Late-onset alopecia areata: a retrospective study of 73 patients from Taiwan.

BACKGROUND: Alopecia areata (AA) is regarded to be mediated by autoimmune process, and manifests as patchy non-scarring hair loss with occult onset. Little is known about AA occurring later in life. OBJECTIVE: To define the characteristics of late-onset AA. METHODS: Patients with first onset of AA at age 50 years and above were retrospectively recruited from two separate institutes in southern and northern Taiwan. The onset age, patterns, severity, past history, serological findings and therapeutic responses were reviewed. RESULTS: Seventy-three AA patients were enrolled, including 49 females (67%) and 24 males (33%). The onset age ranged from 50-78 years with the median age of 57 years. Multifocal lesions (41%) constituted the most common pattern and 55% of the recruited patients had a hair loss of less than 10%. Seventeen patients (23%) had co-existent dermatological or systemic diseases while six patients (8%) had a history of malignancy. Among 27 patients (37%) with available laboratory data, positive anti-nuclear antibody, anti-microsomal antibody and anti-thyroglobulin antibody was demonstrated in 26%, 40% and 30% of them, respectively. Association with personal or family history of atopy was absent. In 15 patients of follow-up longer than 6 months, a complete hair regrowth was found in three patients with mild disease severity. CONCLUSION: Late-onset AA is characterized by marked female predominance and milder disease activity with increasing age. The link to cancer in the old age remains to be determined. The influence of aging on the pathogenesis and prognosis of AA deserves further studies.

Guidelines for management of androgenetic alopecia based on BASP classification--the Asian Consensus Committee guideline.

BACKGROUND: Androgenetic alopecia (AGA), or pattern hair loss, is a common disorder in both Asian men and women. There are several guidelines for the treatment of AGA which are suitable for Caucasian patients; however, each of these has some limitations. Furthermore, in comparison with Caucasian patients, Asian patients with AGA have different types of hair loss and family histories which may alter the treatment response. There is currently no published AGA guideline for Asian patients. OBJECTIVES: The Asian Consensus Committee for Androgenetic Alopecia aimed to develop an algorithmic guideline, based on the basic and specific (BASP) classification, for the treatment of AGA especially in Asian patients. METHODS: The committee collaborated extensively on reviewing available literature on AGA treatment in order to formulate an algorithmic guideline on AGA management. RESULTS: Previously published guidelines based on pre-existing classifications of AGA cannot easily classify the patterns of AGA that are more frequently seen in Asians. The BASP classification not only facilitates the development of a unified and simplified algorithm, but also overcomes the disadvantages of previously reported classification systems. CONCLUSIONS: The proposed treatment guideline for AGA based on the BASP classification may be useful for dermatologists in their approach to treating Asian patients with AGA in clinical practice. Ideally, clinicians should try to utilize this guideline consistently in their practice to monitor treatment response with the goal of enhancing successful outcomes. This will help boost patients' confidence and self-esteem, thus improving patient' compliance with the prescribed treatments.

Research trends of Janus Kinase inhibitors: a bibliometric and visualized study from 2012 to 2023.

OBJECTIVE: Janus Kinase (JAK) inhibitors have been extensively evaluated for their potential in the management of various diseases. Despite previous research on this topic, there is a lack of bibliometric analysis that summarizes research trends on JAK inhibitors. This study aims to provide a comprehensive overview of the top 100 most frequently cited studies on JAK inhibitors over the last ten years. MATERIALS AND METHODS: The Web of Science database was used to screen and extract relevant studies on JAK inhibitors. The top 100 studies most cited within the JAK inhibitor-related research were identified and evaluated, and various data such as the year of publication, study focus and keywords, author information, and number of citations were extracted and analyzed for further examination. RESULTS: In the top 100 most cited studies of JAK inhibitors, more than 70% of studies focused on the role of JAK inhibitors in disease treatments, with 42% of these studies focused on using JAK inhibitors as treatment for autoimmune diseases and 19 of them focused on the treatment of neoplasms. Time trend analysis revealed that the keywords "tofacitinib", "atopic dermatitis", and "rheumatoid arthritis" were widely mentioned in 2016, while new trends emerged in 2018, with "ruxolitinib" and "baricitinib" being more commonly mentioned. CONCLUSIONS: The top 100 most frequently cited studies on JAK inhibitors focused primarily on the safety and efficacy of these inhibitors in the management of various diseases, particularly inflammatory diseases and neoplasms. The results can serve as a valuable reference for rheumatologists and immunologists interested in the development of JAK inhibitors and expanding future research fields.

