Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

OBJECTIVE: Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice. METHODS: To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF). RESULTS: Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area. CONCLUSIONS: LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Association between Temporomandibular Joint Disorder and Parkinson's Disease.

This study performed two different analyses using a large set of population data from the Korean National Health Insurance Service Health Screening Cohort to evaluate the interactional association between temporomandibular disorder (TMD) and Parkinson's disease (PD). Two nested case-control population-based studies were conducted on 514,866 participants. In Study I, 4455 participants with TMD were matched with 17,820 control participants, with a ratio of 1:4. In Study II, 6076 participants with PD were matched with 24,304 control participants, with a ratio of 1:4. Obesity, smoking, alcohol consumption, systolic, diastolic blood pressure, fasting blood glucose level, and total cholesterol were adjusted. The adjusted odds ratio (OR) for TMD was 1.43 (95% confidence interval (CI) = 1.02-2.00) in PD patients compared to non-PD patients in Study I (p < 0.001). The adjusted OR for PD was 1.56 (95% CI = 1.13-2.15) in TMD patients compared to non-TMD patients in Study II (p = 0.007). This study demonstrated that patients with TMD have a significantly higher risk of developing PD and, conversely, those with PD have a significantly higher risk of developing TMD.

Acupuncture stimulation at HT7 as a non-pharmacological therapy for sleep disorder caused by caffeine administration in rats.

OBJECTIVES: Insomnia is one of the most common sleep disorders and is difficult to completely treat because of the undesirable side effects of hypnotics. The present study was designed to investigate the hypnotic effect of acupuncture stimulation at HT7 on caffeine-induced sleep disorders and locomotor activity in rats. We also evaluated neuronal activity changes in the arousal region of the basal forebrain. METHODS: Rats received intraperitoneal injections of caffeine, and then electroencephalogram power spectrum analysis and locomotor activity measurements were performed. Stimulation at HT7 was performed using a mechanical acupuncture instrument (MAI) before caffeine injection, and its effects on caffeine-induced changes in sleep architecture, locomotor activity and c-Fos expression were examined. RESULTS: Caffeine injection (7.5 mg/kg) produced a significant decrease in slow-wave sleep and an increase in wake time compared with saline injection. Caffeine injection also increased locomotor activity and c-Fos expression in the medial septum-vertical limb of the diagonal band of Broca (MS-VDB), one of the arousal regions of the basal forebrain. Stimulation at HT7 with the MAI alleviated the caffeine-induced sleep disturbance and the increase in locomotor activity. In addition, MAI treatment at HT7, compared with treatment at a location not corresponding to any traditional acupuncture point, reduced the caffeine-induced increase in c-Fos expression. CONCLUSION: These results indicate that the hypnotic effect of HT7 acupuncture stimulation on caffeine-induced insomnia was associated with suppression of neuronal activity in the basal forebrain.

Preoperative Cognitive Impairment as a Predictor of Postoperative Outcomes in Elderly Patients Undergoing Spinal Surgery for Degenerative Spinal Disease.

Cognitive status has been reported to affect the peri-operative and post-operative outcomes of certain surgical procedures. This prospective study investigated the effect of preoperative cognitive impairment on the postoperative course of elderly patients (n = 122, >65 years), following spine surgery for degenerative spinal disease. Data on demographic characteristics, medical history, and blood analysis results were collected. Preoperative cognition was assessed using the mini-mental state examination, and patients were divided into three groups: normal cognition, mild cognitive impairment, and moderate-to-severe cognitive impairment. Discharge destinations (p = 0.014) and postoperative cardiopulmonary complications (p = 0.037) significantly differed based on the cognitive status. Operation time (p = 0.049), white blood cell count (p = 0.022), platelet count (p = 0.013), the mini-mental state examination score (p = 0.033), and the Beck Depression Inventory score (p = 0.041) were significantly associated with the length of hospital stay. Our investigation demonstrated that improved understanding of preoperative cognitive status may be helpful in surgical decision-making and postoperative care of elderly patients with degenerative spinal disease.

Treatment of electrical wrist stimulation reduces chemotherapy-induced neuropathy and ultrasound vocalization via modulation of spinal NR2B phosphorylation.

