Descending Pain Inhibitory System Research Articles

Effects of Pain Relief Through Minimal Exercise Intervention in a Rat Model of Neuropathic Pain.

We aimed to minimize the frequency of exercise intervention and test the efficacy of pain relief. We also investigated the mechanism of neuropathic pain to determine the best frequency of pain relief for neuropathic pain. The chronic constriction injury (CCI) rat model was randomly divided into three groups: exercise (Ex), No-Ex, and normal. The treadmill exercise intervention was administered, and the 50% withdrawal threshold was assessed using the Von Frey Test. Ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), C-C chemokine receptor type 2 (CCR2), and tumor necrosis factor receptor-associated factor 6 (TRAF6) activation was determined through immunohistochemistry. In the brain, we examined the increased expression of β-endorphin/met-enkephalin in the gray matter of the midbrain aqueduct. Co-expression of CCR2, IBA1, and Neu-N was observed in the spinal cord dorsal horn by immunofluorescence staining. The 50% pain response threshold was significantly lower in the Ex group than in the No-Ex group at five weeks post-CCI, indicating a high analgesic effect. In the dorsal horn of the spinal cord, IBA1 and GFAP were significantly decreased in the Ex group than in the No-Ex group at five weeks post-CCI. However, no significant difference in activation of BDNF, CCR2, and TRAF6 was observed. In the midbrain, the Ex group showed a significant increase compared to the No-Ex group. In summary, our results suggest that in minimal-exercise intervention, neuropathic pain relief is achieved by activation of the descending pain inhibitory system in the midbrain.

Cerebral Mechanism of Tuina on the Descending Pain Inhibitory System in Knee Osteoarthritis: Protocol for a Randomized Controlled Trial.

Knee osteoarthritis (KOA) is reputedly the most common musculoskeletal disease of the lower limbs and the main cause of pain and disability among older individuals. Pain is the most significant and widespread symptom of KOA. The descending pain inhibitory system has a cardinal role in normal pain consciousness, and its malfunction may be one of the pathophysiological mechanisms in KOA. Crucially, the rostral ventromedial medulla (RVM) and periaqueductal gray (PAG), as important components of the descending pain inhibitory system, directly modulate the activity of the spinal neurons involved in pain transmission. Tuina, a manual therapy, is effective and safe for reducing clinical symptoms of KOA; however, the mechanism that influences pain through the descending pain inhibitory system in KOA is unclear. This study aims to investigate the modulatory implications of Tuina on the RVM and PAG, which have critical roles in the descending pain inhibitory system in patients with KOA. This randomized controlled parallel trial will be conducted at the Tuina Clinic of the Third Affiliated Hospital of Henan University of Chinese Medicine (Zhengzhou, China). Patients with KOA will be randomly assigned (1:1) to 6 weeks of health education or Tuina. All patients in both groups will accept a resting-state functional magnetic resonance scan at the beginning and end of the experiment, and the resting-state functional connectivity and the voxel-based morphometry analysis will be performed to detect the RVM and PAG function and structure changes. The clinical outcome assessments will be (1) the pressure pain thresholds, (2) the Numerical Rating Scale, (3) the Hamilton Depression Scale (HAMD), and (4) the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Considering that this trial is a study of resting-state functional magnetic resonance imaging technology, resting-state functional connectivity and voxel-based morphometry are the primary outcomes, and clinical outcome assessments are secondary outcomes. Adverse events will be documented and assessed throughout. All main analyses will be carried out on the basis of the intention-to-treat principle. The outcome evaluators and data statisticians will be masked to the treatment group assignment to reduce the risk of bias. This trial was approved by the ethics committee of the Third Affiliated Hospital of Henan University of Chinese Medicine. Enrollment began in December 2023, and the results of this trial are expected to be submitted for publication in May 2025. This trial will identify a possible relationship between function and structure changes of RVM and PAG and the improvement of clinical variables, elucidating the effect of Tuina on the descending pain inhibitory system of patients with KOA. This trial will provide much-needed knowledge for Tuina for patients with KOA. Chinese Clinical Trial Registry ChiCTR2300070289; https://www.chictr.org.cn/showproj.html?proj=182570. PRR1-10.2196/52820.

Effect of Catastrophic Thinking on the Analgesic Effect of Electroacupuncture.

