Retinal Thickness and Its Interocular Asymmetry Between Parkinson's Disease and Drug-Induced Parkinsonism.

BACKGROUND: Drug-induced parkinsonism (DIP) is common, but diagnosis is challenging. Although dopamine transporter imaging is useful, the cost and inconvenience are problematic, and an easily accessible screening technique is needed. We aimed to determine whether optical coherence tomography (OCT) findings could differentiate DIP from Parkinson's disease (PD). METHODS: We investigated 97 de novo PD patients and 27 DIP patients using OCT and [18F] N-(3-fluoropropyl)-2b-carbon ethoxy-3b-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography. We compared peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular retinal thickness (mRT) between PD and DIP patients as well as interocular differences in the pRNFLT and the mRT. Asymmetric index (%) for retinal thickness (AIRT) was calculated to measure the interocular differences between pRNFLT and mRT. The correlation between AIRT and total striatal specific/non-specific binding ratio asymmetry index (SNBRAI) was investigated in PD and DIP patients. RESULTS: No significant differences in pRNFLT and mRT values were observed between PD and DIP patients (all P values > 0.090). The mean SNBRAI was significantly higher in PD than in DIP (P = 0.008) patients; however, AIRT did not differ between PD and DIP patients in pRNFLT and mRT (all P values > 0.100). SNBRAI did not correlate with AIRT of pRNFL or mRT in PD and DIP patients (all P values > 0.060). CONCLUSION: Our study showed no benefit of retinal thickness and interocular asymmetry measurements using OCT for distinguishing PD from DIP in the early stages. Additional investigations are needed for confirmation.

Correlations with REM sleep behavior disorder severity in isolated rapid eye movement sleep behavior disorders patients.

OBJECTIVES: The pathogenesis of isolated rapid eye movement sleep behavior disorders (iRBD) is poorly understood. The severity of RBD may reflect its pathogenesis. METHODS: We compared motor function and non-motor symptoms (NMSs) between iRBD patients and healthy volunteers. We correlated motor function, NMSs, and striatal dopaminergic activity with RBD severity using video-polysomnography. RESULTS: Twenty-one iRBD patients and 17 controls participated. The Unified Parkinson's Disease Rating Scale part III scores were higher in patients compared to controls (p < 0.001). There was no difference in upper extremity function between patients and controls (right, p = 0.220; left, p = 0.209), but gait was slower in iRBD patients (walking time, p < 0.001; number of steps, p < 0.001). The mean value of the Korean version of the Mini-Mental State Exam and Clinical Dementia Rating were lower in patients (p = 0.006, p = 0.003, respectively). Patients with were also more depressed (p = 0.002), had decreased olfactory function (p < 0.001), reported more frequent sleep/fatigue episodes (p < 0.001), worse attention/memory capacity (p < 0.001), gastrointestinal problems (p = 0.009), urinary problems (p = 0.007), and pain (p = 0.083). Further, iRBD patients reported more frequent sleep-related disturbances (p = 0.004), but no difference in daytime sleepiness (p = 0.663). Disease severity was correlated with pain (r = 0.686, p = 0.002) and visuospatial function (r= -0.507, p = 0.038). There were no correlations between RBD severity and striatal dopaminergic activities (p > 0.09). CONCLUSIONS: iRBD is a multisystem neurodegenerative disorder, and gait abnormalities may be a disease characteristic, possibly related to the akinetic-rigid phenotype of Parkinson's disease. The correlation between pain/visuospatial dysfunction and RBD severity may be related to its pathogenesis.

Editorial: Chronic Inflammation and Related Diseases: From Mechanisms to Therapies.

The purpose of this Special Issue is to identify the exact mechanism underlying inflammation to direct more effective strategies for inflammation management and to provide basic data for the development of anti-inflammatory and analgesic treatment methods for patients with inflammatory pain [...].

A prospective multi-centre study of susceptibility map-weighted MRI for the diagnosis of neurodegenerative parkinsonism.

