Qipengyuania benthica sp. nov. and Qipengyuania profundimaris sp. nov., two novel Erythrobacteraceae members isolated from deep-sea environments.

Two Gram-stain-negative, rod-shaped and non-motile strains, designated as DY56-A-20T and G39T, were isolated from deep-sea sediment of the Pacific Ocean and deep-sea seawater of the Indian Ocean, respectively. Strain DY56-A-20T was found to grow at 15-37 °C (optimum, 28 °C), at pH 6.0-10.0 (optimum, pH 6.5-7.0) and in 0.5-6.0 % (w/v) NaCl (optimum, 1.0-2.0 %), while strain G39T was found to grow at 10-42 °C (optimum, 35-40 °C), at pH 5.5-10.0 (optimum, pH 6.5-7.0) and in 0-12.0 % (w/v) NaCl (optimum, 1.0-2.0 %). The 16S rRNA gene sequence identity analysis indicated that strain DY56-A-20T had the highest sequence identity with Qipengyuania marisflavi KEM-5T (97.6 %), while strain G39T displayed the highest sequence identity with Qipengyuania citrea H150T (98.8 %). The phylogenomic reconstruction indicated that both strains formed independent clades within the genus Qipengyuania. The digital DNA-DNA hybridization and average nucleotide identity values between strains DY56-A-20T/G39T and Qipengyuania/Erythrobacter type strains were 17.8-23.8 % and 70.7-81.1 %, respectively, which are below species delineation thresholds. The genome DNA G+C contents were 65.0 and 63.5 mol% for strains DY56-A-20T and G39T, respectively. The predominant cellular fatty acids (>10 %) of strain DY56-A-20T were C17 : 1 ω6c, summed feature 8 and summed feature 3, and the major cellular fatty acids of strain G39T were C17 : 1 ω6c and summed feature 8. The major polar lipids in both strains were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid and an unidentified polar lipid. The only respiratory quinone present in both strains was ubiquinone-10. Based on those genotypic and phenotypic results, the two strains represent two novel species belonging to the genus Qipengyuania, for which the names Qipengyuania benthica sp. nov. and Qipengyuania profundimaris sp. nov. are proposed. The type strain of Q. benthica is DY56-A-20T (=MCCC M27941T=KCTC 92309T), and the type strain of Q. profundimaris is G39T (=MCCC M30353T=KCTC 8208T).

[Neurotrophin-associated mechanisms of delayed-onset muscle soreness: research progress and perspective].

Delayed-onset muscle soreness (DOMS) is a common phenomenon that occurs following a sudden increase in exercise intensity or unfamiliar exercise, significantly affecting athletic performance and efficacy in athletes and fitness individuals. DOMS is characterized by allodynia and hyperalgesia, and their mechanisms remain unclear. Recent studies have reported that neurotrophic factors, such as nerve growth factor (NGF) and glial cell derived neurotrophic factor (GDNF), are involved in the development and maintenance of DOMS. This article provides a review of the research progress on the signaling pathways related to the involvement of NGF and GDNF in DOMS, hoping to provide novel insights into the mechanisms underlying allodynia and hyperalgesia in DOMS, as well as potential targeted treatment.

Application of intraoperative evoked potential monitoring in patients with anterior cerebral artery aneurysms.

