Electroacupuncture alleviates traumatic brain injury by inhibiting autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway in rats.

Autophagy, switched by the AMPK/mTOR signaling, has been revealed to contribute greatly to traumatic brain injury (TBI). Electroacupuncture (EA) is a promising therapeutic method for TBI, however, the underlying mechanism is still unclear. Herein, we hypothesize that the therapeutic effect of EA on TBI is associated with its inhibition on AMPK/mTOR-mediated autophagy. Sprague-Dawley rats were randomly divided into three groups: sham, TBI, and TBI + EA. TBI model was established by using an electronic controlled cortical impactor. Rats were treated with EA at 12 h after modeling, 15 min daily for 14 consecutive days. EA was applied at the acupuncture points Quchi (LI 11), Hegu (LI4), Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Yongquan (KI1), using dense-sparse wave, at frequencies of 1 Hz, and an amplitude of 1 mA. After 3, 7 and 14 days of modeling, the modified neurological severity scale (mNSS), rota rod system, and Morris Water Maze (MWM) test showed that EA treatment promoted neurological function recovery in TBI rats. Moreover, EA treatment alleviated brain edema, pathological damage, neuronal apoptosis in TBI rats. EA improved abnormal ultrastructure, including abnormal mitochondrial morphology and increased autophagosomes, in the brain neurons of TBI rats, as measured by transmission electron microscopy, and the concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Western blot and immunohistochemistry (IHC) assays were performed to measure the protein levels of interleukin 10 (IL-10), autophagy-related proteins and key proteins in the AMPK/mTOR signaling pathway. EA treatment increased IL-10 production, inhibited the AMPK/mTOR signaling, and inhibited excessive autophagy in TBI rats. Additionally, AMPK inhibitor Compound C treatment had similar effects to EA. Both AMPK agonist AICAR and IL-10 neutralizing antibody treatments reversed the effects of EA on the related protein levels of autophagy and the AMPK/mTOR signaling pathway, and abolished the protective effects of EA on TBI rats. In conclusion, EA treatment promoted neurological function recovery and alleviated pathological damage and neuronal apoptosis in TBI rats through inhibiting excessive autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway.

Oxytocin inhibits hindpaw hyperalgesia induced by orofacial inflammation combined with stress.

Oxytocin (OT) is recognized as a critical neuropeptide in pain-related disorders. Chronic pain caused by the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) is common, but whether OT plays an analgesic role in the comorbidity of TMD and FMS is unknown. Female rats with masseter muscle inflammation combined with 3-day forced swim (FS) stress developed somatic hypersensitivity, which modeled the comorbidity of TMD and FMS. Using this model, the effects of spinal OT administration on mechanical allodynia and thermal hyperalgesia in hindpaws were examined. Furthermore, the protein levels of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn were analyzed by Western blot. The OT receptor antagonist atosiban and 5-HT2A receptor antagonist ritanserin were intrathecally injected prior to OT injection in the separate groups. Intrathecal injection of 0.125 µg and 0.5 µg OT attenuated the hindpaw hyperalgesia. The expression of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn significantly increased following intrathecal injection of 0.5 µg OT. Intrathecal administration of either the OT receptor antagonist atosiban or 5-HT2A receptor antagonist ritanserin blocked the analgesic effect of OT. These results suggest that OT may inhibit hindpaw hyperalgesia evoked by orofacial inflammation combined with stress through OT receptors and/or 5-HT2A receptors, thus providing a therapeutic prospect for drugs targeting the OT system and for patients with comorbidity of TMD and FMS.

SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes.

Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT2C receptors but downregulated 5-HT3 receptors in the spinal dorsal horn. Subsequent spinal administration of RS102221 to inhibit 5-HT2C receptors or SR57227 to activate 5-HT3 receptors reversed the analgesic effect of SAHA under both conditions. These results indicate that SAHA attenuates the pro-nociceptive effects of stress combined with orofacial inflammation and the effects of stress alone. This likely occurs through epigenetic regulation of spinal 5-HT2C and 5-HT3 receptor expression, suggesting that SAHA has potential therapeutic value in FMS or comorbid FMS-TMD patients with somatic hyperalgesia.

Correlation between nerve atrophy, brain grey matter volume and pain severity in patients with primary trigeminal neuralgia.