OBJECTIVES: This study aimed to compare susceptibility map-weighted imaging (SMwI) using various MRI machines (three vendors) with N-3-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophe nyl)nortropane (18F-FP-CIT) PET in the diagnosis of neurodegenerative parkinsonism in a multi-centre setting. METHODS: We prospectively recruited 257 subjects, including 157 patients with neurodegenerative parkinsonism, 54 patients with non-neurodegenerative parkinsonism, and 46 healthy subjects from 10 hospitals between November 2019 and October 2020. All participants underwent both SMwI and 18F-FP-CIT PET. SMwI was interpreted by two independent reviewers for the presence or absence of abnormalities in nigrosome 1, and discrepancies were resolved by consensus. 18F-FP-CIT PET was used as the reference standard. Inter-observer agreement was tested using Cohen's kappa coefficient. McNemar's test was used to test the agreement between the interpretations of SMwI and 18F-FP-CIT PET per participant and substantia nigra (SN). RESULTS: The inter-observer agreement was 0.924 and 0.942 per SN and participant, respectively. The diagnostic sensitivity of SMwI was 97.9% and 99.4% per SN and participant, respectively; its specificity was 95.9% and 95.2%, respectively, and its accuracy was 97.1% and 97.7%, respectively. There was no significant difference between the results of SMwI and 18F-FP-CIT PET (p > 0.05, for both SN and participant). CONCLUSIONS: This study demonstrated that the high diagnostic performance of SMwI was maintained in a multi-centre setting with various MRI scanners, suggesting the generalisability of SMwI for determining nigrostriatal degeneration in patients with parkinsonism. KEY POINTS: • Susceptibility map-weighted imaging helps clinicians to predict nigrostriatal degeneration. • The protocol for susceptibility map-weighted imaging can be standardised across MRI vendors. • Susceptibility map-weighted imaging showed diagnostic performance comparable to that of dopamine transporter PET in a multi-centre setting with various MRI scanners.

Pain in atypical parkinsonism, vascular parkinsonism, and Parkinson's disease.

BACKGROUND: Pain is a common symptom in Parkinson's disease (PD) and is considered a pre-motor symptom suggesting sensory involvement in the pre-motor stage. Pain in other parkinsonian disorders such as atypical parkinsonism and vascular parkinsonism (VP) has been investigated in only a few studies. The characteristics of pain in other parkinsonian disorders, including the temporal relationships between pain and motor symptoms, were investigated in the present study. METHODS: A total of 236 PD, 42 multiple system atrophy (MSA), 31 progressive supranuclear palsy (PSP), and 38 VP patients were screened for pain. After excluding patients with dementia and pain not related to PD, the presence of pain, severity, onset, type, and location were compared among the four patient groups. RESULTS: Difference was not observed in pain presence (χ2 = 3, p = 0.186), severity (F = 1.534, p = 0.207), or type (χ2 = 6, p = 0.400) among the four groups. However, the temporal relationship between pain and motor symptoms differed (H(3) = 8.764, p = 0.033). Pain predated motor symptoms in PD, MSA, and VP but often followed motor symptoms in PSP. The pain location in the body was different among the four patient groups (χ2 = 21, p = 0.018), and leg involvement was more common in PSP. CONCLUSION: The present study results suggest that pain can be a pre-motor symptom in PD, MSA, and VP but not in PSP, implying different pain pathogeneses in these disorders. Pain locations were other for each group, which requires further investigation with a more extensive study cohort.

Motor Asymmetry and Interocular Retinal Thickness in Parkinson's Disease.

BACKGROUND: To analyze the relationship between interocular difference of retinal thickness and motor asymmetry in Parkinson's disease (PD). METHODS: Prospective case-control series analyzed 62 eyes of 31 patients with PD and 62 eyes of 31 age- and sex-matched control. Ophthalmologic examinations including optical coherence tomography (OCT) scans were performed in both groups, and in the patients with PD, motor function was evaluated on the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) to determine the clinically more affected side. Peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular retinal thickness (mRT) were measured in both eyes, after which the interocular asymmetry of the OCT parameters was determined. Additionally, the more and less affected sides of the UPDRS-III were evaluated using Symmetric index. RESULTS: The average and quadrant pRNFLT and mRT values between the two groups were not different, but the interocular asymmetry of the average mRT and asymmetry index of retinal thickness (AIRT) of temporal mRT were significantly higher in the PD patients than in the controls (P = 0.026 and 0.044). The sum of UPDRS-III showed a discrepancy between the more and less affected sides (P = 0.002); the calculated Symmetric index was 0.21 ± 0.19, which suggested asymmetric motor symptoms. The Symmetric index of UPDRS-III showed significant relations for interocular asymmetry of superior mRT and AIRT of average mRT (P = 0.001 and 0.008). CONCLUSION: In the PD patients, the interocular asymmetry of mRT was larger than in the controls, and the motor symptoms were asymmetric. Additionally, the interocular asymmetry of mRT showed a significant correlation with motor-symptom laterality.

