Chronic Pain States Research Articles

ID: 206388 Evaluation of PROMIS-29 Function Scores in Patients Using Differential Target Multiplexed Stimulation

The UPGRADE study is a Real-world Outcomes® longitudinal study evaluating the multidimensional chronic pain state of patients with neurostimulation systems before and after the introduction of differential target multiplexed spinal cord stimulation (DTM-SCS) programming. DTM-SCS is associated with superiority labeling for back pain and is available within the approved specifications of commercially approved devices with a large install base.

ID: 206156 Evaluation of PROMIS-29 Sleep Disturbance and Fatigue Scores in Patients Using Differential Target Multiplexed Stimulation

The UPGRADE study is a Real-world Outcomes® longitudinal study evaluating the multidimensional chronic pain state of patients with neurostimulation systems before and after the introduction of differential target multiplexed spinal cord stimulation (DTM-SCS) programming. DTM-SCS is associated with superiority labeling for back pain and is available within the approved specifications of commercially approved devices with a large install base.

First-in-human prediction of chronic pain state using intracranial neural biomarkers.

Chronic pain syndromes are often refractory to treatment and cause substantial suffering and disability. Pain severity is often measured through subjective report, while objective biomarkers that may guide diagnosis and treatment are lacking. Also, which brain activity underlies chronic pain on clinically relevant timescales, or how this relates to acute pain, remains unclear. Here four individuals with refractory neuropathic pain were implanted with chronic intracranial electrodes in the anterior cingulate cortex and orbitofrontal cortex (OFC). Participants reported pain metrics coincident with ambulatory, direct neural recordings obtained multiple times daily over months. We successfully predicted intraindividual chronic pain severity scores from neural activity with high sensitivity using machine learning methods. Chronic pain decoding relied on sustained power changes from the OFC, which tended to differ from transient patterns of activity associated with acute, evoked pain states during a task. Thus, intracranial OFC signals can be used to predict spontaneous, chronic pain state in patients.

Post-injury pain and behaviour: a control theory perspective.

Injuries of various types occur commonly in the lives of humans and other animals and lead to a pattern of persistent pain and recuperative behaviour that allows safe and effective recovery. In this Perspective, we propose a control-theoretic framework to explain the adaptive processes in the brain that drive physiological post-injury behaviour. We set out an evolutionary and ethological view on how animals respond to injury, illustrating how the behavioural state associated with persistent pain and recuperation may be just as important as phasic pain in ensuring survival. Adopting a normative approach, we suggest that the brain implements a continuous optimal inference of the current state of injury from diverse sensory and physiological signals. This drives the various effector control mechanisms of behavioural homeostasis, which span the modulation of ongoing motivation and perception to drive rest and hyper-protective behaviours. However, an inherent problem with this is that these protective behaviours may partially obscure information about whether injury has resolved. Such information restriction may seed a tendency to aberrantly or persistently infer injury, and may thus promote the transition to pathological chronic pain states.

Effectiveness of motor control exercise, aerobic walking, and muscle strengthening programs in improving outcomes in a subgroup of population with chronic low back pain positive for central sensitization: a study protocol for a randomized controlled trial