OBJECTIVES: The location of the aneurysm can affect the relationship between changes in intraoperative neurophysiological monitoring indicators and postoperative outcomes. The current study aimed to evaluate the application value of motor evoked potential and somatosensory evoked potential monitoring in anterior cerebral artery aneurysm surgery. METHODS: The data of 219 patients with anterior cerebral artery aneurysms treated via surgical clipping were retrospectively reviewed. The correlation of motor/somatosensory evoked potential monitoring with postoperative motor dysfunction was assessed using false positive rate, false negative rate, sensitivity, and specificity. Binary multivariate logistic regression analysis was applied to identify potential predictors for postoperative motor dysfunction. RESULTS: Motor evoked potential monitoring showed satisfactory effectiveness in predicting postoperative motor dysfunction (Sensitivity, 60.00%; Specificity, 85.43%; False positive rate, 14.57%; False negative rate, 40%). While somatosensory evoked potential did not (Sensitivity, 15.00%; Specificity, 96.98%; False positive rate, 3.02%; False negative rate, 85%). Abnormal motor evoked potential was identified as the only independent predictor for both short-term (odds ratio, 8.893; 95% confidence interval, 2.749-28.773; p<0.001) and long-term postoperative motor dysfunction (odds ratio, 7.877; 95% confidence interval, 2.144-28.945; p=0.002). CONCLUSIONS: During intraoperative neurophysiological monitoring for patients with anterior cerebral artery aneurysms, paying more attention to motor evoked potential changes was a reasonable choice. And somatosensory evoked potential monitoring can serve as an auxiliary reference.

[Progress on the mechanism and treatment of Parkinson's disease-related pathological pain].

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms, including bradykinesia, resting tremor, and progressive rigidity. More recently, non-motor symptoms of PD, such as pain, depression and anxiety, and autonomic dysfunction, have attracted increasing attention from scientists and clinicians. As one of non-motor symptoms, pain has high prevalence and early onset feature. Because the mechanism of PD-related pathological pain is unclear, the clinical therapy for treating PD-related pathological pain is very limited, with a focus on relieving the symptoms. This paper reviewed the clinical features, pathogenesis, and therapeutic strategies of PD-related pathological pain and discussed the mechanism of the chronicity of PD-related pathological pain, hoping to provide useful data for the study of drugs and clinical intervention for PD-related pathological pain.

Sphingomicrobium nitratireducens sp. nov., isolated from a tidal flat in Guangxi.

An aerobic, yellow-pigmented and Gram-stain-negative strain, designated as O-35 T, was isolated from a tidal flat sediment collected in Dangjiang Town, the southern China. Colonies of strain O-35 T were circular with 0.5-1.0 mm in diameter, convex and smooth. Cells of strain O-35 T were coccoid-shaped, non-spore forming, non-motile and the strain could reduce nitrate. Growth of strain O-35 T was observed at 15-40 °C (optimum 30 °C), at pH 6.0-9.5 (optimum 7.5-8.0) and in 0.5-5.0% NaCl (optimum 2%, w/v). Strain O-35 T showed 16S rRNA gene sequence identities of 97.3-97.5% with Sphingomicrobium lutaoense CC-TBT-3 T and Sphingomicrobium aestuariivivum AH-M8T, higher than the rest of Sphingomicrobium type strains. Phylogenetic trees based on the 16S rRNA gene and the core-genome sequences demonstrated that strain O-35 T was affiliated within the genus Sphingomicrobium. Overall genome relatedness index calculations revealed that strain O-35 T had < 75.8% of average nucleotide identity and < 19.2% of digital DNA-DNA hybridization values with Sphingomicrobium type strains. The sole isoprenoid quinone was ubiquinone-10. The major fatty acids (> 10%) were summed feature 8, summed feature 3, C16:0 and C18:1 2-OH. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, sphingoglycolipid, two unidentified glycolipids, one unidentified lipid and one unidentified phospholipid. On the basis of the phenotypic, chemotaxonomic and genomic properties, strain O-35 T represents a novel species in the genus Sphingomicrobium, for which the name Sphingomicrobium nitratireducens sp. nov. is proposed. The type strain is O-35 T (= KCTC 92308 T = MCCC 1K07589T).

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Efficacy of evoked potential monitoring for predicting postoperative motor status in internal carotid artery aneurysm surgeries.