Using brachial-ankle pulse wave velocity to associate arterial stiffness with cardiovascular risks.

BACKGROUND AND AIMS: This study aimed to elucidate the relationship between brachial-ankle pulse wave velocity (baPWV) and conventional cardiovascular risk factors. METHODS AND RESULTS: A total of 192 subjects with low to intermediate risk was enrolled in a cardiovascular evaluation program. A multiple regression model was built to find significant cardiovascular biomarkers for predicting baPWV. A logistic regression model was developed to associate baPWV and other biomarkers with the risk of cardiac diastolic dysfunction. A total of 123 men (mean age: 52.6+/-12.0) and 69 women (mean age: 51.7+/-10.4) was included. Age, blood pressure, C-reactive protein, serum homocysteine, heart rate, and blood urea nitrogen were positively predictive of increased pulse wave velocity. In turn, baPWV increased the risk (odds ratio: 1.257 for each m/s, 95% CI: 1.105 approximately 1.430, p<0.001) and high-density lipoprotein decreased the risk for cardiac diastolic dysfunction (0.962 for each mg/dl, 95% CI: 0.925 approximately 1.000, p=0.05). The correlation between baPWV and Framingham 10-year risk was moderate (men: r=0.306, p=0.002; women r=0.548, p<0.001). CONCLUSION: The results suggest that baPWV is a composite risk factor for early atherosclerotic change and a predictor for the development of diastolic dysfunction and long-term cardiovascular risk.

A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma.

BACKGROUND: Melasma is an acquired, chronic hypermelanosis for which therapy remains a challenge. OBJECTIVES: To compare the efficacy and safety of a triple combination [TC: fluocinolone acetonide 0.01%, hydroquinone (HQ) 4%, tretinoin 0.05%] vs. HQ 4% after 8 weeks of treatment of moderate to severe facial melasma in Asian patients. METHODS: This was a multicentre, randomized, controlled, investigator-blinded, parallel comparison study. East and South-East Asian patients aged 18 years or older, with a clinical diagnosis of moderate to severe melasma, were enrolled in this study. Patients were enrolled at baseline and treated daily for 8 weeks with TC cream (one application at bedtime) or HQ cream (twice daily). There were four study visits: at baseline and weeks 2, 4 and 8. The primary efficacy variable was the melasma global severity score (GSS). Other outcome measures included Melasma Area and Severity Index, global improvement and patient satisfaction. Safety was assessed through the reporting of adverse events. RESULTS: TC had superior efficacy to HQ for the primary variable: 77/120 patients (64.2%) on TC had GSS 'none' or 'mild' at week 8 vs. 48/122 patients (39.4%) on HQ (P < 0.001). The secondary efficacy variables confirmed these results. Patient satisfaction was in favour of TC (90/127, 70.8%, vs. 64/129, 49.6%; P = 0.005). More patients had related adverse events on TC (63/129, 48.8%) than on HQ (18/131, 13.7%) but most were mild and none was severe. CONCLUSIONS: Efficacy in Asians and patient satisfaction were superior with the fixed TC than with HQ 4%.

Identification of DNA recognition sequences and protein interaction domains of the multiple-Zn-finger protein Roaz.

Roaz, a rat C2H2 zinc finger protein, plays a role in the regulation of olfactory neuronal differentiation through its interaction with the Olf-1/EBF transcription factor family. An additional role for the Roaz/Olf-1/EBF heterodimeric protein is suggested by its ability to regulate gene activation at a distinct promoter lacking Olf-1/EBF-binding sites. Using an in vitro binding-site selection assay (Selex), we demonstrate that Roaz protein binds to novel inverted perfect or imperfect repeats of GCACCC separated by 2 bp. We show that Roaz is capable of binding to a canonical consensus recognition sequence with high affinity (Kd = 3 nM). Analysis of the structural requirement for protein dimerization and DNA binding by Roaz reveals the role of specific zinc finger motifs in the Roaz protein for homodimerization and heterodimerization with the Olf-1/EBF transcription factor. The DNA-binding domain of Roaz is mapped to the N-terminal 277 amino acids, containing the first seven zinc finger motifs, which confers weak monomeric binding to a single half site and a stronger dimeric binding to the inverted repeat in a binding-site-dependent manner. Full-length protein can form dimers on both the inverted repeat and direct repeat but not on a single half site. These findings support the role of the TFIIIA-type Zn fingers in both protein-protein interaction and protein-DNA interaction and suggest distinct functions for specific motifs in proteins with a large number of zinc finger structures.

