Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn.

BACKGROUND: The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury. METHODS: The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro-adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated. RESULTS: Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1ß expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice. CONCLUSION: These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Two-Dimensional Micro-/Nanoradian Angle Generator with High Resolution and Repeatability Based on Piezo-Driven Double-Axis Flexure Hinge and Three Capacitive Sensors.

This study presents a two-dimensional micro-/nanoradian angle generator (2D-MNAG) that achieves high angular displacement resolution and repeatability using a piezo-driven flexure hinge for two-dimensional deflections and three capacitive sensors for output angle monitoring and feedback control. The principal error of the capacitive sensor for precision microangle measurement is analyzed and compensated for; so as to achieve a high angle output resolution of 10 nrad (0.002 arcsec) and positioning repeatability of 120 nrad (0.024 arcsec) over a large angular range of ±4363 µrad (±900 arcsec) for the 2D-MNAG. The impact of each error component, together with the synthetic error of the 2D-MNAG after principal error compensation are determined using Monte Carlo simulation for further improvement of the 2D-MNAG.

PSD-95 Protein: A Promising Therapeutic Target in Chronic Pain.

Chronic pain, as a social public health problem, has a serious impact on the quality of patients' life. Currently, the main drugs used to treat chronic pain are opioids, antipyretic, and nonsteroidal anti-inflammatory drugs (NSAIDs). But the obvious side effects limit their use, so it is urgent to find new therapeutic targets. Postsynaptic density (PSD)-95 protein plays an important role in the occurrence and development of chronic pain. The over-expression of the PSD-95 protein and its interaction with other proteins are closely related to the chronic pain. Besides, the PSD-95-related drugs that inhibit the expression of PSD-95 as well as the interaction with other protein have been proved to treat chronic pain significantly. In conclusion, although more deep studies are needed in the future, these studies indicate that PSD-95 and the related proteins, such as NMDA receptor (NMDAR) subunit 2B (GluN2B), AMPA receptor (AMPAR), calmodulin-dependent protein kinase II (CaMKII), 5-hydroxytryptamine 2A receptor (5-HT2AR), and neuronal nitric oxide synthase (nNOS), are the promising therapeutic targets for chronic pain.

Intradermal miR-16-5p targets Akt3 and reduces RTX-induced postherpetic neuralgia-mimic pain in mice.

The molecular mechanisms of refractory pain in postherpetic neuralgia (PHN) patients are not fully understood. PHN may be related to skin abnormality after herpes zoster induced skin lesions. We previously reported 317 differentially expressed microRNAs (miRNAs) in PHN skin compared with the contralateral normal mirror skin. In this study, 19 differential miRNAs were selected and the expression was validated in other 12 PHN patients. The expression levels of miR-16-5p, miR-20a-5p, miR-505-5p, miR-3664-3p, miR-4714-3p and let-7a-5p are lower in PHN skin, which is the same as those in microarray experiment. To evaluate the effects of cutaneous miRNA on PHN, the expression of candidate miRNAs is further observed in resiniferatoxin (RTX) induced PHN-mimic mice model. In the plantar skin of RTX mice, miR-16-5p and let-7a-5p are downregulated, with the same expression trend of PHN patients. In addition, intraplantar injection of agomir-16-5p reduced mechanical hyperalgesia, and improved thermal hypoalgesia in RTX mice. Furthermore, agomir-16-5p down-regulated the expression levels of Akt3, which is the target gene of agomir-16-5p. These results suggest that intraplantar miR-16-5p may alleviate RTX induced PHN-mimic pain by inhibiting the expression of Akt3 in the skin.

Stellate ganglion intervention for chronic pain: A review.

Stellate ganglion (SG) intervention is currently widely being studied in many kinds of chronic pain. As one of the convenient ways to treat the sympathetic nervous system, the indications for stellate ganglion intervention (SGI) include complex regional pain syndrome, postherpetic neuralgia, cancer pain of different origins, orofacial pain, and so forth. SGI refers to the reversible or irreversible blocking of the cervical sympathetic trunk, cervical sympathetic ganglion, and their innervation range through noninvasive or minimally invasive treatment. Current treatment options include stellate ganglion block (SGB), SG pulsed radiofrequency, continuous radiofrequency treatment, and noninvasive SGB. In particular, SGB continues to be one of the most studied methods in chronic pain management. However, a single SGB usually provides only short-term effects; repeated SGB may result in complications such as hoarseness, light-headedness, and vessel or nerve injury. Meanwhile, the mechanism of SGI is still unclear. This review discusses the research progress of SGI methods, effectiveness, complications, and possible mechanisms in the management of chronic pain.

Identification of the Genome-wide Expression Patterns of Long Non-coding RNAs and mRNAs in Mice with Streptozotocin-induced Diabetic Neuropathic Pain.