This study aimed to investigate the efficacy of intraoperative motor evoked potential (MEP) and somatosensory evoked potential (SSEP) monitoring for predicting postoperative motor deficits (PMDs) in patients with internal carotid artery (ICA) aneurysms. The data for 138 patients with ICA aneurysms who underwent surgical clipping as well as their intraoperative neuromonitoring data were retrospectively reviewed. The efficacy of MEP/SSEP changes for predicting PMDs was assessed using binary logistic regression analysis. Subsequently, receiver operating characteristic curve analysis was used to obtain a supplementary critical value of the MEP/SSEP deterioration duration. The sensitivity and specificity of MEP changes for predicting PMDs were 0.824 and 0.843, respectively. For SSEP changes, the sensitivity and specificity were 0.529 and 0.959, respectively. MEP and SSEP changes were identified as independent predictors for short-term (p = 0.002 and 0.011, respectively) and long-term PMDs (p = 0.040 and 0.006, respectively). The supplementary critical value for MEP deterioration duration for predicting PMDs was 14 min (p = 0.007, AUC = 0.805). For SSEP, the value was 14.5 min (p = 0.042, AUC = 0.875). The MEP/SSEP changes adjusted by those optimal values were also identified as independent predictors for short-term (p < 0.001 and p = 0.005, respectively) and long-term PMDs (p = 0.019 and 0.003, respectively). Intraoperative MEP and SSEP deterioration durations are effective in predicting PMDs in patients with ICA aneurysms.

Efficient expression of heterologous genes by the introduction of the endogenous glyceraldehyde-3-phosphate dehydrogenase gene intron 1 in Ganoderma lucidum.

BACKGROUND: Ganoderma lucidum, a well-known medicinal mushroom, has received wide attention as a promising cell factory for producing bioactive compounds. However, efficient expression of heterologous genes remains a major challenge in Ganoderma, hindering metabolic regulation research and molecular breeding of this species. RESULTS: We show that the presence of glyceraldehyde-3-phosphate dehydrogenase gene (gpd) intron 1 at the 5' end of, the 3' end of, or within the heterologous phosphinothricin-resistant gene (bar) is efficient for its expression in G. lucidum. The enhanced expression of bar is exhibited by the higher accumulation of mRNA and increased amounts of protein. Moreover, the insertion of the gpd intron 1 in the ß-glucuronidase gene (gus) elevates its mRNA accumulation and enzyme activity, which facilitates the use of this reporter gene in Ganoderma. CONCLUSIONS: This study has demonstrated the importance of the introduction of gpd intron 1 for the efficient expression of bar and gus in G. lucidum. The presence of the gpd intron 1 in heterologous genes increases levels of mRNA accumulation and protein expression in basidiomycete Ganoderma. The developed method may be utilized in upregulating the expression of other heterologous genes in Ganoderma.

U-Shaped Relationship Between Cardiovascular Mortality and Serum Uric Acid May Be Attributed to Stroke- and Heart-Specific Mortality, Respectively, Among Hypertensive Patients: A Nationally Representative Cohort Study.

BACKGROUND Serum uric acid (UA) is involved in the development of hypertension. However, its impact on mortality in hypertension remains unclear. We aimed to assess the association of cardiovascular and all-cause mortality with UA in a hypertensive population. MATERIAL AND METHODS This study included 15 583 hypertensive patients from the NHANES study during 1999-2014. Weighted Cox regression analyses and cubic spline fitting were used to assess the relationship between UA and mortality risk. RESULTS Over a median follow-up of 7.4 years (116 351 person-years), a total of 3291 deaths occurred. Mortality was examined according to 5 predefined UA levels: £3.5, 3.5-5, 5-6, 6-7.5, and >7.5 mg/dL. In multivariable analysis with 5-6 mg/dL as a reference, the hazard ratios (95% confidence interval) of total mortality across the 5 groups were 1.40 (1.05-1.88), 1.08 (0.95-1.21), 1.00 (reference), 1.14 (1.02-1.29), and 1.74 (1.50-2.02), respectively. According to a restricted cubic spline, we noted a U-shaped relationship between UA and total mortality. The U-shaped relationship between UA and cardiovascular mortality remained in both females and males. The increased cardiovascular mortality in the lowest and highest UA groups was attributed to stroke and heart-specific mortality, respectively. However, serum UA was not significantly associated with cancer mortality. CONCLUSIONS Our findings showed a U-shaped relationship between serum UA levels and total and cardiovascular mortality in patients with hypertension. Furthermore, low UA was associated with stroke mortality, while higher UA was associated with heart-related mortality. Further research is needed to identify the potential mechanisms of UA in hypertension.