Genes encoding components of the olfactory signal transduction cascade contain a DNA binding site that may direct neuronal expression.

Genes which mediate odorant signal transduction are expressed at high levels in neurons of the olfactory epithelium. The molecular mechanism governing the restricted expression of these genes likely involves tissue-specific DNA binding proteins which coordinately activate transcription through sequence-specific interactions with olfactory promoter regions. We have identified binding sites for the olfactory neuron-specific transcription factor, Olf-1, in the sequences surrounding the transcriptional initiation site of five olfactory neuron-specific genes. The Olf-1 binding sites described define the consensus sequence YTCCCYRGGGAR. In addition, we have identified a second binding site, the U site, in the olfactory cyclic nucleotide gated channel and type III cyclase promoters, which binds factors present in all tissue examined. These experiments support a model in which expression of Olf-1 in the sensory neurons coordinately activates a set of olfactory neuron-specific genes. Furthermore, expression of a subset of these genes may be modulated by additional binding factors.

Cell contact regulates fate choice by cortical stem cells.

Cell fate is determined by intrinsic programs and external cues, such as soluble signals and cell-cell contact. Previous studies have demonstrated the roles of soluble factors in the proliferation and differentiation of cortical stem cells and cell-cell contact in maintaining stem cells in a proliferative state. In the present study, we focused on the effect of cell-cell interaction on cell-fate determination. We found that density could exert a strong influence on the cell-type composition when cortical stem cells differentiate. Multipotent stem cells, which normally gave rise to neurons, astrocytes, and oligodendrocytes under high-density culture condition, differentiated almost exclusively into smooth muscle at low density. Clonal analysis indicated that smooth muscle and astrocytes were derived from a common precursor and that the density effect on cell types used an instructive mechanism on the choice of fate rather than an effect of selective survival and/or proliferation. This instructive mechanism depended on the local and not the average density of the cells. This local signal could be mimicked by membrane extract. These findings demonstrate the importance of membrane-bound signals in specifying lineage and provide the first evidence for a short-range regulatory mechanism in cortical stem cell differentiation.

Nitric oxide synthesis inhibition retards surgical reversal of one-kidney Goldblatt hypertension in rats.

Surgical correction of renal artery stenosis in Goldblatt hypertension rapidly normalizes blood pressure and increases renal function. This study was conducted in 1-kidney, 1 clip (1K1C) Goldblatt hypertensive rats to examine whether the unclipping-induced reversal of blood pressure and renal function is mediated by nitric oxide (NO). The 1K1C rats were prepared and given tap water with or without supplementation of NG-nitro-L-arginine methyl ester (L-NAME). Systolic blood pressure (SBP) before and after renal artery clipping was measured with the tail-cuff method. Four weeks later, surgical unclipping was performed while blood pressure and renal function responses were determined. The results show that clipping the renal artery for 4 weeks increased SBP from 140+/-5 to 183+/-6 mm Hg (P<0.05). Concurrent L-NAME treatment accelerated and aggravated the clipping-induced increases in SBP from 138+/-6 to 219+/-8 mm Hg (P<0.05). Surgical unclipping reduced blood pressure to normotensive levels within 2 hours in all hypertensive rats with and without chronic or acute L-NAME treatment. However, the magnitude of reductions in blood pressure in the initial 1 hour after unclipping was significantly less in L-NAME-treated rats than in nontreated rats (9+/-2% versus 16+/-1%, P<0.05). Despite reducing blood pressure, unclipping significantly increased glomerular filtration rate, urine flow, and sodium and potassium excretions, but the extent of the increases in these renal functions was significantly attenuated in L-NAME-treated rats. These data suggest that NO production partly contributes to the hypotensive and renal responses to unclipping but does not mediate the reversal of renovascular hypertension of this model.