BackgroundThe role of pain sensitivity in the development and maintenance of chronic pain states, impaired executive functioning, and patient recovery is being investigated. Conditioned pain modulation (CPM) is widely used to measure musculoskeletal pain associated with central sensitization (CS). Despite the recommendations of many reviews and clinical practice guidelines that exercise programs reduce pain and disability, the overall confidence in these results is considered “critically low.” The “active ingredient” of exercise programs and the dominant factor influencing CPM remain largely unknown.The objectives of this trial are to determine:• If different exercises cause different results on the CPM in a subgroup of people with chronic low back pain (CLBP) who are labeled as having CS pain,• If a program of exercise interventions for 12 weeks would alter executive functioning, quality of life (QoL), disability, and pain in persons with CLBP.• The relationship between patient characteristics, executive functions, CPM, and QoLMethodsThe trial is a randomized, controlled, multi-center study with four experimental groups and one healthy control group. Both the researchers and the people in the study will be blinded to the results. This paper describes the protocol for a trial examining the effects of 12-week individualized, twice-weekly exercise sessions lasting 30 to 60 min in persons with CLBP, who are positive for CS. Participants will be randomized to receive either patient education with motor control exercises (MCE), superficial strengthening (SS), aerobic exercises (AE), or patient education alone. Another group comprised of healthy volunteers will serve as controls. The primary outcomes are changes in CPM outcomes as measured by the cold pressor test (CPT). The secondary objectives are to evaluate executive functioning, pain, disability, quality of life, and spine muscle strength. The outcomes will be measured at 3 months and at a 6-month follow-up.DiscussionThe outcomes of the study will help in gaining more information and evidence about exercise-induced analgesia from the perspective of CPM. Measuring exercise outcomes will aid in scientifically prescribing exercise prescriptions in people with CLBP. The study outcomes will also assist in identifying the characteristics of individuals who will respond or respond indifferently to exercises. Investigating the relationship between the study’s various outcomes could provide information for future trials.Trial registrationClinical Trials Registry of India (CTRI) identifier: CTRI/2022/03/041143. Registered on 16 March 2022.

Low level TGF-β1-treated Umbilical mesenchymal stem cells attenuates microgliosis and neuropathic pain in chronic constriction injury by exosomes/lncRNA UCA1／miR-96-5p／FOXO3a

Neuropathic pain is a chronic pain state that usually caused by injuries in peripheral or central nerve. Inhibition of spinal microglial response is a promising treatment of neuropathic pain caused by peripheral nerve injury. In recent years, mesenchymal stem cells (MSCs) that characterized with multipotent ability have been widely studied for disease treatment. TGF-β1 is a well-known regulatory cytokine that participate in the response to cell stress and is closely correlated with the function of nerve system as well as MSC differentiation. This work aimed to determine the effects of exosomes that extracted from TGF-β1-induced umbilical mesenchymal stem cells (hUCSMCs) on the neuropathic pain. In this work, we established a rat model of chronic constriction injury (CCI) of the sciatic nerve and LPS-induced microglia cell model. The hUCSMCs cell surface biomarker was identified by flow cytometry. Exosomes that extracted from TGF-β1-treated hUCSMCs were characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) and used for treatment. We observed that TGF-β1 upregulates the level of lncRNA UCA1 (UCA1) in hUCMSC-derived exosomes. Treatment with exosomal lncRNA UCA1 (UCA1) alleviated the neuropathic pain, microgliosis, and production of inflammatory mediator both in vivo and in vitro. UCA1 directly interact with the miR-96-5p, and the miR-96-5p acts as sponge of FOXO3a. Knockdown of UCA1 upregulated the level of miR-96-5p and downregulated the FOXO3a expression, which could be recovered by inhibition of miR-96-5p. In summary, the TGF-β1-stimulated exosomal UCA1 from hUCMSCs alleviates the neuropathic pain and microgliosis. These findings may provide novel evidence for treatment of neuropathic pain caused by chronic constriction injury.

Ventral Column Spinal Cord Stimulation for Post Lumbar Laminectomy Syndrome: A Case Report.

Spinal cord stimulation is an increasingly utilized treatment for a number of chronic pain states. Dorsal column stimulation is historically and currently the anatomical target of choice for most chronic pain conditions, including post-laminectomy syndrome and radicular pain. However early studies suggested that stimulation of an alternative target, the ventral columns that carry pain fibers in the anterior and lateral spinothalamic tracts, may offer comparable or superior pain relief. A patient undergoing standard-of-care spinal cord stimulation trial had an additional lead placed on the right ventrolateral aspect of the spinal cord. Following the usual 7-day trial of dorsal column stimulation, the dorsal leads were removed and ventrolateral column stimulation was applied through the retained ventral lead for a period of 3 days. The Brief Pain Index Short Form and Numeric Rating Scale were recorded for both dorsal and ventral stimulation. Ventrolateral spinal cord stimulation provided comparable outcomes compared with dorsal column stimulation using non-paresthesia-based stimulation. The results suggest further investigation into spinal cord stimulation anatomical placement and mechanism of action is warranted.