Inhibition of Spinal TRPV1 Reduces NMDA Receptor 2B Phosphorylation and Produces Anti-Nociceptive Effects in Mice with Inflammatory Pain.

Transient receptor potential vanilloid 1 (TRPV1) has been implicated in peripheral inflammation and is a mediator of the inflammatory response to various noxious stimuli. However, the interaction between TRPV1 and N-methyl-D-aspartate (NMDA) receptors in the regulation of inflammatory pain remains poorly understood. This study aimed to investigate the analgesic effects of intrathecal administration of capsazepine, a TRPV1 antagonist, on carrageenan-induced inflammatory pain in mice and to identify its interactions with NMDA receptors. Inflammatory pain was induced by intraplantar injection of 2% carrageenan in male ICR mice. To investigate the analgesic effects of capsazepine, pain-related behaviors were evaluated using von Frey filaments and a thermal stimulator placed on the hind paw. TRPV1 expression and NMDA receptor phosphorylation in the spinal cord and glutamate concentration in the spinal cord and serum were measured. Intrathecal treatment with capsazepine significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia. Moreover, carrageenan-enhanced glutamate and phosphorylation of NMDA receptor subunit 2B in the spinal cord were suppressed by capsazepine administration. These results indicate that TRPV1 and NMDA receptors in the spinal cord are associated with inflammatory pain transmission, and inhibition of TRPV1 may reduce inflammatory pain via NMDA receptors.

Acupuncture Alleviates Anxiety and 22-kHz Ultrasonic Vocalizations in Rats Subjected to Repeated Alcohol Administration by Modulating the Brain-Derived Neurotrophic Factor/Corticotropin-Releasing Hormone Signaling Pathway.

The Shenmen point (acupuncture point heart 7: HT7), located in the heart meridian, is frequently used to treat mental disorders, including drug addiction, anxiety, and depression. This study aimed to determine how HT7 regulates anxiety and negative emotions caused by repeated alcohol administration, focusing on the amygdala and paraventricular nucleus (PVN). Repeated administration of alcohol (ETOH; 2 g/kg, i.p. injection, 16% v/v) for 14 days increased the corticosterone (CORT) levels, and HT7 stimulation reduced the plasma CORT levels. HT7 stimulation mitigated anxiety-like behaviors and reduced 22-kHz ultrasonic vocalizations in rats receiving repeated ETOH injections. HT7 stimulation increased the amygdala expression of mature brain-derived neurotropic factor (mBDNF) and phosphorylated tropomyosin receptor kinase B (pTrkB) and decreased the PVN corticotropin-releasing hormone (CRH) expression. Amygdala microinjections of the TrkB antagonist ANA-12 (0.1 pmol/1 µL) reversed the increase in PVN CRH levels. The reduced PVN CRH levels were regulated by CRH-expressing neurons in the amygdala, and the increased amygdala CRH levels were affected by the HT7-stimulation induced increases in mBDNF. HT7 stimulation alleviates increased stress hormone levels and mitigates anxiety and negative emotions caused by repeated ETOH administration. These results provide scientific support for the clinical use of acupuncture to treat various alcoholism-induced diseases.

Multiple Daily Rounds of Theta-Burst Stimulation for Tinnitus: Preliminary Results.

Background and Objectives: Tinnitus is a condition that negatively affects the quality of life and is difficult to treat. Theta burst stimulation (TBS), a new method of repetitive transcranial magnetic stimulation (rTMS), is a promising treatment approach because it shows stronger and more prolonged effects in a shorter time of stimulation than other rTMS protocols. However, the therapeutic effect of TBS for tinnitus was inconsistent. We hypothesized that more stimulation would be more effective. Therefore, this study aimed to explore the safety and effectiveness of multiple daily rounds of TBS over five consecutive days. Materials and Methods: The continuous TBS (cTBS) protocol is 300 pulses/day, but we applied 8 sessions of 300 pulses in a day (total 2400 pulses/day). A total of 15 patients with tinnitus were randomly assigned to treatment and sham groups. Outcome measurements were taken three times: before and after 5-day of stimulation; at a 1-3 month follow-up visit. Outcome measurements were the degree of annoyance due to ear fullness, duration of tinnitus, visual analog scales of tinnitus for annoyance, Tinnitus Handicap Inventory, pitch, loudness, minimum masking level, and residual inhibition. Results: Five-day cTBS was completed without adverse events. We did not find any significant therapeutic effect in the treatment group, but we needed to be cautious to interpret our result due to the small sample size. Conclusions: In conclusion, multiple rounds of cTBS in a day may be safe. Further research is needed in a larger sample size to determine the effectiveness and confirm the safety.