Patients with chronic pain and high-level catastrophic thoughts often do not respond to acupuncture. This may be related to hypofunctioning of the dorsolateral prefrontal cortex and the descending pain inhibitory system. Therefore, we examined the relationship between the level of catastrophic thinking and the analgesic effect of electroacupuncture using the pain catastrophizing scale (PCS). We also evaluated the descending pain inhibitory system using conditioned pain modulation (CPM) and offset analgesia (OA). The relationship between catastrophic thinking and the descending pain inhibitory system was also examined. After testing the hospital anxiety and depression scale and the PCS in 14 healthy adults, the current pain threshold (CPT), CPM, and OA were measured, in order, before the intervention. Thereafter, electroacupuncture was applied to 3 limbs (the dominant hand and both lower extremities) at 4 Hz, and to the scalp at 100 Hz, for 30 minutes, and the CPT was measured again immediately after the intervention. The difference in the CPT before and after the intervention was taken as the analgesic effect. The participants were divided into 2 groups, the H-PCS group (≥16 points) and the L-PCS group (≤15 points), according to the PCS score, and the analgesic effects of electroacupuncture were significantly different (P = 0.04). However, no relationship was found between the PCS score and the CPM (r = -0.02, P = 0.94) and OA effects (r = -0.19, P = 0.49). It was suggested that people with high-level catastrophic thinking may find it difficult to obtain the analgesic effects of electroacupuncture.

Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study

This randomized, double-blind, controlled clinical trial compared the effectiveness of home-based-(HB) active transcranial direct current stimulation (a-tDCS) over the left dorsolateral prefrontal cortex (l-DLPFC) or primary motor cortex (M1) with their respective sham-(s)-tDCS to determine whether a-tDCS would be more effective than s-tDCS in reducing pain and improving disability due to pain. The study included 102 patients with fibromyalgia aged 30 to 65 years old randomly assigned to 1 of 4 tDCS groups using a ratio of 2:1:2:1. The groups included l-DLPFC (a-tDCS, n = 34) and (s-tDCS, n = 17), or tDCS on the M1 (a-tDCS, n = 34) or (s-tDCS, n = 17). Patients self-administered 20 sessions of tDCS, with 2 mA for 20 minutes each day under remote supervision after in-person training. The Mixed Model for Repeated Measurements revealed that a-tDCS on DLPFC significantly reduced pain scores by 36.53% compared to 25.79% in s-tDCS. From baseline to the fourth week of treatment, a-tDCS on M1 reduced pain scores by 45.89% compared to 22.92% over s-tDCS. A generalized linear model showed a significant improvement in the disability scale in the groups that received a-tDCS compared to s-tDCS over M1 20.54% versus 2.49% (χ2 = 11.06, df = 1, P < .001]), while on DLPFC the improvement was 14.29% and 5.77%, with a borderline significance (χ2 = 3.19, df = 1, P = .06]), respectively. A higher reduction in serum brain-derived neurotrophic factor from baseline to treatment end was positively correlated with decreased pain scores regardless of the treatment group. The application of a-tDCS over M1 increased the heat pain threshold and the function of the descending pain inhibitory system. PerspectiveThese findings provide important insights: (1) HB-tDCS has effectively reduced pain scores and improved disability due to fibromyalgia. (2) The study provides evidence that HB-a-tDCS is a viable and effective therapeutic approach. (3) HB-a-tDCS over M1 improved the function of the descending pain inhibitory system and increased the heat pain threshold. Finally, our findings also emphasize that brain-derived neurotrophic factor, as an index of neuroplasticity, may serve as a valuable marker associated with changes in clinical pain measures. Trial registrationNumber NCT03843203.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

The potential of Mulligan mobilization with movement and blood flow restriction training for lateral epicondylitis

Background: One activity that might cause lateral epicondylitis is sports. The symptoms of lateral epicondylitis include pain, a loss of strength, and decreased functional status. To counteract this problem by applying mulligan mobilization with movement and blood flow restriction training. This study aimed to determine the potential of mulligan mobilization with movement and blood flow restriction training to alleviate the problems in lateral epicondylitis.&#x0D; Methods: This study uses a literature review by conducting data studies related to mulligan mobilization with movement, blood flow restriction, and lateral epicondylitis. The initial search in 4 databases found a total of 31 articles. After the selection, using inclusion and exclusion criteria obtained, 24 articles.&#x0D; Results: Based on some literature shows that mulligan mobilization with movement and blood flow restriction training effectively can engage descending pain inhibitory systems and increase muscle activation for strength and functional status effect.&#x0D; Conclusion: Providing mulligan mobilization with movement and blood flow restriction training could ease pain and improve hand grip strength and functional activity that occurs when lateral epicondylitis occurs.