Prediction of postoperative motor deficits using intraoperative motor-evoked potentials in middle cerebral artery aneurysm.

To explore the relationship between postoperative motor deficits and the duration of reduced motor-evoked potentials (MEPs) in patients with middle cerebral artery (MCA) aneurysm. This study included 285 cases of MCA aneurysm treated with clipping surgery with MEP monitoring. The effects of MEP changes on postoperative motor function were assessed, and the key time point for minimizing the incidence of postoperative motor dysfunction was found through receiver operating characteristic (ROC) curve analysis. Motor dysfunction was significantly associated with the occurrence of MEP changes, and patients with irreversible changes were more likely to suffer motor dysfunction than were those with reversible changes. The critical duration of MEP changes that minimized the risk of postoperative motor dysfunction was 8.5 min. This study revealed that MEP monitoring is an effective method for preventing ischemic brain injury during surgical treatment of MCA aneurysm and proposes a critical cutoff for the duration of MEP deterioration of 8.5 min for predicting postoperative motor dysfunction.

The Critical Role of Dopant Cations in Electrical Conductivity and Thermoelectric Performance of n-Doped Polymers.

The low n-doping efficiency of conjugated polymers with the molecular dopants limits their availability in electrical conductivity, thermoelectrics, and other electric applications. Recently, considerable efforts have focused on improving the ionization of dopants by modifying the structures of host polymers or n-dopants; however, the effect of ionized dopants on the electrical conductivity and thermoelectric performance of the polymers is still a puzzle. Herein, we try to reveal the role of molecular dopant cations on carrier transport through the systematic comparison of two n-dopants, TAM and N-DMBI-H. These two n-dopants exhibit various doping features with the polymer due to their different chemical structure characteristics. For instance, while doping, TAM negligibly perturbs the polymer backbone conformation and microstructural ordering; then after ionization, TAM cations possess weak π-backbone affinity but strong intrinsic affinity with side chains, which enables the doped system to screen the Coulomb potential spatially. Such doping features lead to high carrierization capabilities for TAM-doped polymers and further result in an excellent conductivity of up to 22 ± 2.5 S cm-1 and a power factor of over 80 µW m-1 K-2, which are significantly higher than the state of the art values of the common n-dopant N-DMBI-H. More importantly, this strategy has also proven to be widely applicable in other doped polymers. Our investigations indicate the vital role of dopant counterions in high electrical and thermoelectric performance polymers and also suggest that, without sacrificing Seebeck coefficients, high conductivities can be realized with precise regulation of the interaction between the cations and the host.

Tübingen hip flexion splints for developmental dysplasia of the hip in infants aged 0-6 months.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common disorder in infants. The present study aimed to evaluate the efficacy and safety of the Tübingen hip flexion splints in treating DDH in infants aged 0-6 months. METHODS: This is a retrospective study analyzing 259 hips in 195 infants with DDH of Graf type IIc or worse classifications treated between January 2015 and December 2017. Patients were followed up for at least 6 months. Avascular necrosis of the femoral head was diagnosed using plain radiographs at the last follow-up visit according to the Bucholz-Ogden classification. Successful treatment was defined as an improvement of the Graft classification to type I, or an improvement of the International Hip Dysplasia Institute classification to type I in patients aged > 6 months. RESULTS: Treatment was deemed successful in 128 patients (83.7%). Avascular necrosis occurred in 3 patients (3 hips). Univariate analysis showed that late treatment initiation, family history of DDH, Graf type IV and bilateral involvement were independent risk factors for treatment failure (p < 0.05). The receiver operating characteristic curve showed a cut-off value of 12 weeks for age at treatment initiation regarding successful treatment. Logistic regression analysis showed that gender, breech presentation, firstborn, swaddling, birth weight > 3.5 kg, oligohydramnios, foot deformity and torticollis did not affect the success rate of treatment (p > 0.05). CONCLUSIONS: The Tübingen splint showed good efficacy and safety in treating DDH in infants aged 0-6 months. Family history of DDH, Graf classification of type IV, bilateral involvement and treatment initiation after 12 weeks of age are risk factors of treatment failure. TRIAL REGISTRATION: N/A.