Neural and dopaminergic correlates of fatigue in Parkinson's disease.

Fatigue is one of the most common non-motor symptoms in Parkinson's disease (PD). Despite its clinical importance, there are few studies on the cause or mechanism of fatigue. Our aim was to find brain areas related to fatigue and to explore the association between striatal dopaminergic dysfunction and fatigue. We consecutively screened forty-seven patients with de novo PD from 2012 to 2017 and enrolled 32 patients. The gray matter volumes, white matter tracts, and striatal dopaminergic activity between PD without fatigue and with fatigue were compared. The correlation between fatigue and striatal dopaminergic activity was also analyzed. Our data did not show any significant difference in gray matter volume between PD without fatigue and with fatigue (familywise error [FWE] corrected p > 0.05) but revealed significantly higher mean fractional anisotropy (FA) values for all analyzed white matter tracts in PD with fatigue (false discovery rate [FDR] corrected p < 0.05), except left cingulum-hippocampus (CH), right superior longitudinal fasciculus, and right longitudinal fasciculus temporal part (FDR corrected p > 0.06); lower mean diffusivity (MD) values for all analyzed white matter tracts in PD with fatigue (FDR corrected p < 0.05), except in the left CH and uncinate fasciculus (FDR corrected p > 0.05). The mean radial diffusivity (RD) values, except for the left CH (FDR corrected p = 0.0576), were also significantly lower (FDR corrected p < 0.05). There was no difference in dopaminergic deficits between PD without fatigue and PD with fatigue (p > 0.50). The alteration of the white matter tract may reflect the degree of fatigue in PD. This is not true of the gray matter and striatal dopaminergic activity. These results show the possibility that white matter changes can be used as a biomarker for fatigue.

Astrocyte D-serine modulates the activation of neuronal NOS leading to the development of mechanical allodynia in peripheral neuropathy.

Spinal D-serine plays an important role in nociception via an increase in phosphorylation of the N-Methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). However, the cellular mechanisms underlying this process have not been elucidated. Here, we investigate the possible role of neuronal nitric oxide synthase (nNOS) in the D-serine-induced potentiation of NMDA receptor function and the induction of neuropathic pain in a chronic constriction injury (CCI) model. Intrathecal administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt (LSOS) or the D-serine degrading enzyme, D-amino acid oxidase (DAAO) on post-operative days 0-3 significantly reduced the CCI-induced increase in nitric oxide (NO) levels and nicotinamide adenine dinucleotide phosphate-diaphorase staining in lumbar dorsal horn neurons, as well as the CCI-induced decrease in phosphorylation (Ser847) of nNOS (pnNOS) on day 3 post-CCI surgery. LSOS or DAAO administration suppressed the CCI-induced development of mechanical allodynia and protein kinase C (PKC)-dependent (Ser896) phosphorylation of GluN1 on day 3 post-surgery, which were reversed by the co-administration of the NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1). In naïve mice, exogenous D-serine increased NO levels via decreases in pnNOS. D-serine-induced increases in mechanical hypersensitivity, NO levels, PKC-dependent pGluN1, and NMDA-induced spontaneous nociception were reduced by pretreatment with the nNOS inhibitor, 7-nitroindazole or with the NMDA receptor antagonists, 7-chlorokynurenic acid and MK-801. Collectively, we show that spinal D-serine modulates nNOS activity and concomitant NO production leading to increases in PKC-dependent pGluN1 and ultimately contributing to the induction of mechanical allodynia following peripheral nerve injury.

Comprehensive risk factor evaluation of postoperative delirium following major surgery: clinical data warehouse analysis.