Dual contribution of ASIC1a channels in the spinal processing of pain information by deep projection neurons revealed by computational modeling

Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but its exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of rat spinal neurons with computational modeling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a homomeric channels. A computational model of WDR neuron supplemented with different ASIC1a channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using the Texas coral snake ASIC-activating toxin (MitTx) and calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin). This study supports a dual contribution to windup of calcium permeable ASIC1a channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.

Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain.

The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies.

No Evidence for Cognitive Impairment in an Experimental Rat Model of Knee Osteoarthritis and Associated Chronic Pain

Although chronic pain states have been associated with impaired cognitive functions, including memory and cognitive flexibility, the cognitive effects of osteoarthritis (OA) pain remain to be clarified. The aim of this study was to measure cognitive function in the mono-iodoacetate (MIA) rat model of chronic OA-like knee pain. We used young adult male Lister hooded rats, which are well-suited for cognitive testing. Rats received either a unilateral knee injection of MIA (3 mg/50 µL) or saline as control. Joint pain at rest was assessed for up to 12 weeks, using weight-bearing asymmetry, and referred pain at a distal site, using determination of hindpaw withdrawal thresholds. The watermaze delayed-matching-to-place test of rapid place learning, novel object recognition memory assay, and an operant response-shift and -reversal task were used to measure memory and behavioral flexibility. Open-field locomotor activity, startle response, and prepulse inhibition were also measured for comparison. MIA-injected rats showed markedly reduced weight-bearing on the injured limb, as well as pronounced cartilage damage and synovitis, but interestingly no changes in paw withdrawal threshold. Rearing was reduced, but otherwise, locomotor activity was normal and no changes in startle and prepulse inhibition were detected. MIA-injected rats had intact watermaze delayed-matching-to-place performance, suggesting no substantial change in hippocampal function, and there were no changes in novel object recognition memory or performance on the operant task of behavioral flexibility. Our finding that OA-like pain does not alter hippocampal function, unlike other chronic pain conditions, is consistent with human neuroimaging findings. PerspectiveYoung adult rats with OA-like knee pain showed no impairments in hippocampal memory function and behavioral flexibility, suggesting that OA pain impacts cognitive functions less than other chronic pain conditions. In patients, OA pain may interact with other factors (e.g., age, socio-economic factors, and medication) to impair cognition.

459 Caspase-1 mediated inflammatory response - a critical player in concussive mild traumatic brain injury (mTBI) associated long term pain

OBJECTIVES/GOALS: Patients who have experienced conjunctive mild traumatic brain injuries (mTBIs) suffer from a number of comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation after mTBI and its contribution to long-term pain are still poorly understood. METHODS/STUDY POPULATION: Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes and their effects on TBI-related pain. Utilizing a recently developed transgenic caspase-1 luciferase reporter mouse, we characterized the bioluminescence signal evident in both in vivo and ex vivo tissues following repetitive closed head mTBIs. This allowed us to reveal the spatiotemporal dynamics of caspase-1 activation in individual animals over time. Furthermore, we utilize various proteomic and behavioral assays to evaluate the role of caspase-1 mediated inflammation in the development and progression of injury-associated chronic pain. Lastly, by blocking inflammasome caspase-1 activation with a specific inhibitor, we assess its clinical potential as the next therapeutic approach to pain. RESULTS/ANTICIPATED RESULTS: We established that there were significant increases in bioluminescent signals upon protease cleavage in the brain, thorax, abdomen, and paws in vivo, which lasted for at least one week after each injury. Enhanced inflammation was also observed in ex vivo brain slice preparations following injury events that lasted for at least 3 days. Concurrent with the in vivo detection of the bioluminescent signal were persistent decreases in mouse hind paw withdrawal thresholds that lasted for more than two months postinjury. Using MCC950, a potent small molecule inhibitor of NLRP3 inflammasome-caspase 1 activity, we observed reductions in both caspase-1 bioluminescent signals in vivo and caspase-1 p45 expression by immunoblotting and an increase in hind paw withdrawal thresholds. DISCUSSION/SIGNIFICANCE: Overall, these findings suggest that neuroinflammation in the brain following repeated mTBIs is coincidental with a chronic nociplastic pain state, and repeated mTBI-associated events can be ameliorated by a highly specific small molecule inhibitor of NLRP3 inflammasome activation.