Rigid Coplanar Polymers for Stable n-Type Polymer Thermoelectrics.

Low n-doping efficiency and inferior stability restrict the thermoelectric performance of n-type conjugated polymers, making their performance lag far behind of their p-type counterparts. Reported here are two rigid coplanar poly(p-phenylene vinylene) (PPV) derivatives, LPPV-1 and LPPV-2, which show nearly torsion-free backbones. The fused electron-deficient rigid structures endow the derivatives with less conformational disorder and low-lying lowest unoccupied molecular orbital (LUMO) levels, down to -4.49 eV. After doping, two polymers exhibited high n-doping efficiency and significantly improved air stability. LPPV-1 exhibited a high conductivity of up to 1.1 S cm-1 and a power factor as high as 1.96 µW m-1 K-2 . Importantly, the power factor of the doped LPPV-1 thick film degraded only 2 % after 7 day exposure to air. This work demonstrates a new strategy for designing conjugated polymers, with planar backbones and low LUMO levels, towards high-performance and potentially air-stable n-type polymer thermoelectrics.

Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine.

KEY POINTS: Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood. We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo. Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation. Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days. This study provides insight into the organization of thalamic modulation in pre-emptive analgesia. ABSTRACT: We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 µg kg(-1)) and dexmedetomidine (Dex, 1-10 µg kg(-1); a highly selective α2-adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (α2-adrenoceptor antagonist) or WAY-100635 (5-HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia.

Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs.

To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD) in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3) was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat.

Polyampholyte Brushes Grafted on the Surface of a Spherical Cavity: Effect of the Charged Monomer Sequence, Grafting Density, and Chain Stiffness.

Molecular dynamics simulations are used to study the conformational behaviors of the flexible and semiflexible polyampholytes coated onto the internal surface of a spherical cavity. Dependences of the brush structure and the local conformation of grafted chains on the sequence of charged monomers, the grafting density, and the chain stiffness are addressed. In the range of parameters studied, it was found that a significant transition of the brush structure occurs due to the variation of the charged monomer sequence. As the number of repeat charged monomers increases, both the flexible and semiflexible polyampholyte brushes change to the collapsed conformation. The spherical concave geometry tends to exclude the conformation of chains perpendicular to the grafting surface for the semiflexible case. In addition, we find that most counterions are depleted in the polyampholyte brush due to the strong electrostatic correlation between the oppositely charged monomers.

Influence of intramuscular heat stimulation on modulation of nociception: complex role of central opioid receptors in descending facilitation and inhibition.