BACKGROUND: Recent neuroimaging studies have reported grey matter alterations in primary trigeminal neuralgia patients. However, few studies have focused on quantitative measurements of trigeminal nerves and the interaction between trigeminal nerve volume and brain morphology, particularly grey matter volume. In this study, we investigated the link between trigeminal nerves and grey matter volume changes in primary trigeminal neuralgia patients compared to healthy controls. Moreover, we explored the association of structure of trigeminal nerves and grey matter to collected pain clinical variables. METHODS: Eighty participants (40 patients and 40 controls) were recruited for the study. All participants underwent MRI sessions and clinical pain assessment. Trigeminal nerve volume and whole brain grey matter volume were evaluated using quantitative imaging techniques. Sensory and affective pain rating indices were assessed using the visual analog scale and short-form McGill Pain Questionnaire. Mediation analysis was conducted to investigate the relationship between clinical pain variables and volumetric changes in trigeminal nerves and grey matter. RESULTS: Decreased trigeminal nerve volume was detected in primary trigeminal neuralgia patients compared to controls. Additionally, reduced grey matter volume was found in several regions associated with pain in primary trigeminal neuralgia subjects, including the insula, secondary somatosensory cortex, hippocampus, dorsal anterior cingulate cortex, precuneus, and several areas of the temporal lobe. Mediation analysis revealed that decreased trigeminal nerve volume drove grey matter volume abnormality of the left insula, and further led to increased pain ratings. CONCLUSION: This study showed a predominantly direct effect of trigeminal nerve atrophy on clinical pain variables in primary trigeminal neuralgia patients, providing new insight into the pathophysiology of the disease. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02713646.

The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System.

Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.

Electroacupuncture Improves Baroreflex and γ-Aminobutyric Acid Type B Receptor-Mediated Responses in the Nucleus Tractus Solitarii of Hypertensive Rats.

Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1-0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.

EXPRESS: Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats.

Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stressinduced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome.

Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity.

OBJECTIVE: Epigenetic mechanisms are potential targets to relieve somatic pain. However, little is known whether epigenetic regulation interferes with visceral pain. Previous studies show that oestrogen facilitates visceral pain. This study aimed to determine whether histone hyperacetylation in the spinal cord could attenuate oestrogen-facilitated visceral pain. DESIGN: The effect of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on the magnitude of the visceromotor response (VMR) to colorectal distention was examined in ovariectomised rats with/without oestrogen replacement. An additional interaction with the metabotropic glutamate receptor 2/3 (mGluR2/3) antagonist LY341495 was tested. The levels of acetylated histone and mGluR2 mRNA and protein were analysed. The binding of acetylated H3 and oestrogen receptor α (ERα) to the GRM2 promoter was measured by chromatin immunoprecipitation coupled with qPCR. RESULTS: In ovariectomised rats, 17ß-estradiol (E2), but not safflower oil, increased the magnitude of the VMR to colorectal distention. SAHA attenuated the E2-facilitated VMR, but had no effect in safflower oil-treated rats. Subsequent spinal administration of LY341495 reversed the antinociceptive effect of SAHA in E2 rats. In addition, SAHA increased mGluR2 mRNA and protein in the spinal dorsal horn following E2, but not vehicle, treatment. In contrast, neither E2 nor SAHA alone altered mGluR2 mRNA. SAHA increased binding of H3K9ac and ERα to the same regions of the GRM2 promoter in E2-SAHA-treated animals. CONCLUSIONS: Histone hyperacetylation in the spinal cord attenuates the pronociceptive effects of oestrogen on visceral sensitivity, suggesting that epigenetic regulation may be a potential approach to relieve visceral pain.

Associations Between Temporomandibular Disorders and Brain Imaging-Derived Phenotypes.

OBJECTIVE: Temporomandibular disorders (TMD) affect the temporomandibular joint and associated structures. Despite its prevalence and impact on quality of life, the underlying mechanisms of TMD remain unclear. Magnetic resonance imaging studies suggest brain abnormalities in patients with TMD. However, these lines of evidence are essentially observational and cannot infer a causal relationship. This study employs Mendelian randomisation (MR) to probe causal relationships between TMD and brain changes. METHODS: Genome-wide association study (GWAS) summary statistics for TMD were collected, along with brain imaging-derived phenotypes (IDPs). Instrumental variables were selected from the GWAS summary statistics and used in bidirectional 2-sample MR analyses. The inverse-variance weighted analysis was chosen as the primary method. In addition, false discovery rate (FDR) correction of P value was used. RESULTS: Eleven IDPs related to brain imaging alterations showed significant causal associations with TMD (P-FDR < .05), validated through sensitivity analysis. In forward MR, the mean thickness of left caudal middle frontal gyrus (OR, 0.76; 95% CI, 0.67-0.87; P-FDR = 1.15 × 10-2) and the volume of right superior frontal gyrus (OR, 1.24; 95% CI, 1.10-1.39; P-FDR = 2.26 × 10-2) exerted significant causal effects on TMD. In the reverse MR analysis, TMD exerted a significant causal effect on 9 IDPs, including the mean thickness of the left medial orbitofrontal cortex (ß = -0.10; 95% CI, -0.13 to -0.08; P-FDR = 2.06 × 10-11), the volume of the left magnocellular nucleus (ß = -0.15; 95% CI, -0.22 to -0.09; P-FDR = 3.26 × 10-4), the mean intensity of the right inferior-lateral ventricle (ß = -0.09; 95% CI, -0.14 to -0.04; P-FDR = 2.23 × 10-2), the volume of grey matter in the anterior division of the left superior temporal gyrus (ß = 0.09; 95% CI, 0.04-0.14; P-FDR = 1.69 × 10-2), and so forth. CONCLUSIONS: This study provides genetic evidence supporting the bidirectional causal associations between TMD and brain IDPs, shedding light on potential neurobiological mechanisms underlying TMD development and its relationship with brain structure.