Neurotropin® accelerates peripheral nerve regeneration in a rat sciatic nerve crush injury model

BackgroundPeripheral nerve injuries are common and serious conditions. The effect of Neurotropin® (NTP), a nonprotein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus, on peripheral nerve regeneration has not been fully elucidated. However, it has analgesic properties via the activation of descending pain inhibitory systems. Therefore, the current study aimed to determine the effects of NTP on peripheral nerve regeneration. MethodsWe examined axonal outgrowth of dorsal root ganglion (DRG) neurons using immunocytochemistry in vitro. In addition, nerve regeneration was evaluated functionally, electrophysiologically, and histologically in a rat sciatic nerve crush injury model in vivo. Furthermore, gene expression of neurotrophic factors in the injured sciatic nerves and DRGs was evaluated. ResultsIn the dorsal root ganglion neurons in vitro, NTP promoted axonal outgrowth at a concentration of 10 mNU/mL. Moreover, the systemic administration of NTP contributed to the recovery of motor and sensory function at 2 weeks, and of sensory function, nerve conduction velocity, terminal latency, and axon-remyelination 4 weeks after sciatic nerve injury. In the gene expression assessment, insulin-like growth factor 1 and vascular endothelial growth factor expressions were increased in the injured sciatic nerve 2 days postoperatively. ConclusionsTherefore, NTP might be effective in not only treating chronic pain but also promoting peripheral nerve regeneration after injury.

Development of a Clinical Prediction Rule for Treatment Success with Transcranial Direct Current Stimulation for Knee Osteoarthritis Pain: A Secondary Analysis of a Double-Blind Randomized Controlled Trial.

The study's objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities' Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant (p &lt; 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66-56.69) and an 85% (95%CI: 60-96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets.

Intramuscular Electrical Stimulation to Trigger Points: Insights into Mechanisms and Clinical Applications-A Scoping Review.

Intramuscular electrical stimulation (IMES) is a modality used by clinicians to treat myofascial pain. Recent studies have shown positive results for the use of IMES on pain outcomes, yet studies investigating the potential mechanisms of IMES directly to trigger points (TrPs) are lacking. We performed a scoping review of the literature to summarize the current evidence from human and animal studies on the mechanisms of IMES to the TrP location, and to identify gaps in the existing literature. Electronic literature searches were conducted across five databases from inception to 15 August 2022, including PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), Scopus and Cochrane Register of Controlled Trials. Four studies met our full criteria for inclusion in this review. Three studies assessed the effects of IMES to TrPs on human subjects with MPS, and only one study used an animal model with experimentally generated TrPs. Based on the results of the included studies, IMES within a TrP region was reported to normalize muscle blood flow, decrease endplate noise of the TrP and elicit antinociceptive effects, at least partially, through engaging supraspinal descending pain inhibitory systems. At present, no clinical implications can be determined on the use of IMES to TrPs due to the limited amount and quality of the available evidence. Further studies investigating the clinical effectiveness and also underlying mechanisms of IMES to TrPs are clearly needed.

Antagonism of the orexin receptors in the ventral tegmental area diminished the stress-induced analgesia in persistent inflammatory pain

As a part of descending pain inhibitory system, orexin (OXs) in the ventral tegmental area (VTA) are implicated in nociceptive responses. The current study aimed to evaluate the role of OX receptors (OXRs) in the VTA in stress-induced analgesia in persistent inflammatory pain. Ninety-nine adult male Wistar rats underwent forced swim stress (FSS) following intra-VTA infusion of various doses of SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol/0.3 μL) as an OX1R or OX2R antagonist, respectively. The nociceptive threshold was evaluated using the formalin test as an animal model of persistent inflammatory pain. Current results demonstrated FSS as acute stress produced analgesic responses in the persistent inflammatory pain. Moreover, either OX1R or OX2R antagonist infusion in the VTA hindered the FSS-induced analgesia in both early and late phases. The inhibitory effect of SB334768 in the FSS-induced analgesia was stronger than TCS OX2 29 in both early and late phases of the formalin test. Neither SB334768 nor TCS OX2 29 alone affects pain-related behaviors in formalin tests. Intra-VTA microinjection of each treatment could not modify locomotion in rats. The findings suggest that OX1R and OX2R in the VTA are implicated in FSS-induced analgesia mechanisms.