Rare variant analyses in large-scale cohorts identified SLC13A1 associated with chronic pain.

Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in chronic pain patients have identified hundreds of common pathogenic variants, yet they only explained a portion of individual variance of chronic pain. With the advances in next-generation sequencing technologies, it is now feasible to conduct rarer variants studies in large-scale databases. Here, we performed gene-based rare variant analyses in 200,000 human subjects in the UK biobank whole-exome sequencing database for investigating 9 different chronic pain states and validated our findings in 3 other large-scale databases. Our analyses identified the SLC13A1 gene coding for sodium/sulfate symporter associated with chronic back pain and multisite pain at the genome-wide level and with chronic headache, knee, and neck and shoulder pain at the nominal level. Seven loss-of-function rare variants were identified within the gene locus potentially contributing to the development of chronic pain, with 2 of them individually associated with back pain and multisite pain. These 2 rare variants were then tested for replication in 3 other biobanks, and the strongest evidence was found for rs28364172 as an individual contributor. Transcriptional analyses of Slc13a1 in rodents showed substantial regulation of its expression in the dorsal root ganglia and the sciatic nerve in neuropathic pain assays. Our results stress the importance of the SLC13A1 gene in sulfate homeostasis in the nervous system and its critical role in preventing pain states, thus suggesting new therapeutic approaches for treating chronic pain in a personalized manner, especially in people with mutations in the SLC13A1 gene.

The Biology of Stress Intolerance in Patients with Chronic Pain-State of the Art and Future Directions.

Stress has been consistently linked to negative impacts on physical and mental health. More specifically, patients with chronic pain experience stress intolerance, which is an exacerbation or occurrence of symptoms in response to any type of stress. The pathophysiological mechanisms underlying this phenomenon remain unsolved. In this state-of-the-art paper, we summarised the role of the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis, the two major stress response systems in stress intolerance. We provided insights into such mechanisms based on evidence from clinical studies in both patients with chronic pain, showing dysregulated stress systems, and healthy controls supported by preclinical studies, highlighting the link between these systems and symptoms of stress intolerance. Furthermore, we explored the possible regulating role for (epi)genetic mechanisms influencing the ANS and HPA axis. The link between stress and chronic pain has become an important area of research as it has the potential to inform the development of interventions to improve the quality of life for individuals living with chronic pain. As stress has become a prevalent concern in modern society, understanding the connection between stress, HPA axis, ANS, and chronic health conditions such as chronic pain is crucial to improve public health and well-being.

Proteomic Analysis of the Spinal Dorsal Horn in Mice with Neuropathic Pain After Exercise.

Neuropathic pain (NP) is a chronic pain state with a complex etiology that currently lacks effective treatment in clinical practice. Studies have found that exercise training can alleviate NP hyperalgesia, but the specific mechanism remains unclear. Here, we sought to identify proteins and signaling pathways critical for mediating the effects of treadmill training on NP in a mouse model of spared nerve injury (SNI). We used Tandem Mass Tag (TMT) technology for proteins and signaling pathways identification. Functional enrichment analyses were conducted using DAVID and Metascape software. Ingenuity pathway analysis was used to conduct functional annotation and analyze alterations in canonical pathways and molecular networks. Reverse transcription quantitative PCR (RT-qPCR) was used to confirm the results of proteomics analysis. A total of 270 differentially expressed proteins were screened in the detrained and trained groups (P ≤0.05). Enrichment and ingenuity pathway analysis revealed the effects of treadmill training on autophagy, cAMP-mediated signaling, calcium signaling and NP signaling in dorsal horn nerves. Treadmill training reduced the expression of Akt3, Atf2, Gsk3b, Pik3c3, Ppp2ca, and Sqstm1, and increased the expression of Pik3cb in the autophagic pathway. Our results suggest that treadmill training may alleviate nociceptive hyperalgesia in NP mice by modulating the autophagic pathway, providing unique mechanistic insights into the analgesic effects of exercise.

Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.