Docetaxel, a chemotherapeutic agent used to treat breast cancer, produces a robust painful neuropathy that is aggravated by mechanical and thermal stimuli. This study was undertaken to investigate the analgesic effects of electrical stimulation on docetaxel-induced neuropathic pain in mice and to identify associated changes in ultrasound vocalizations. Peripheral neuropathy was induced with intraperitoneally injected docetaxel (5 mg/kg) on 3 times every 2 days in male ICR mice. Electrical wrist stimulation was administered and pain behavior signs were evaluated by von Frey filaments and thermal stimulation on the hind paw. Ultrasound vocalizations were measured using ultrasound microphones, after electrical stimulation. After mice developed docetaxel-induced neuropathic pain behavior, an electrical stimulation temporarily attenuated mechanical allodynia and thermal hyperalgesia. In formalin and NMDA test, pain-induced mice showed increases in 10-30 kHz ultrasound vocalizations, but not in 30-50 and 50-80 kHz vocalizations. Treatment with docetaxel selectively increased 10-30 kHz ultrasound vocalizations, whereas electrical stimulation caused a meaningful decrease. Moreover, electrical stimulation suppressed the docetaxel-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn. These results of the analgesic effect of electrical stimulation in chemotherapy-induced neuropathy could potentially provide a new method to treat and manage peripheral neuropathy in patients with cancer.

A mechanical acupuncture instrument mitigates the endoplasmic reticulum stress and oxidative stress of ovariectomized rats.

BACKGROUND: Acupuncture has become a common complementary and alternative treatment approach for anxiety and depression. However, there is little research on the detailed mechanism of acupuncture therapy relieving depression. Previously, 17ß-estradiol (E2) was shown to prevent oxidative stress and endoplasmic reticulum (ER) stress in ovariectomized (OVX) rats. This study investigated whether stimulation of Sanyinjiao (SP6) using a mechanical acupuncture instrument can alleviate depression-like behavior caused by estrogen deficiency in OVX rats. Furthermore, we found that acupuncture reduced ER stress and oxidative stress-related proteins expression. METHODS: The OVX operation was performed on female SD rats that were separated into four groups: The E2 (2.5 µg/kg, i.p.) injection group (OVX + E2), the OVX group (OVX), and the OVX with acupuncture stimulation group (OVX + SP6). Non-acupoint stimulation group (OVX + NonAcu). The acupuncture point stimulation began three weeks after surgery. The depressive behavior was analyzed by the forced swim test and open field test. The 8-OHDG, BiP, Sigma receptor 1, pJNK, PDI, Ero1-Iα and Calnexin protein levels were evaluated by immunoreactivity in the amygdala. RESULTS: Acupuncture stimulation reduced depressive behavior and altered depression-related proteins. Stimulation of SP6 decreased the immobility time of the FST and altered the ER stress and oxidative stress marker proteins, such as 8-OHDG, BiP, pJNK, PDI, Ero1-Ia and Calnexin. CONCLUSION: Our results indicated that acupuncture at SP6 showed a significant antidepressant-like effect on an OVX-induced depression rat model by mitigation of ER stress and oxidative stress in amygdala.

The risk factors associated with delirium after lumbar spine surgery in elderly patients.

BACKGROUND: To prospectively explore the incidence and risk factors for postoperative delirium in elderly patients following lumbar spine surgery. METHODS: This prospective study enrolled 148 consecutive patients over the age of 65 who were scheduled to undergo spine surgery. Patients were screened for delirium using the short Confusion Assessment Method (CAM) postoperatively. Patient demographics and relevant medical information were collected. Logistic regression analysis was used to identify the risk factors associated with postoperative delirium. RESULTS: Eighty-three patients (56.1%) who underwent lumbar spine surgery (not coexisting with cervical or thoracic spine surgery) were enrolled in our study. Post-operative delirium was noted in 14.5% of patients over 65 years old. The presence of preoperative Parkinsonism was significantly higher in the delirium group (41.7% vs. 8.5%, P=0.002), as was a higher preoperative C-reactive protein (CRP) (7.0±15.2 vs. 1.3±2.3 mg/L, P=0.017) when compared with the non-delirium group. Of the risk factors, male sex [odds ratio (OR) =0.10, 95% confidence interval (CI): 0.01-0.66, P=0.017], Parkinsonism (OR =5.83, 95% CI: 1.03-32.89, P=0.046), and lower baseline MMSE score (OR =0.71, 95% CI: 0.52-0.97, P=0.032) were independently associated with postoperative delirium in elderly patients undergoing lumbar spine surgery. CONCLUSIONS: Post-operative delirium occurred in 14.5% of elderly patients who underwent lumbar spine surgery. Male sex, Parkinsonism, and lower baseline MMSE score were identified as independent risk factors for postoperative delirium in elderly patients following lumbar surgery.

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.

Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: Involvement of astrocyte sigma-1 receptors.

While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3ß-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3ß-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by 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.