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Reduced perception of pain via baroreceptor unloading in patients with chronic back pain

Nociceptive transmission at the spinal cord is modulated by descending pain inhibitory systems originating in the brainstem that interact with neural cardiovascular pathways, such as baroreceptor input. However, data regarding antinociceptive properties of cardiopulmonary baroreceptors are largely mixed, and no studies have examined cardiopulmonary baroreceptor modulation of pain perception in patients with chronic pain. Therefore, we tested the hypothesis that cardiopulmonary baroreceptor unloading would reduce pain perception in chronic back pain (CBP) patients and healthy participants. Mechanical pressure pain threshold (algometer on the upper trapezius) and pain perception of a repetitive heat stimulus (thermode on the anterior forearm) was tested in 12 CBP patients and 8 healthy controls during supine lower body negative pressure (LBNP) of ‐10 mmHg and 0 mmHg (control condition). Pressure pain threshold during LBNP was significantly increased compared with the control condition in CBP patients (270 ± 31 vs. 240 ± 27 kPa, P=0.04) and healthy controls (293 ± 59 vs. 259 ± 50 kPa, P=0.02), indicating reduced pain perception. Similarly, the average pain rating (scale 0‐100) of the repetitive heat stimulus was significantly reduced during LBNP compared with the control condition in CBP patients (42 ± 6 vs. 48 ± 6, P&lt;0.01). However, no significant change was observed in average pain rating of the repetitive heat stimulus during LBNP in healthy controls (38 ± 5 vs. 37 ± 7, P=0.89). Together, these preliminary findings suggest reduced pain perception during cardiopulmonary baroreceptor unloading with a potentially greater effect in patients with CBP compared with healthy individuals.

The effect of high-definition transcranial direct current stimulation on pain processing in a healthy population: A single-blinded crossover controlled study

Transcranial direct current stimulation (tDCS) is increasingly used in pain treatment. tDCS targeting both primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) may modulate the descending pain inhibitory system, however, it remains controversial regarding the optimal stimulation region for pain modulation. Therefore, this study aimed to explore the effects of high-definition anodic stimulation of M1 and DLPFC on conditioned pain modulation (CPM) and pain thresholds and establish a preferred stimulation setting. Twenty-six healthy adults were randomly assigned to M1-tDCS, DLPFC-tDCS, or sham-tDCS groups. During the three sessions, each participant received an active or sham stimulation of 2 mA for 20 min, with at least 3 days’ interval between sessions. Quantitative sensory tests were performed to obtain pressure pain threshold (PPT), cold pain threshold (CPT), and CPM before and after the tDCS intervention. Only M1-tDCS significantly increased CPM in healthy individuals compared with sham control (P = 0.004). No statistically significant difference was found in PPT and CPT between tDCS vs. sham control (P > 0.05). Our findings further support the important role of M1 as a target in pain regulation. Further large-scale, multicenter studies in chronic pain populations are needed to validate the alterations of distinct target brain regions related to pain and thus for an optimal target stimulation strategy in pain management.

Neuronal Sensitization and Synaptic Facilitation in the Superficial Dorsal Horn of a Rat Reserpine-induced Pain Model