BACKGROUND: Postoperative delirium (POD) in older adults is a very serious complication. Due to the complexity of too many risk factors (RFs), an overall assessment of RFs may be needed. The aim of this study was to evaluate comprehensively the RFs of POD regardless of the organ undergoing operation, efficiently incorporating the concept of comprehensive big data using a smart clinical data warehouse (CDW). METHODS: We reviewed the electronic medical data of inpatients aged 65 years or older who underwent major surgery between January 2010 and June 2016 at Hallym University Sacred Heart Hospital. The following six major operation types were selected: cardiac, stomach, colorectal, hip, knee, and spine. Clinical features, laboratory findings, perioperative variables, and medication history were compared between patients without POD and with POD. RESULTS: Six hundred eighty-six of 3634 patients (18.9%) developed POD. In multivariate logistic regression analysis, common, independent RFs of POD were as follows (descending order of odds ratio): operation type ([hip] OR 8.858, 95%CI 3.432-22.863; p = 0.000; [knee] OR 7.492, 95%CI 2.739-20.487; p = 0.000; [spine] OR 6.919, 95%CI 2.687-17.815; p = 0.000; [colorectal] OR 2.037, 95%CI 0.784-5.291; p = 0.144; [stomach] OR 1.500, 95%CI 0.532-4.230; p = 0.443; [cardiac] reference), parkinsonism (OR 2.945, 95%CI 1.564-5.547; p = 0.001), intensive care unit stay (OR 1.675, 95%CI 1.354-2.072; p = 0.000), stroke history (OR 1.591, 95%CI 1.112-2.276; p = 0.011), use of hypnotics and sedatives (OR 1.307, 95%CI 1.072-1.594; p = 0.008), higher creatinine (OR 1.107, 95%CI 1.004-1.219; p = 0.040), lower hematocrit (OR 0.910, 95%CI 0.836-0.991; p = 0.031), older age (OR 1.053, 95%CI 1.037-1.069; p = 0.000), and lower body mass index (OR 0.967, 95%CI 0.942-0.993; p = 0.013). The use of analgesics (OR 0.644, 95%CI 0.467-0.887; p = 0.007) and antihistamines/antiallergics (OR 0.764, 95%CI 0.622-0.937; p = 0.010) were risk-reducing factors. Operation type with the highest odds ratio for POD was orthopedic surgery. CONCLUSIONS: Big data analytics could be applied to evaluate RFs in electronic medical records. We identified common RFs of POD, regardless of operation type. Big data analytics may be helpful for the comprehensive understanding of POD RFs, which can help physicians develop a general plan to prevent POD.

Biological safety of Electroacupuncture with STS316 needles.

BACKGROUND: Electroacupuncture (EA) is often used in clinical settings due to its analgesic effect, but its safety has not been verified due to the lack of clear criteria. This study examined the critical range of the corrosion of stainless steel types STS304 and STS316, which have been used clinically, and the relationship between needle corrosion and cell necrosis. METHOD: The critical point of corrosion for STS304 and STS316 was identified by varying the time, frequency, and stimulation intensity. In a tissue necrosis experiment, EA stimulation was applied to rats using STS316 needles with different thicknesses at maximum intensity for 60 min, and the presence of corrosion and tissue necrosis was determined. A cytotoxicity experiment was also conducted and assessed the needles and tissue necrosis. RESULTS: The results showed that STS316 was more stable than STS304 and that only coated needles corroded. Furthermore, tissue necrosis was observed regardless of corrosion, and slight cell necrosis was associated with needles with corrosion. CONCLUSIONS: This study demonstrated that non-coated STS316 was the most stable for EA stimulation and that corrosion byproducts and cell necrosis were not directly related.

Uric acid level may not be reduced in essential tremor.

BACKGROUND: Essential tremor is very common, but characterization is difficult because of its heterogeneity. Neuropathology is important to elucidate the characteristics of neurological disorders. However, pathological findings in essential tremor have been inconsistent among studies. Uric acid is a strong antioxidant and might be a biomarker in neurodegenerative process. We hypothesized that uric acid level would be reduced if essential tremor is a neurodegenerative disease. Our aim was to compare uric acid level between essential tremor patients and healthy individuals. METHODS: This was a prospective, case-control, multicenter study with 92 essential tremor patients and 77 healthy subjects. For homogeneity, the essential tremor group was subdivided into two groups (hereditary and sporadic). Clinical and laboratory findings were compared among the essential tremor and healthy groups. RESULTS: The demographic characteristics were comparable among the groups. The uric acid level was lower in the essential tremor group than in healthy subjects, but the difference did not reach statistical significance. There was a negative correlation between uric acid level and disease duration in the hereditary group (p = .046) and between uric acid level and age at onset in the sporadic group (p = .012). The mean values of total cholesterol were significantly lower in the sporadic group than in the other groups (p = .011). Total cholesterol was positively correlated with age at onset in the hereditary essential tremor group (p = .010). CONCLUSIONS: We did not find any evidence that uric acid levels suggested essential tremor is a neurodegenerative disease. However, further research with more patients might be needed given the negative correlations of disease duration and age at onset with uric acid level.