Downregulation of lysine-specific histone demethylase 1A (KDM1A/LSD1) in medial prefrontal cortex facilitates chronic stress-induced pain and emotional dysfunction in female mice.

Chronic primary pain, characterized by overlapping symptoms of chronic pain, anxiety, and depression, is strongly associated with stress and is particularly prevalent among females. Recent research has convincingly linked epigenetic modifications in the medial prefrontal cortex (mPFC) to chronic pain and chronic stress. However, our understanding of the role of histone demethylation in the mPFC in chronic stress-induced pain remains limited. In this study, we investigated the function of lysine-specific histone demethylase 1A (KDM1A/LSD1) in the context of chronic overlapping pain comorbid with anxiety and depression in female mice. We employed a chronic variable stress model to induce pain hypersensitivity in the face and hindpaws, as well as anxiety-like and depression-like behaviors, in female mice. Our findings revealed that chronic stress led to a downregulation of KDM1A mRNA and protein expression in the mPFC. Notably, overexpressing KDM1A in the mPFC alleviated the pain hypersensitivity, anxiety-like behaviors, and depression-like behaviors in female mice, without affecting basal pain responses or inducing emotional distress. Conversely, conditional knockout of KDM1A in the mPFC exacerbated pain sensitivity and emotional distress specifically in females. In summary, this study highlights the crucial role of KDM1A in the mPFC in modulating chronic stress-induced overlapping pain, anxiety, and depression in females. Our findings suggest that KDM1A may serve as a potential therapeutic target for treating chronic stress-related overlap pain and associated negative emotional disorders.

Chronic stress induces wide-spread hyperalgesia: The involvement of spinal CCK1 receptors.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.

Valproate attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress through inhibiting spinal IL-6 and STAT1 phosphorylation.

Temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) may present as comorbid conditions, but treatment options are ineffective. The purpose of this study was to investigate whether valproate (VPA) attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress, which represents a model of pain associated with TMD and FMS comorbidity, and to explore the potential mechanisms. The results showed that VPA inhibited somatic hyperalgesia induced by orofacial inflammation combined with stress, and down-regulated the interleukin-6 (IL-6) expression in the L4-L5 spinal dorsal horn of female rats. The anti-nociceptive effect of VPA was blocked by single or 5 consecutive day intrathecal administration of recombinant rat IL-6. Orofacial inflammation combined with stress up-regulated the ratio of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) to STAT1 (p-STAT1/STAT1) in the spinal cord. VPA did not affect the STAT1 expression, while it down-regulated the ratio of p-STAT1/STAT1. The expression of STAT3 and the ratio of p-STAT3/STAT3 were not affected by orofacial inflammation combined with stress and VPA treatment. Intrathecal administration of exogenous IL-6 up-regulated the ratio of p-STAT1/STAT1. These data indicate that VPA attenuated somatic hyperalgesia induced by orofacial inflammation combined with stress via inhibiting spinal IL-6 in female rats, and the mechanism may involve the alteration of activation status of spinal STAT1. Thus, VPA may be a new candidate analgesic that targets IL-6 and STAT1 for the treatment of pain associated with the comorbidity of TMD and FMS.

Using vertebral movement and intact paraspinal muscles to determine the distribution of intrafusal fiber innervation of muscle spindle afferents in the anesthetized cat.

