collateral meridian therapy for knee osteoarthritis pain management: a pilot study.

OBJECTIVE: The purpose of this preliminary study was to examine whether collateral meridian (CM) therapy was feasible in treating knee osteoarthritis (OA) pain. METHODS: Twenty-eight patients with knee OA and knee pain were randomly allocated to 2 groups. The CM group patients received CM therapy, whereas the control patients received placebo treatment for knee pain relief. Patients in the CM group received 2 CM treatments weekly for 3 weeks. The outcome measures were pain intensity on a visual analog scale, and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: In the CM group, the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group; a significant reduction in pain intensity (P = .02, P = .01, respectively) and improvement in knee function (P = .04, P = .03, respectively) were shown in the CM group at the second and third week. CONCLUSION: Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery. Therefore, additional randomized control trials are warranted.

Intrathecal pramipexole and selegiline for sensory and motor block in rats.

BACKGROUND: The purpose of the study was to investigate spinal sensory and motor block by antiparkinsonian drugs (pramipexole and selegiline), and the combination of pramipexole and the local anesthetic lidocaine. METHODS: Using a technique of spinal blockade in rats, the effects of pramipexole, selegiline, and coadministration of pramipexole and lidocaine on spinal blockades of motor and sensory function were investigated. RESULTS: Under a concentration of 100 mM, pramipexole displayed more potent and had a longer duration of nociceptive, proprioceptive, and motor block than selegiline, whereas pramipexole and selegiline were less potent in comparison to lidocaine. Pramipexole produced spinal nociceptive, proprioceptive, and motor blocks in a dose-related manner. On the ED50 (50% effective dose) basis, the rank-order potency on nociceptive, proprioceptive, and motor block was pramipexole < lidocaine. The spinal block duration of pramipexole was greater than lidocaine at every equipotent dose tested (ED25, ED50, and ED75). Coadministration of lidocaine (ED50 or ED95) with pramipexole (4.5 µmol/kg) improved the effect (efficacy) and duration of the spinal block. CONCLUSIONS: Pramipexole and selegiline were less potent than lidocaine to block sensory and motor responses. The duration of the spinal anesthetic effect of pramipexole was longer than lidocaine. At a non-effective dose, pramipexole increased the duration of efficacy of lidocaine.

Multimodal Analgesia with Extended-Release Dinalbuphine Sebacate for Perioperative Pain Management in Upper Extremity Trauma Surgery: A Retrospective Comparative Study.

INTRODUCTION: Patients undergoing upper extremity fracture surgery (UEFS) commonly suffer from unbearable acute pain. Opioids remain the mainstay of moderate to severe pain alleviation, although there is a growing concern regarding the increasing trend in misuse and abuse. This study aimed to observe the safety and efficacy of dinalbuphine sebacate (DS), a novel extended-release analgesic, along with multimodal analgesia (MMA) for post-UEFS pain control. METHODS: We retrospectively reviewed the records of patients undergoing UEFS between August 2020 and January 2021. Eligible patients were included and divided into two groups, depending on the analgesic regimen. In the DS group, 150 mg DS was administered intramuscularly at least 12 h pre-operatively, while in the conventional analgesia (CA) group, 40 mg parecoxib was given within 3 h before surgery. Intraoperative fentanyl administration was guided by the Analgesia Nociception Index System in both groups. For breakthrough pain, fentanyl was used as rescue medicine in the postanaesthesia care unit while tramadol and parecoxib were administered in the ward. RESULTS: Forty-nine patients were allocated to the DS group and 60 patients were allocated to the CA group. In comparison with the CA group, the proportion of patients requiring opioids for breakthrough pain post-operatively was significantly lower in the DS group (fentanyl: 31% vs. 68%, p < 0.001; tramadol: 27% vs. 70%, p < 0.001). The DS group also consumed lower amounts of post-operative rescue opioids. Furthermore, both mean worst and least pain scores were significantly lower in the DS group from post-operative day (POD) 1 to POD 5. There was no significant difference in intraoperative consumption of fentanyl or incidence of adverse events. CONCLUSION: This result suggests that extended-release DS is a suitable analgesic incorporated in MMA and a promising solution to the misuse and abuse of opioids.

Prescription Opioid Use among Patients with Chronic Noncancer Pain before and after the COVID-19 Outbreak in Taiwan: A Multicenter Prospective Observational Study.

BACKGROUND: The COVID-19 outbreak disrupted medical access for patients receiving chronic opioid therapy. This study investigated their prescription opioid dosages before and after the 2020 outbreak in Taiwan. METHODS: A prospective questionnaire survey was conducted among registered outpatients receiving long-term opioids before July 2019 in Taiwan. The questionnaire included items from the Taiwanese Brief Pain Inventory and quality of life assessment. Follow-up surveys in outpatient departments through October 2020 were conducted to collect opioid prescription data. RESULTS: After a mean of 531 days, the questionnaire responses of 103 of the initial 117 respondents were reviewed. Daily opioid doses decreased for 31 respondents (30.1%), remained roughly equivalent (defined as ±2.5%) for 27 (26.2%), and increased for 45 (43.7%) after the first wave of the pandemic. The use of strong opioids and nonopioid medications did not significantly differ among the three groups, but less fentanyl patch use was noted in the decreased-dose group after the outbreak. More than 70% of the patients received daily high-dose opioids (≥90 morphine milligram equivalents); moreover, 60% reported constipation. No deaths due to opioid overdose occurred during the study period. CONCLUSIONS: The COVID-19 outbreak in 2020 did not interrupt access to long-term opioid prescriptions for most registered patients with chronic pain in Taiwan. Less fentanyl patch use was observed in participants whose opioid dose was tapering.