Fibromyalgia (FM) is a chronic musculoskeletal pain disorder primarily diagnosed in women. Historically, clinical literature focusing on cytokines and immune cells has been inconsistent. However, recent key studies show several layers of immune system dysfunction in FM. Preclinically, studies of the immune system have focused on monocytes with little focus on other immune cells. Importantly, T-cells are implicated in the development and resolution of chronic pain states, particularly in females. Our previous work showed that monocytes from women with FM produced more interleukin 5 (IL-5) and systemic treatment of IL-5 reversed mechanical hypersensitivity in a preclinical model of FM. Typically, IL-5 is produced by TH2-cells, so in this study we assessed T-cell populations and cytokine production in female mice using the acid-induced chronic muscle pain model of FM before and after treatment with IL-5. Two unilateral injections of pH4.0 saline, five days apart, into the gastrocnemius muscle induce long-lasting widespread pain. We found that peripheral (blood) regulatory Thelper-cells (CD4+ FOXP3+) are downregulated in pH4.0-injected mice, with no differences in tissue (lymph nodes) or CD8+ T-cell populations. We tested the analgesic properties of IL-5 using a battery of spontaneous and evoked pain measures. Interestingly, IL-5 treatment induced place preference in mice previously injected with pH4.0 saline. Mice treated with IL-5 show limited changes in T-cell populations compared to controls, with a rescue in regulatory T-cells which positively correlates with improved mechanical hypersensitivity. The experiments in this study provide novel evidence that downregulation of regulatory T-cells play a role in chronic muscle pain pathology in the acidic saline model of FM and that IL-5 signaling is a promising target for future development of therapeutics.

Does baseline EEG activity differ in the transition to or from a chronic pain state? A longitudinal study.

Identifying EEG brain markers might yield better mechanistic insights into how chronic pain develops and could be treated. An existing longitudinal EEG study gave us the opportunity to determine whether the development of pain is accompanied by less alpha power-ie, a "relaxed" brain state-and vice versa. Five-minute resting EEG with the eyes open was measured 2 times in 95 subjects at T0 (baseline) and T1 (6months later). Based on the Short-Form Health Survey and Brief Pain Inventory questionnaire, subjects were divided into 4 groups: staying pain-free (n=44), developing chronic pain (n=8), becoming pain-free (n=15), and ongoing chronic pain (n=28). The EEG data of 14 electrodes were analyzed by multilevel regression. The group that developed chronic pain demonstrated less power in the lower-frequency bands over time during the resting state EEG, whereas the transition to a pain-free state had the opposite pattern. Thus, the a priori hypothesis was confirmed. Transitions in pain states are linked to a change in baseline EEG activity. Future research is needed to replicate these results in a larger study sample and in targeted clinical populations. Furthermore, these results might be beneficial in optimizing neurofeedback algorithms for the treatment of chronic pain.

Brainstem pain-modulating neurons are sensitized to visual light in persistent inflammation

Many individuals with chronic pain report abnormal sensitivity to visual light, referred to as “photosensitivity” or “photophobia,” yet how processing of light and nociceptive information come together remains a puzzle. Pain-modulating neurons in the rostral ventromedial medulla (RVM) have been shown to respond to bright visual light in male rats: activity of pain-enhancing ON-cells is increased, while that of pain-inhibiting OFF-cells is decreased. Since the RVM is the output node of a well-known pain modulation pathway, light-related input to these neurons could contribute to photosensitivity. The purpose of the present study was to fully characterize RVM ON– and OFF-cell responses to visual light by defining stimulus–response curves in male and female rats across a range of intensities (30 to 16,000 lx). We also determined if light-evoked responses are altered in animals subjected to persistent inflammation. We found that ON– and OFF-cells responded to relatively dim light (<1000 lx in naïve animals), with no difference between the sexes in threshold for light-evoked changes in firing or the percentage of responsive cells. Second, light-evoked suppression of OFF-cell firing was enhanced in persistent inflammation, with no change in light-evoked activation of ON-cells. These data indicate that pain-modulating neurons can be engaged by dim light, even under normal conditions. Further, they suggest that decreased descending inhibition during light exposure could contribute to reduced nociceptive thresholds in chronic pain states, resulting in light-induced somatic discomfort and aversion to light. Lastly, our findings argue for differences in how light and somatic stimuli engage RVM, and suggest that light-related input acts as a “top-down” regulatory input to RVM.