Bee venom stimulation of a lung meridian acupoint reduces inflammation in carrageenan-induced pleurisy: an alternative therapeutic approach for respiratory inflammation.

Respiratory inflammation is a frequent and fatal pathologic state encountered in veterinary medicine. Although diluted bee venom (dBV) has potent anti-inflammatory effects, the clinical use of dBV is limited to several chronic inflammatory diseases. The present study was designed to propose an acupoint dBV treatment as a novel therapeutic strategy for respiratory inflammatory disease. Experimental pleurisy was induced by injection of carrageenan into the left pleural space in mouse. The dBV was injected into a specific lung meridian acupoint (LU-5) or into an arbitrary non-acupoint located near the midline of the back in mouse. The inflammatory responses were evaluated by analyzing inflammatory indicators in pleural exudate. The dBV injection into the LU-5 acupoint significantly suppressed the carrageenan-induced increase of pleural exudate volume, leukocyte accumulation, and myeloperoxidase activity. Moreover, dBV acupoint treatment effectively inhibited the production of interleukin 1 beta, but not tumor necrosis factor alpha in the pleural exudate. On the other hand, dBV treatment at non-acupoint did not inhibit the inflammatory responses in carrageenan-induced pleurisy. The present results demonstrate that dBV stimulation in the LU-5 lung meridian acupoint can produce significant anti-inflammatory effects on carrageenan-induced pleurisy suggesting that dBV acupuncture may be a promising alternative medicine therapy for respiratory inflammatory diseases.

Parkinson's disease-related non-motor features as risk factors for post-operative delirium in spinal surgery.

BACKGROUND: The clinical features of postoperative delirium are similar to the core features of alpha synuclein-related cognitive disorders, such as Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Therefore, we hypothesized that the non-motor symptoms (NMSs) in Parkinson's disease (PD), which precede the cardinal motor features of PD, are likely to be risk factors for developing postoperative delirium. We investigated the association between PD-related NMSs and postoperative delirium in old people undergoing elective spinal surgery. METHODS: This study was a prospective study. Participants were aged 65 years and older and scheduled to undergo elective spinal surgery. During the enrollment period, 338 individuals were screened, 104 participants were included in the analysis. We assessed eight easily-assessed and representative PD-related NMSs 1 day before the scheduled surgery using tests or questionnaires for each symptom. The presence of delirium was determined by using the short version of the Confusion Assessment Method (CAM). RESULTS: Fifteen (14.4%) of the 104 participants (age, 71.7 ± 4.7 years; men, 34.6%) met the CAM criteria for post-operative delirium. Multivariate logistic analysis showed that decreased olfactory function (odds ratio [OR] 0.63, 95% CI 0.44-0.91) and exhibiting rapid eye movement sleep behavior disorder (RBD, OR 1.45, 95% CI 1.09-1.93) were significantly independent predictors of postoperative delirium. CONCLUSIONS: Our study shows that hyposmia and RBD are significantly independent risk factors for postoperative delirium in general elderly population. Considering that NMSs may represent burden of alpha synuclein deposit, we postulate that an underlying alpha synucleinopathy may correlates with postoperative delirium. SIGNIFICANCE: This study gives a novel insight for the risk factor of postoperative delirium.

An estradiol-independent BDNF-NPY cascade is involved in the antidepressant effect of mechanical acupuncture instruments in ovariectomized rats.

Menopause-related depression devastates women's quality of life after middle age. Previous research has shown that estrogen hormone therapy has serious adverse effects; thus, complementary and integrative therapies have been considered clinically. The present study investigates whether stimulation of an acupoint using a mechanical acupuncture instrument (MAI) can mitigate depression-like behavior caused by estrogen deficiency in ovariectomized (OVX) rats. The animals were divided into Sham OVX, OVX, OVX + Sameumgyo (SP6) and OVX + NonAcu (non-acupuncture point) groups. MAI stimulation significantly increased the total distance traveled in the open-field test and the number of open-arm entries in the elevated plus maze and decreased the duration of immobility in the forced swim test. In addition to this decrease in depression-like behavior, brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) release increased in the hippocampus in response to MAI treatment, but estradiol levels did not recover. Furthermore, microinjection of the BDNF receptor antagonist ANA-12 (0.1 pmol/1 µl) into the hippocampus before MAI stimulation significantly suppressed the recovery of NPY levels. Taken together, these findings indicate that MAI stimulation at SP6 facilitates an estradiol-independent BDNF-NPY cascade, which may contribute to its antidepressant effects in OVX rats, an animal model of menopausal disorders.