Assessment of the anti-nociceptive effects of fetal ventral mesencephalic tissue allografts in a rat model of hemi-Parkinson's disease using fMRI.

Extensive studies showed increased subjective pain sensitivity in Parkinson's disease (PD), which appeared to be partially reversed by dopaminergic (DA) treatment. Although cell replacement represents an attractive therapeutic strategy, its potential for PD-related hyperalgesia remains unclear. We investigated re-establishment of DA function via allografting exogenic DA cells on pain hypersensitivity in a rat model of PD. We evaluated the anti-nociceptive effects of fetal ventral mesencephalic (rVM) tissue allografts in PD rats after unilateral 6-OHDA-induced toxicity in the medial forebrain bundle. The drug -induced rotation test was used to validate the severity of the nigrostriatal lesion; von Frey and thermal pain tests were employed to evaluate nociceptive function. Nociception-induced cerebral blood volume (CBV) response was measured using a 4.7-T MR system. Finally, the immunohistochemical (IHC) studies were performed and the results were compared with the imaging findings from functional magnetic resonance imaging (fMRI). The grafts significantly improved drug-induced rotation behavior and increased mechanical and thermal nociceptive thresholds in PD rats. The elevation of CBV signals significantly recovered on the grafted striatum, whereas this effect was inhibited by the D2R antagonist eticlopride in each striatum. Quantitative IHC analysis revealed the transplantation markedly increased the numbers of tyrosine hydroxylase immunoreactive cells. Therefore, we concluded transplantation of rVM tissue results in anti-nociceptive effects and improves motor function. Moreover, in vivo CBV response confirmed the key role of D2R-mediated pain modulation. Therefore, we demonstrate fMRI as a reliable imaging index in evaluating the anti-nociceptive therapeutic effects of fetal rVM transplantation in the rat model of PD.

Temporal changes in glutamate, glutamate transporters, basilar arteries wall thickness, and neuronal variability in an experimental rat model of subarachnoid hemorrhage.

BACKGROUND: Glutamate and glutamate transporters (GTs) (including glutamate/aspartate transporter, glutamate transporter-1, and excitatory amino acid carrier 1) have important roles in the pathogenesis of ischemic neurological injury. The changes in glutamate, GTs, and neuronal injury after subarachnoid hemorrhage (SAH) have not been widely investigated. In this study, we examined the changes in extracellular glutamate concentration, GTs, wall thickness of basilar arteries (BAs), and neuronal degeneration in experimental SAH rats. METHODS: An intrathecal microdialysis probe was inserted into male Sprague Dawley rats. SAH was induced using a double-hemorrhage model. To measure glutamate concentrations, extracellular dialysates were collected for 30 minutes before, and daily for 7 days after SAH. Changes in neurological scores, body weight, and BA wall thickness were measured. The neuron degeneration in the hippocampus and the changes of GTs in the cerebral cortex and hippocampus were measured. RESULTS: Glutamate concentrations were significantly higher in SAH rats from day (D)1 to D7 after SAH compared with the sham rats, especially at D1. A significant body weight reduction and neurological defects were observed at D3 after SAH. The walls of BAs in SAH rats were significantly thicker compared with those of sham rats; the maximum change was observed at D7. Hippocampal neuronal degeneration was observed after SAH and the highest severity was at D7. The expression of GTs was downregulated after SAH and persisted for 7 days. CONCLUSIONS: SAH induced in the double-hemorrhage rat model may produce an excessive and prolonged increase of extracellular glutamate concentrations and downregulation of GTs, which are accompanied by BA wall thickness, and hippocampal neuronal degeneration.

Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions.

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-ß are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-ß can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.

Endogenous Expression of G-CSF in Rat Dorsal Root Ganglion Neurons after Nerve Injury.

Granulocyte colony-stimulating factor (G-CSF) has been reported to modulate pain function following nerve injury. However, the expression of endogenous G-CSF in the dorsal root ganglion (DRG) and the response to nerve injury remain unclear. In the present study, we demonstrated that G-CSF and G-CSFR are mainly expressed in both small- and medium-diameter DRG neurons in rats and are responsible for transmitting pain responses. G-CSF and G-CSFR were co-expressed in certain nociceptive DRG neurons. In addition, G-CSF was expressed in satellite glial cells around large-diameter DRG neurons. After sciatic nerve injury, the number of G-CSF-positive DRG neurons was increased in both the ipsilateral and contralateral lesion sites in rats. However, G-CSF expression in satellite glial cells was not affected by nerve injury. To clarify the role of G-CSF in pain, exogenous G-CSF was administered to a rat model of neuropathic pain induced by partial sciatic nerve transaction (PST). Our results indicate that treatment with G-CSF did not attenuate but exacerbated neuropathic pain. In summary, G-CSF may directly activate sensory neurons and contribute to nociceptive signaling.

Intrathecal IGF2 siRNA injection provides long-lasting anti-allodynic effect in a spared nerve injury rat model of neuropathic pain.

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.