Cellular mechanisms underlying central sensitization in a mouse model of chronic muscle pain.

Chronic pain disorders are often associated with negative emotions, including anxiety and depression. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during central pain development. Prior adverse injuries are precipitating factors thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent development of chronic pain remains unknown. Here, we investigated the cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or chemogenetic inactivation of the somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented the chronification of pain. Further, electrophysiological recording revealed that the CeA-SST neurons had increased excitatory synaptic drive and enhanced neuronal excitability in the chronic pain states. Finally, either chemogenetic inactivation of the CeA-SST neurons or pharmacological suppression of the nociceptive afferents from the brainstem to the CeA-SST neurons alleviated chronic pain and anxio-depressive symptoms. These data raise the possibility of targeting treatments to CeA-SST neurons to prevent central pain sensitization.

A novel implantable device for sensory and affective assessment of orofacial pain in rats

Orofacial pain, in particular, chronic orofacial pain remains a great challenge in clinical practice. To better understand the underlying mechanism of disease, it is essential to apply a feasible and stable preclinical measurement of facial pain. Here, we introduced a novel electrical noxious stimulator in freely behavioral rodents and examined its validation in both naïve and chronic orofacial pain animals. One subcutaneous device of electrical stimulator was implanted in the facial region for delivery of the nociceptive input. The sensory component of orofacial pain was assessed by response scoring tool, and conditioned place aversion (CPA) paradigm for pain affect respectively. To confirm its usage in chronic pain state, the chronic constriction injury of the infraorbital nerve (ION-CCI) model was then applied. We found that responsive scores increased with stimulation intensity, and acted in a dosage-dependent manner, which can be attenuated by the administration of morphine intraperitoneally. Naïve rats displayed significant aversive reaction to the noxious electrical stimulation (25V) in the CPA testing. In addition, an obvious sensory hypersensitivity to electrical stimulation was confirmed by the increased response scores in ION-CCI rats. Furthermore, ION-CCI animal showed significant avoidance to electrical stimulation at relatively low intensity (10V), which was innoxious to naïve rats. Our findings may provide an alternative pre-clinical measurement of orofacial pain, to quantitively assess both sensory and affective component of orofacial pain.

Study on positive reaction of foot three yin-meridians in patients with typeⅢ chronic prostatitis based on meridian diagnosis

To explore the relationship between typeⅢ chronic prostatitis and the positive reaction of foot three yin-meridians based on meridian diagnosis. Using the traditional meridian diagnosis combined with tenderness meter detection, the positive reaction rate of meridians and acupoints of crural foot three yin-meridians and tenderness pain threshold of standard acupoint location were compared in the typeⅢ chronic prostatitis patients (prostatitis group, 32 cases) and healthy subjects (health group, 30 cases). The positive reaction rate of the spleen meridian was higher than those in the kidney meridian and the liver meridian in the prostatitis group (P<0.001). The positive reaction rates of the spleen meridian, the kidney meridian and the liver meridian and the total positive reaction rate of foot three yin-meridians in the prostatitis group were higher than those in the health group (P<0.001). In the prostatitis group, the positive reaction rates of Sanyinjiao (SP 6), Yinlingquan (SP 9), Taixi (KI 3), Ligou (LR 5), Diji (SP 8), Ququan (LR 8), Shangqiu (SP 5) and Zhongfeng (LR 4) were higher than those in the health group (P<0.001), the tenderness pain threshold of acupoints of crural foot three yin-meridians was lower than the health group (P<0.001). The positive reaction rate of the spleen meridian was positively correlated with the pain score and the total score of National Institute of Health chronic prostatitis symptom index (NIH-CPSI), and the positive reaction rate of the kidney meridian was positively correlated with age and international prostate symptom score (IPSS) in the prostatitis group. The positive reactions of foot three yin-meridians, especially the spleen meridian, are closely related to the pathological state of typeⅢ chronic prostatitis, pain and urination symptom are significantly correlated with the spleen meridian and the kidney meridian respectively.