Nitric oxide modulates the development and surgical reversal of renovascular hypertension in rats.

OBJECTIVE: To evaluate the role of nitric oxide (NO) in the development and unclipping-induced reversal of blood pressure and bilateral renal function in two-kidney, one clip (2K1C) Goldblatt hypertensive rats. METHODS: Goldblatt hypertensive rats were prepared by clipping the left renal artery 4 weeks before unclipping experiments. NG-nitro-L-arginine methyl ester (L-NAME) was administered after clipping and during unclipping to inhibit nitric oxide (NO) synthesis. Blood pressure and bilateral renal responses were measured. RESULTS: Chronic L-NAME treatment accelerated and aggravated blood pressure elevations and increased plasma nitrite and nitrate levels in 2K1C rats. Surgical removal of the renal artery clip induced profound reductions in blood pressure in rats with and without L-NAME treatment. However, the magnitude of the unclipping-induced depressor response at the first post-unclipping hour was significantly smaller in L-NAME-treated rats compared to those without L-NAME administration (15 +/- 1 versus 22 +/- 1%, P < 0.05). Two hours after unclipping, blood pressure of both groups fell to a comparable, normal level. Acute intravenous infusion of L-NAME in established 2K1C hypertensive rats further increased blood pressure. Subsequent unclipping caused a depressor response similar to that observed in hypertensive rats treated chronically with L-NAME. Despite the marked decreases in blood pressure, unclipping induced striking increases in glomerular filtration rate (GFR), urine flow and sodium and potassium excretion rates in the ipsilateral kidney. However, the magnitudes of increases in GFR and the diuretic and natriuretic responses in rats without L-NAME treatment were significantly greater than in rats with L-NAME administration. In contrast, unclipping reduced these function indices in the contralateral kidney to a similar level in rats with and without L-NAME treatment. CONCLUSIONS: NO exerts vasodilator action and thereby lessens renal artery clipping-induced blood pressure elevation. Furthermore, unclipping-induced release of NO partially contributes to the early reduction in blood pressure and changes in bilateral renal function but does not directly mediate the normalization of blood pressure after unclipping in this hypertension model.

Intraoperative dermatomal evoked potential monitoring fails to predict outcome from lumbar decompression surgery.

STUDY DESIGN: Thirty-three patients with single-level, unilateral lumbosacral radiculopathy underwent micro-decompression and intraoperative dermatomal evoked potential monitoring. Side-to-side latency asymmetry was calculated. A criteria for "abnormal" was defined. Intraoperative dermatomal evoked potentials were obtained before and after decompression. The changes were correlated with clinical outcome at the 3-month follow-up examination. OBJECTIVES: To determine whether intraoperative dermatomal evoked potential latency asymmetry confirms nerve root compression and whether an improvement of latency asymmetry after decompression predicts a good clinical outcome. SUMMARY OF BACKGROUND DATA: Intraoperative dermatomal evoked potential has been proposed as a test to assess the adequacy of nerve root decompression. Initial reports suggested improvement of dermatomal evoked potential amplitude and latency after decompression. The clinical efficacy is controversial because of its technical difficulty and inherent variation. METHODS: Cervical recording was chosen to reduce the effects of anesthesia. The asymptomatic nerve root was used as a control. Quality of the tracings was determined by evoked potentials-to-noise amplitude ratio. Clinical outcome was based on patient's pain relief and satisfaction. RESULTS: Tracings of acceptable quality were obtained at baseline in 57.6% (19 of 33) of patients. A side-to-side latency asymmetry > 5% was defined as abnormal. Before decompression, 68.4% (13 of 19) of patients had an abnormal dermatomal evoked potential. After decompression, latency asymmetry returned to normal in every patient. Clinical outcome was good or excellent in 13 patients, fair in four patients, and poor in two patients. Dermatomal evoked potential latency improvements were not related to variation in clinical outcome. CONCLUSIONS: Intraoperative dermatomal evoked potential monitoring is technically demanding. Finding reproducible potentials is difficult. More research is necessary before general use of dermatomal evoked potentials for monitoring nerve root decompression.

Multiframe image point matching and 3-d surface reconstruction.