Increasing our knowledge regarding intrafusal fiber distribution and physiology of paraspinal proprioceptors may provide key insights regarding proprioceptive deficits in trunk control associated with low back pain and lead to more effective clinical intervention. The use of vertebral movement as a means to reliably stretch paraspinal muscles would greatly facilitate physiological study of paraspinal muscle proprioceptors where muscle tendon isolation is either very difficult or impossible. The effects of succinylcholine (SCh) on 194 muscle spindle afferents from lumbar longissimus or multifidus muscles in response to computer-controlled, ramp-and-hold movements of the L(6) vertebra were investigated in anesthetized cats. Paraspinal muscles were stretched by moving the L(6) vertebra 1.5-1.7 mm in the dorsal-ventral direction. Initial frequency (IF), dynamic difference (DD), their changes (∆) following SCh injection (100-400 µg kg(-1)), and post-SCh dynamic difference (SChDD) were measured. Muscle spindle intrafusal fiber terminations were classified as primary or secondary fibers as well as bag(1) (b(1)c), bag(2) (b(2)c), b(1)b(2)c, or chain (c) fibers. Intrafusal fiber subpopulations were distinguished using logarithmic transformation of SChDD and ∆IF distributions as established by previous investigators. Increases in DD indicate strength of b(1)c influence while increases in IF indicate strength of b(2)c influence. Out of 194 afferents, 46.9 % of afferents terminated on b(2)c fibers, 46.4 % on b(1)b(2)c fibers, 1 % on b(1)c fibers, and 5.7 % terminated on c fibers. Based on these intrafusal fiber subpopulation distributions, controlled vertebral movement can effectively substitute for direct tendon stretch and allow further investigation of paraspinal proprioceptors in this anatomically complex body region.

Effects of thrust amplitude and duration of high-velocity, low-amplitude spinal manipulation on lumbar muscle spindle responses to vertebral position and movement.

OBJECTIVE: Mechanical characteristics of high-velocity, low-amplitude spinal manipulations (HVLA-SMs) can vary. Sustained changes in peripheral neuronal signaling due to altered load transmission to a sensory receptor's local mechanical environment are often considered a mechanism contributing to the therapeutic effects of spinal manipulation. The purpose of this study was to determine whether variation in an HVLA-SM's thrust amplitude and duration alters the neural responsiveness of lumbar muscle spindles to either vertebral movement or position. METHODS: Anesthetized cats (n = 112) received L6 HVLA-SMs delivered to the spinous process. Cats were divided into 6 cohorts depending upon the peak thrust force (25%, 55%, 85% body weight) or thrust displacement (1, 2, 3 mm) they received. Cats in each cohort received 8 thrust durations (0-250 milliseconds). Afferent discharge from 112 spindles was recorded in response to ramp and hold vertebral movement before and after the manipulation. Changes in mean instantaneous frequency (∆MIF) during the baseline period preceding the ramps (∆MIFresting), during ramp movement (∆MIFmovement), and with the vertebra held in the new position (∆MIFposition) were compared. RESULTS: Thrust duration had a small but statistically significant effect on ∆MIFresting at all 6 thrust amplitudes compared with control (0-millisecond thrust duration). The lowest amplitude thrust displacement (1 mm) increased ∆MIFresting at all thrust durations. For all the other thrust displacements and forces, the direction of change in ∆MIFresting was not consistent, and the pattern of change was not systematically related to thrust duration. Regardless of thrust force, displacement, or duration, ∆MIFmovement and ∆MIFposition were not significantly different from control. CONCLUSION: Relatively low-amplitude thrust displacements applied during an HVLA-SM produced sustained increases in the resting discharge of paraspinal muscle spindles regardless of the duration over which the thrust was applied. However, regardless of the HVLA-SM's thrust amplitude or duration, the responsiveness of paraspinal muscle spindles to vertebral movement and to a new vertebral position was not affected.

[Inhibitory effect of octreotide on the cross excitation of adjacent segment of spinal nerve in rat].

This study was to observe the effect and possible mechanism of somatostatin analogue octreotide (OCT) on cross excitation of adjacent segment of spinal nerve in rat. Cutaneous branches of T9-T13 spinal dorsal rami were chosen and dissected free for the following recording and stimulation. Only single unit fiber was used for recording, and the adjacent segment of nerve stem was used for antidromic electrical stimulation. To investigate the change of discharge rate and mechanical threshold, OCT and (or) somatostatin receptor antagonist cyclo-somatostatin (c-SOM) were applied to the receptive field following the antidromic electrical stimulation. The result showed that injection of OCT inhibited the increase of discharge rate and the decrease of mechanical threshold induced by the electrical stimulation (cross excitation); c-SOM reversed the effects of OCT. Application of c-SOM alone enhanced the cross excitation effects. The results suggest local application of somatostatin analogue OCT can inhibit the cross excitation between the two segments of spinal nerve by somatostatin receptor.