Spinal D-Serine Increases PKC-Dependent GluN1 Phosphorylation Contributing to the Sigma-1 Receptor-Induced Development of Mechanical Allodynia in a Mouse Model of Neuropathic Pain.

We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1-phenylcyclohexane carboxylate. Exogenous D-serine increased protein kinase C (PKC)-dependent (Ser896) pGluN1 expression and facilitated NMDA-induced nociception, which was attenuated by preteatment with the PKC inhibitor, chelerythrine. In CCI mice, administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt or D-amino acid oxidase on postoperative days 0 to 3 suppressed CCI-induced mechanical allodynia (MA) and pGluN1 expression on day 3 after CCI surgery. Intrathecal administration of D-serine restored MA as well as the GluN1 phosphorylation on day 3 after surgery that was suppressed by the Sig-1R antagonist, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide or the astrocyte inhibitor, fluorocitrate. In contrast, D-serine had no effect on CCI-induced thermal hyperalgesia or GluN1 expression. These results indicate that spinal D-serine: 1) mediates the facilitative effect of Sig-1R on NMDA-induced nociception, 2) modulates PKC-dependent pGluN1 expression, and 3) ultimately contributes to the induction of MA after peripheral nerve injury. PERSPECTIVE: This report shows that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain and that this process is modulated by spinal Sig-1Rs. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury-induced neuropathy.

Antinociceptive Profile of Levo-tetrahydropalmatine in Acute and Chronic Pain Mice Models: Role of spinal sigma-1 receptor.

We have recently reported that repeated systemic treatments of extract from Corydalis yanhusuo alleviate neuropathic pain and levo-tetrahydropalmatine (l-THP) is one of active components from Corydalis. We designed this study to investigate antinociceptive effect of l-THP in acute and chronic pain models and related mechanism within the spinal cord. We found that intraperitoneal pretreatment with l-THP significantly inhibited the second phase of formalin-induced pain behavior. In addition, intrathecal as well as intraperitoneal pretreatment with l-THP reduced the mechanical allodynia (MA) induced by direct activation of sigma-1 receptor (Sig-1). In chronic constriction injury mice, these treatments remarkably suppressed the increase in MA and spinal phosphorylation of the NMDA receptor NR1 subunit expression on day 7 after surgery. Intrathecal treatment with l-THP combined with the Sig-1R antagonist, BD1047 synergistically blocked MA suggesting that l-THP modulates spinal Sig-1R activation. CatWalk gait analysis also supported that antinociceptive effect of l-THP as demonstrated by restoration of percentages of print area and single stance. Meanwhile, intrathecal pretreatment with naloxone, non-selective opioid receptor antagonist, did not affect the effect of l-THP. In conclusion, these results demonstrate that l-THP possesses antinociceptive effects through spinal Sig-1R mechanism and may be a useful analgesic in the management of neuropathic pain.

Peripheral neurosteroids enhance P2X receptor-induced mechanical allodynia via a sigma-1 receptor-mediated mechanism.

The role of peripheral neurosteroids and their related mechanisms on nociception have not been thoroughly investigated. Based on emerging evidence in the literature indicating that neurosteroids and their main target receptors, i.e., sigma-1, GABAA and NMDA, affect P2X-induced changes in neuronal activity, this study was designed to investigate the effect of peripherally injected dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulfate (PREGS) on P2X receptor-mediated mechanical allodynia in rats. Intraplantar injection of either neurosteroids alone did not produced any detectable changes in paw withdrawal frequency to the innocuous mechanical stimulation in naïve rats. However, When DHEAS or PREGS were co-injected with a sub-effective dose of αßmeATP, mechanical allodynia was developed and this was dose dependently blocked by pre-injection of the P2X antagonist, TNP-ATP. These results demonstrates that DHEAS and PREGS potentiate the activity of P2X receptors which results in the enhancement of αßmeATP-induced mechanical allodynia. In order to investigate the potential role of peripheral sigma-1, GABAA and NMDA receptors in this facilitatory action, we pretreated animals with BD-1047 (a sigma-1 antagonist), muscimol (a GABAA agonist) or MK-801 (a NMDA antagonist) prior to DHEAS or PREGS+αßmeATP injection. Only BD-1047 effectively prevented the facilitatory effects induced by neurosteroids on αßmeATP-induced mechanical allodynia. Collectively, we have shown that peripheral neurosteroids potentiate P2X-induced mechanical allodynia and that this action is mediated by sigma-1, but not by GABAA nor NMDA, receptors.

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.

Analgesic effect of electroacupuncture on paclitaxel-induced neuropathic pain via spinal opioidergic and adrenergic mechanisms in mice.

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.