This paper presents two new methods, the Joint Moment Method (JMM) and the Window Variance Method (WVM), for image matching and 3-D object surface reconstruction using multiple perspective views. The viewing positions and orientations for these perspective views are known a priori, as is usually the case for such applications as robotics and industrial vision as well as close range photogrammetry. Like the conventional two-frame correlation method, the JMM and WVM require finding the extrema of 1-D curves, which are proved to theoretically approach a delta function exponentially as the number of frames increases for the JMM and are much sharper than the two-frame correlation function for both the JMM and the WVM, even when the image point to be matched cannot be easily distinguished from some of the other points. The theoretical findings have been supported by simulations. It is also proved that JMM and WVM are not sensitive to certain radiometric effects. If the same window size is used, the computational complexity for the proposed methods is about n - 1 times that for the two-frame method where n is the number of frames. Simulation results show that the JMM and WVM require smaller windows than the two-frame correlation method with better accuracy, and therefore may even be more computationally feasible than the latter since the computational complexity increases quadratically as a function of the window size.

Uniqueness and estimation of three-dimensional motion parameters of rigid objects with curved surfaces.

Two main results are established in this paper. First, we show that seven point correspondences are sufficient to uniquely determine from two perspective views the three-dimensional motion parameters (within a scale factor for the translations) of a rigid object with curved surfaces. The seven points should not be traversed by two planes with one plane containing the origin, nor by a cone containing the origin. Second, a set of ``essential parameters'' are introduced which uniquely determine the motion parameters up to a scale factor for the translations, and can be estimated by solving a set of linear equations which are derived from the correspondences of eight image points. The actual motion parameters can subsequently be determined by computing the singular value decomposition (SVD) of a 3×3 matrix containing the essential parameters.

GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest.

Guanine nucleotide binding protein-like 3-like (GNL3L) is a nucleolar protein and the vertebrate paralogue of nucleostemin (NS). We previously reported that nucleoplasmic mobilization of NS stabilizes MDM2 (mouse double minute 2). Here, we investigated the role of GNL3L as a novel MDM2 regulator. We found that GNL3L binds MDM2 in vivo and displays the same function as NS in stabilizing MDM2 protein and preventing its ubiquitylation. The interaction between GNL3L and MDM2 also takes place in the nucleoplasm. However, the MDM2 regulatory activity of GNL3L occurs constitutively and does not so much depend on the nucleolar release mechanism as NS does. GNL3L depletion triggers G2/M arrest in the p53-wild-type HCT116 cells more than in the p53-null cells, and upregulates specific p53 targets (that is, Bax, 14-3-3σ and p21) without affecting the ubiquitylation or stability of p53 proteins. The inhibitory activity of GNL3L on p53-mediated transcription correlates with the increased expression of GNL3L and reduced expression of 14-3-3σ and p21 in human gastrointestinal tumors. This work shows that in contrast to most nucleolar proteins that negatively control MDM2, GNL3L and NS are the only two that are designed to stabilize MDM2 protein under basal or induced condition, respectively, and may act as tumor-promoting genes.

Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats by reversing the coupling of mu-opioid receptors from Gs-protein to coupling to Gi-protein.

Pertussis toxin (PTX) treatment results in ADP-ribosylation of Gi-protein and thus in disruption of mu-opioid receptor signal transduction and loss of the antinociceptive effect of morphine. We have previously demonstrated that pretreatment with ultra-low dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The present study further examined the effect of ultra-low dose naloxone on mu-opioid receptor signaling in PTX-treated rats and the underlying mechanism. Male Wistar rats implanted with an intrathecal catheter received an intrathecal injection of saline or PTX (1 microg in 5 microl of saline), then, 4 days later, were pretreated by intrathecal injection with either saline or ultra-low dose naloxone (15 ng in 5 microl of saline), followed, 30 min later, by saline or morphine (10 microg in 5 microl of saline). Four days after PTX injection, thermal hyperalgesia was observed, together with increased coupling of excitatory Gs-protein to mu-opioid receptors in the spinal cord. Ultra-low dose naloxone pretreatment preserved the antinociceptive effect of morphine, and this effect was completely blocked by the mu-opioid receptor antagonist CTOP, but not by the kappa-opioid receptor antagonist nor-BNI or the delta-opioid receptor antagonist naltrindole. Moreover, a co-immunoprecipitation study showed that ultra-low dose naloxone restored mu-opioid receptor/Gi-protein coupling and inhibited the PTX-induced mu-opioid receptor/Gs-protein coupling. In addition to the anti-neuroinflammatory effect and glutamate transporter modulation previously observed in PTX-treated rats, the re-establishment of mu-opioid receptor Gi/Go-protein coupling is involved in the restoration of the antinociceptive effect of morphine by ultra-low dose naloxone pretreatment by normalizing the balance between the excitatory and inhibitory signaling pathways. These results show that ultra-low dose naloxone preserves the antinociceptive effect of morphine, suppresses spinal neuroinflammation, and reduces PTX-elevated excitatory Gs-coupled opioid receptors in PTX-treated rats. We suggest that ultra-low dose naloxone might be clinically valuable in pain management.

Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats and prevents glutamate transporter downregulation by suppressing the p38 mitogen-activated protein kinase signaling pathway.

We previously demonstrated that ultra-low dose naloxone restores the antinociceptive effect of morphine in rats with pertussis toxin (PTX)-induced thermal hyperalgesia by reversing the downregulation of glutamate transporter (GT) expression and suppressing spinal neuroinflammation. In the present study, we examined the underlying mechanisms of this anti-inflammatory effect in PTX-treated rats, particularly on the expression of GTs. Male Wistar rats were implanted with an intrathecal catheter and, in some cases, with a microdialysis probe. All rats were injected intrathecally with saline (5 microl) or PTX (1 microg), then, 4 days later, were randomly assigned to receive a single injection of saline, ultra-low dose naloxone (15 ng), or the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 microg), followed by morphine injection (10 microg) 30 min later. Our results showed that PTX injection induced activation of microglia and a significant increase in P-p38 MAPK expression in the spinal cord. Ultra-low dose naloxone plus morphine significantly inhibited the effect of PTX on P-p38 MAPK expression in the spinal cord, while the p38 MAPK inhibitor SB203580 attenuated the PTX-induced mechanical allodynia, thermal hyperalgesia, increase in spinal cerebrospinal fluid excitatory amino acids, and downregulation of GTs. These results show that the restoration of the antinociceptive effect of morphine and GT expression in PTX-treated rats by ultra-low dose naloxone involves suppression of the p38 MAPK signal transduction cascade.

Amitriptyline induces nuclear transcription factor-kappaB-dependent glutamate transporter upregulation in chronic morphine-infused rats.

We previously showed that intrathecal co-administration of amitriptyline with morphine upregulates the expression of the glial glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and restores neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression in chronically morphine-infused rats. The present study examined the role of nuclear transcription factor-kappaB (NF-kappaB) in the regulation of the expression of GLAST, GLT-1, and EAAC1 following long-term amitriptyline/morphine co-infusion. Male Wistar rats were implanted with two intrathecal catheters with or without a microdialysis probe; one of the catheters was used for continuous infusion of saline (control), morphine (15 microg/h), or morphine plus amitriptyline (both 15 microg/h) for 5 days, while the other was used for a single daily intrathecal injection of the NF-kappaB inhibitor Ro106-9920 (10 microl of 10 microM) for 5 days. We found that amitriptyline co-infusion restored the antinociceptive effect of morphine (4.5-fold right-shift in the morphine dose-response curve compared with a 65-fold right-shift in its absence) and this effect was inhibited by Ro106-9920 administration (48-fold right-shift). Moreover, amitriptyline/morphine co-infusion increased IkappaBalpha phosphorylation and the translocation of NF-kappaB p65 from the cytosol to the nucleus. Daily intrathecal injection of Ro106-9920 prevented the amitriptyline/morphine-induced NF-kappaB p65 translocation and reversed the amitriptyline/morphine-induced GLAST and GLT-1 upregulation and inhibited the restoration of EAAC1 expression. The Ro106-9920 injections abolished the inhibitory effect of amitriptyline on the morphine-evoked release of excitatory amino acids into the spinal cerebrospinal fluid (CSF) dialysates. In conclusion, amitriptyline/morphine co-infusion restores the antinociceptive effect of morphine and upregulates GLAST and GLT-1 expression and restores EAAC1 expression to baseline levels, thus reducing excitatory amino acid levels in the spinal CSF dialysates. The mechanism involves activation of the NF-kappaB pathway, but may also involve other pathways.