It has been reported that the threshold to activate 'silent' or inactive descending facilitation of nociception is lower than that of descending inhibition. Thus, the development of pain therapy to effectively drive descending inhibition alone, without the confounding influences of facilitation is a challenge. To address this issue we investigated the effects of intramuscular stimulation with a heating-needle on spinal nociception, assessed by measuring nociceptive paw withdrawal reflex in rats. Additionally, involvement of the thalamic 'nociceptive discriminators' (thalamic mediodorsal (MD) and ventromedial (VM) nuclei), and opioid-mediated mechanisms were further explored. Descending facilitation and inhibition were elicited by 46°C noxious heating-needle stimulation, and were regulated by thalamic MD and VM nuclei, respectively. In contrast, innocuous heating-needle stimulation at a temperature of 43°C elicited descending inhibition modulated by the thalamic VM nucleus alone. Microinjection of µ/δ/κ-opioid receptor antagonists ß-funaltrexamine hydrochloride/naltrindole/nor-binaltorphimine, into the VM nucleus attenuated the 46°C intramuscular heating-needle stimulation-evoked descending inhibition, whereas treatment of the MD nucleus with ß-funaltrexamine hydrochloride significantly decreased the descending facilitation. By contrast, descending inhibition evoked by 43°C heating-needle stimulation was only depressed by naltrindole, as opposed to µ- and κ-opioid receptor antagonists, which failed to influence descending inhibition. The present study reveals distinct roles of µ-opioid receptors in the function of thalamic MD and VM nuclei,which exert facilitatory and inhibitory actions on nociception. Furthermore, innocuous, but not noxious, intramuscular heating-needle stimulation targeting δ-opioid receptors is suggested to be a promising avenue for the effective inhibition of pain.

Periaqueductal grey cyclooxygenase-dependent facilitation of C-nociceptive drive and encoding in dorsal horn neurons in the rat.

The experience of pain is strongly affected by descending control systems originating in the brainstem ventrolateral periaqueductal grey (VL-PAG), which control the spinal processing of nociceptive information. A- and C-fibre nociceptors detect noxious stimulation, and have distinct and independent contributions to both the perception of pain quality (fast and slow pain, respectively) and the development of chronic pain. Evidence suggests a separation in the central processing of information arising from A- vs. C-nociceptors; for example, inhibition of the cyclooxygenase-1 (COX-1)-prostaglandin system within the VL-PAG alters spinal nociceptive reflexes evoked by C-nociceptor input in vivo via descending pathways, leaving A-nociceptor-evoked reflexes largely unaffected. As the spinal neuronal mechanisms underlying these different responses remain unknown, we determined the effect of inhibition of VL-PAG COX-1 on dorsal horn wide dynamic-range neurons evoked by C- vs. A-nociceptor activation. Inhibition of VL-PAG COX-1 in anaesthetised rats increased firing thresholds of lamina IV-V wide dynamic-range dorsal horn neurons in response to both A- and C-nociceptor stimulation. Importantly, wide dynamic-range dorsal horn neurons continued to faithfully encode A-nociceptive information, even after VL-PAG COX-1 inhibition, whereas the encoding of C-nociceptor information by wide dynamic-range spinal neurons was significantly disrupted. Dorsal horn neurons with stronger C-nociceptor input were affected by COX-1 inhibition to a greater extent than those with weak C-fibre input. These data show that the gain and contrast of C-nociceptive information processed in individual wide dynamic-range dorsal horn neurons is modulated by prostanergic descending control mechanisms in the VL-PAG.

Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity.

Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10µg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

Pathological pain: Non-motor manifestations in Parkinson disease and its treatment.

In addition to motor symptoms, non-motor manifestations of Parkinson's disease (PD), i.e. pain, depression, sleep disturbance, and autonomic disorders, have received increasing attention. As one of the non-motor symptoms, pain has a high prevalence and is considered an early pre-motor symptom in the development of PD. In relation to pathological pain and its management in PD, particularly in the early stages, it is hypothesized that the loss of dopaminergic neurons causes a functional deficit in supraspinal structures, leading to an imbalance in endogenous descending modulation. Deficits in dopaminergic-dependent pathways also affect non-dopaminergic neurotransmitter systems that contribute to the pathological processing of nociceptive input, the integration, and modulation of pain in PD. This review examines the onset and progression of pain in PD, with a particular focus on alterations in the central modulation of nociception. The discussion highlights the importance of abnormal endogenous descending facilitation and inhibition in PD pain, which may provide potential clues to a better understanding of the nature of pathological pain and its effective clinical management.