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. METHODS: Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS: In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION: Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD. © 2017 International Parkinson and Movement Disorder Society.

Case report: fainting during acupuncture stimulation at acupuncture point LI4.

BACKGROUND: Fainting is one of the major adverse events that can occur as a result of acupuncture treatment. However, the observation of changes in biological parameters is rarely available when fainting occurs. In this case report, we could observe changes in the electroencephalogram (EEG) in a participant who fainted while participating in a clinical trial aiming to observe a relationship between acupuncture stimulation at LI4 acupuncture point and EEG in healthy adults. CASE PRESENTATION: The EEG pattern of participant changed twice. The first change was in response to the acupuncture needle insertion, and the second change occurred during fainting. Both changes consisted of a burst in EEG amplitude, but the pattern of details was different. Multiple areas of the cortex were activated, and the increased ratio of the γ wave was not observed during fainting. While acupuncture needle insertion, only the sensory cortex were activated and increased the ratio of the γ wave. CONCLUSIONS: This single case is presented to improve the understanding of fainting during acupuncture as an adverse event and to explore the mechanism of acupuncture treatment, despite the absence of statistics and repeatability. This information can provide a new viewpoint about the mechanism of acupuncture treatment and the possibility of new techniques based on acupuncture.

Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.

We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-d-aspartate (NMDA) receptor. Sig-1Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. d-serine, synthesized from l-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of d-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of d-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and d-serine were only localized to astrocytes in the superficial dorsal horn, while d-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1Rs. The CCI-induced increase in the levels of d-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous d-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous d-serine. These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes. The increased production of d-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice.

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination.

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

Acid evoked thermal hyperalgesia involves peripheral P2Y1 receptor mediated TRPV1 phosphorylation in a rodent model of thrombus induced ischemic pain.

BACKGROUND: We previously developed a thrombus-induced ischemic pain (TIIP) animal model, which was characterized by chronic bilateral mechanical allodynia without thermal hyperalgesia (TH). On the other hand we had shown that intraplantar injection of acidic saline facilitated ATP-induced pain, which did result in the induction of TH in normal rats. Because acidic pH and increased ATP are closely associated with ischemic conditions, this study is designed to: (1) examine whether acidic saline injection into the hind paw causes the development of TH in TIIP, but not control, animals; and (2) determine which peripheral mechanisms are involved in the development of this TH. RESULTS: Repeated intraplantar injection of pH 4.0 saline, but not pH 5.5 and 7.0 saline, for 3 days following TIIP surgery resulted in the development of TH. After pH 4.0 saline injections, protein levels of hypoxia inducible factor-1α (HIF-1α) and carbonic anhydrase II (CA II) were elevated in the plantar muscle indicating that acidic stimulation intensified ischemic insults with decreased tissue acidity. At the same time point, there were no changes in the expression of TRPV1 in hind paw skin, whereas a significant increase in TRPV1 phosphorylation (pTRPV1) was shown in acidic saline (pH 4.0) injected TIIP (AS-TIIP) animals. Moreover, intraplantar injection of chelerythrine (a PKC inhibitor) and AMG9810 (a TRPV1 antagonist) effectively alleviated the established TH. In order to investigate which proton- or ATP-sensing receptors contributed to the development of TH, amiloride (an ASICs blocker), AMG9810, TNP-ATP (a P2Xs antagonist) or MRS2179 (a P2Y1 antagonist) were pre-injected before the pH 4.0 saline. Only MRS2179 significantly prevented the induction of TH, and the increased pTRPV1 ratio was also blocked in MRS2179 injected animals. CONCLUSION: Collectively these data show that maintenance of an acidic environment in the ischemic hind paw of TIIP rats results in the phosphorylation of TRPV1 receptors via a PKC-dependent pathway, which leads to the development of TH mimicking what occurs in chronic ischemic patients with severe acidosis. More importantly, peripheral P2Y1 receptors play a pivotal role in this process, suggesting a novel peripheral mechanism underlying the development of TH in these patients.