Investigation Into Environmental Selenium and Arsenic Levels and Arseniasis Prevalence in an Arsenic-Affected Coal-Burning Area.

This study aims to explore whether selenium (Se) concentration correlates with arseniasis in a high-arsenic coal area in the southern Shaanxi Province, China. Herein, an epidemiological investigation was conducted among 100 arsenic (As)-poisoned patients in Ziyang County, an area with high soil As and Se levels. Fifty healthy subjects were selected from areas without endemic As poisoning. The subjects in the high-As coal area were diagnosed with either normal, suspicious, mild, moderate, or severe As poisoning. Local coal, water, soil, corn, and pepper samples, as well as hair, blood, and urine samples of subjects and patients were collected and analyzed for their As and Se contents. The contents of As and Se in coal, soil, corn, pepper, and hair samples from Ziyang County were significantly higher than those in the control area. The As content of hair in Ziyang County positively correlated with As poisoning, whereas the Se content of hair and urine negatively correlated with As poisoning. The Se content in the body was negatively correlated with the degree of As poisoning, indicating that Se may accelerate the metabolism and decumulation of As and antagonize As toxicity.

Spinal CCK1 Receptors Contribute to Somatic Pain Hypersensitivity Induced by Malocclusion via a Reciprocal Neuron-Glial Signaling Cascade.

Recent studies have shown that the incidence of chronic primary pain including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell signaling cascade. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, interleukin-18 (IL-18) and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS. PERSPECTIVE: CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities.

Lengthening but not shortening history of paraspinal muscle spindles in the low back alters their dynamic sensitivity.

Proprioception is considered important for maintaining spinal stability and for controlling posture and movement in the low back. Previous studies demonstrate the presence of thixotropic properties in lumbar muscle spindles, wherein a vertebra's positional history alters spindle responsiveness to position and movement. This study investigated whether a vertebra's movement history affects the velocity sensitivity of paraspinal muscle spindles in the low back. Afferent activity from multifidus and longissimus muscle spindles was recorded in the L(6) dorsal root in 30 anesthetized cats. To alter movement history, a feedback-controlled motor attached to the L(6) spinous process held (conditioned for 4 s) the L(6) vertebra at an intermediate position or at positions that either lengthened or shortened the muscles. With the vertebra returned to the intermediate position, resting spindle discharge was measured over the next 0.5 s (static test) and then during a dynamic test consisting of ramp vertebral movement at four velocities (0.2, 0.5, 1.0, 2.0 mm/s). Spindle activity during the tests was measured relative to hold-intermediate. For both tests, hold-long decreased and hold-short increased muscle spindle responsiveness. For the static test position responsiveness was not different among the velocity protocols for either hold-long or hold-short (P = 0.42 and 0.24, respectively). During the dynamic test, hold-long conditioning significantly decreased [F((3,119)) = 7.99, P < 0.001] spindle responsiveness to increasing velocity. Mean velocity sensitivity was 4.44, 3.39, and 1.41 (impulses/s)/(mm/s) for the hold-short, hold-intermediate, and hold-long protocols, respectively. The nearly 2.5-fold decrease in velocity sensitivity following hold-long was significantly less than that for either hold-intermediate (P = 0.005) or hold-short conditioning (P < 0.001). Hold-short conditioning had little effect on velocity responses during the dynamic test [F((3,119)) = 0.23, P = 0.87]. In conclusion, only movement histories that stretch but not shorten muscle spindles alter their velocity sensitivity. In the low back, forward flexion and lateral bending postures would likely be the most provocative.

Octreotide inhibits capsaicin-induced activation of C and Aδ afferent fibres in rat hairy skin in vivo.

1. The present study investigated whether the somatostatin receptor (SSTR) agonist, octreotide, could inhibit the activation of dorsal skin afferent fibres induced by local injection of capsaicin in the rat. 2. Single unit activity from Aδ mechano-heat sensitive (AMH; n = 41) and C mechano-heat sensitive (CMH; n = 30) afferents was recorded after their isolation in thin filaments from the dorsal cutaneous nerve branches. The effect of subcutaneous octreotide injection on the change in discharge rate and mechanical threshold induced by capsaicin was determined. 3. Capsaicin (0.05%) injection into the edge of the receptive field of both AMH and CMH units increased their discharge rate and decreased their mechanical threshold. Pre-injection of octreotide inhibited these responses, and co-application of SSTR antagonist, cyclosomatostatin, reversed the inhibitory effect of octreotide. 4. The present study provides electrophysiological evidence that the signal evoked by the somatostatin receptor inhibits the activation and mechanical sensitization evoked by capsaicin in the terminals in small-diameter sensory neurons.