Diabetic neuropathic pain (DNP), an early symptom of diabetic neuropathy, involves complex mechanisms. Long non-coding RNA (lncRNA) dysregulation contributes to the pathogenesis of various human diseases. Here, we investigated the genome-wide expression patterns of lncRNAs and genes in the spinal dorsal horn of mice with streptozotocin-induced DNP. Microarray analysis identified 1481 differentially expressed (DE) lncRNAs and 1096 DE mRNAs in DNP mice. Functional analysis showed that transforming growth factor-beta receptor binding was the most significant molecular function and retrograde endocannabinoid signaling was the most significant pathway of DE mRNAs. Calcium ion transport was the second most significant biological process of DE lncRNAs. Finally, we found 289 neighboring and 57 overlapping lncRNA-mRNA pairs, including ENSMUST00000150952-Mbp and AK081017-Usp15, which may be involved in DNP pathogenesis. Microarray data were validated through quantitative PCR of selected lncRNAs and mRNAs. These results suggest that aberrant expression of lncRNAs may contribute to the pathogenesis of DNP.

Intravenous infusion of lidocaine enhances the efficacy of conventional treatment of postherpetic neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is one kind of severe neuropathic pain which currently cannot be effectively cured. Recent researches suggest that intravenous infusion of lidocaine has a therapeutic effect on neuropathic pain such as PHN; however, the optimal dose and frequency of lidocaine infusion and the effectiveness and safety of this treatment in PHN patients still needs more clinical research. The aim of this study was to evaluate the therapeutic effects of daily intravenous lidocaine infusion on the outcome of the routine treatment of PHN. METHODS: Sixty PHN patients were randomly divided into two groups: 1) control group (Control), treated with conventional therapies, such as antiepileptic pills, analgesics, neurotrophic medicines, paravertebral spinal nerve block and physiotherapy; 2) lidocaine group (Lido) received daily infusion of lidocaine (4 mg/kg) besides the conventional treatments. If the pain is not controlled sufficiently, additional tramadol is given and the average consumption of tramadol is calculated. Pain intensity was assessed before and after each infusion, and the number of breakthrough pain in the last 24 hrs were recorded. The incidence of adverse reactions related to intravenous lidocaine infusion was recorded. RESULTS: For five consecutive days, numeric rating scale (NRS) scores were significantly decreased after 1 hr of intravenous infusion of lidocaine. Compared with Control, the NRS scores and the frequency of breakthrough pain in the Lido were significantly reduced. In addition, the extra tramadol consumption in the Lido was significantly lower than that in the Control, and the average hospital stay of patients in Lido was decreased. However, anxiety and depression scores showed no difference between Lido and Control. CONCLUSION: Daily intravenous lidocaine (4 mg/kg for 5 days) enhanced the outcome of PHN treatment, reduced the amount of analgesic medicine and shortened the length of hospital stay with no obvious adverse side effects.

Improved accuracy of capacitive sensor-based micro-angle measurement with angular-to-linear displacement conversion.

This paper presents a capacitive sensor-based micro-angle measurement (CSMAM) method that uses an angular-to-linear displacement conversion to achieve high accuracy. The principal and secondary error components of CSMAMs are modeled and analyzed to reveal their impacts on the measurement accuracy. The theoretical accuracies of six types of commonly used CSMAMs are analyzed to determine the optimum configuration of capacitive sensors for 1D and 2D micro-angle measurements. An angular-to-linear displacement conversion method with a linear motional stage and a hemisphere decoupler is used to eliminate the principal error of CSMAM. Experimental results indicate that the optimized CSMAM can achieve accuracies of 0.157 arc sec and 0.052 arc sec in the ranges of ±900 arc sec and ±300 arc sec, respectively, in the case that the effective length of the rotation arm is 100 mm and the linear displacement measurement accuracy of the capacitive sensor is 2 nm. These results can be used as a reference to further improve CSMAM designs and achieve high accuracy in a large measurement range, for use in a wide range of precision engineering applications including angle metrology, micro- and nano-radian angle generators, beam steering mechanisms, and high-performance precision stages.

Note: Autocollimation with ultra-high resolution and stability using telephoto objective together with optical enlargement and beam drift compensation.

An autocollimation (AC) setup with ultra-high resolution and stability for micro-angle measurement is presented. The telephoto objective, which is characterized in long focal length at a compact structure size, and the optical enlargement unit, which can magnify the image displacement to improve its measurement resolution and accuracy, are used to obtain an ultra-high measurement resolution of the AC. The common-path beam drift compensation is used to suppress the drift of measurement results, which is evident in the high-resolution AC, thus to obtain a high measurement stability. Experimental results indicate that an effective resolution of better than 0.0005 arc sec (2.42 nrad) over a measurement range of ±30 arc sec and a 2-h stability of 0.0061 arc sec (29.57 nrad) can be achieved.