Chronic widespread pain is one of the important issues to be solved in medical practice. Impaired spinal descending pain inhibitory system due to decreased monoamine neurotransmitters is assumed to cause nociceptive hypersensitivities in chronic painful conditions like that described in patients with fibromyalgia (FM). However, response behaviors and synaptic transmission of the spinal dorsal horn neurons in response to reserpine remain to be clarified. Here we examined the activities of superficial dorsal horn (SDH) neurons, as well as excitatory and inhibitory postsynaptic inputs to SDH neurons, using a putative rat model of FM that was established by injecting reserpine. Extracellular recordings in vivo revealed that SDH neurons were sensitized to mechanical stimulation applied to the neurons’ receptive fields, and the mechanically sensitized neurons were spontaneously more active. The sensitizing effect was evident 1 day and 3 days after the reserpine treatment, but subsided 5 days after the treatment or later. Using patch-clamp recordings in vivo, spontaneous excitatory postsynaptic currents (sEPSCs) to SDH neurons were found to increase in the pain model, while spontaneous inhibitory postsynaptic currents (sIPSCs) to SDH neurons decreased. These results demonstrate that the SDH neurons were strongly sensitized in response to the reserpine treatment, and that increased excitatory and decreased inhibitory postsynaptic inputs could be responsible for the spinal nociceptive hypersensitivity in the putative FM model.

Involvement of Serotonergic System in Oxaliplatin-Induced Neuropathic Pain.

Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain.

Modulatory role of the orexin system in stress-induced analgesia: Involvement of the ventral tegmental area.

Exposure to stressful experiences is often accompanied by suppressing pain perception, referred to as stress-induced analgesia. The neuropeptides orexins are essential in regulating the mechanism that responds to stressful and painful stimuli. Meanwhile, the ventral tegmental area (VTA), as a part of descending pain inhibitory system, responds to noxious stimuli. This study aimed to investigate the role of intra-VTA administration of orexin receptor antagonists on stress-induced antinociceptive responses in the animal model of acute pain. Ninety-three adult Wistar rats weighing 230-250g were unilaterally implanted by a cannulae above the VTA. Animals were pretreated with different doses (1, 3, 10 and 30nM/0.3μl) of SB334867 as the orexin-1 receptor antagonist and TCS OX2 29 as the orexin-2 receptor antagonist into the VTA, just 5min before 6min exposure to forced swim stress (FSS). Nociceptive threshold was measured using the tail-flick test as a model of acute pain. The results showed that exposure to FSS could significantly increase analgesic responses. Moreover, intra-VTA administration of SB334768 and TCS OX2 29 blocked the antinociceptive effect of FSS in the tail-flick test. The findings suggest that OX1 and OX2 receptors in the VTA might modulate the antinociceptive behaviours induced by FSS in part. Acute exposure to physical stress suppresses pain-related behaviors in the animal model of acute pain. Blockade of the OX1 and OX2 receptors in the VTA attenuates antinociceptive responses induced by FSS. The contribution of the OX2 receptors in the VTA is more predominant than OX1 receptors in stress-induced analgesia.

Specific Electroencephalographic Signatures for Pain and Descending Pain Inhibitory System in Spinal Cord Injury.

The pain related to spinal cord injury (SCI) is difficult to treat, and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI. In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 39 patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM. We included 39 SCI patients, 74% reported SCI-related pain. We found that (1) less alpha and beta power are related to pain presence, (2) less alpha and beta power are associated with higher pain levels among patients with pain, (3) patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4) more relative theta power are related to the presence of low CPM efficiency, (5) higher relative theta power is associated with lower CPM efficiency. Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.

Motor cortex transcranial direct current stimulation effects on knee osteoarthritis pain in elderly subjects with dysfunctional descending pain inhibitory system: A randomized controlled trial

BackgroundAlthough evidence has indicated a positive effect of transcranial direct current stimulation (tDCS) on reducing pain, few studies have focused on the elderly population with knee osteoarthritis (KOA). ObjectiveTo evaluate whether tDCS reduces KOA pain in elderly individuals with a dysfunctional descending pain inhibitory system (DPIS). MethodsIn a double-blind trial, individuals ≥ 60 years with KOA pain and a dysfunctional DPIS, we randomly assigned patients to receive 15 daily sessions of 2 mA tDCS over the primary motor cortex (anode) and contralateral supraorbital area (cathode) (M1-SO) for 20 min or sham tDCS. Change in pain perception indexed by the Brief Pain Inventory (BPI) at the end of intervention was the primary outcome. Secondary outcomes included: disability, quantitative sensory testing, pain pressure threshold and conditioned pain modulation (CPM). Subjects were followed-up for 2 months. ResultsOf the 104 enrolled subjects, with mean (SD) age of 73.9 (8.01) years and 88 (84.6%) female, 102 finished the trial. In the intention-to-treat analysis, the active tDCS group had a significantly greater reduction in BPI compared to the sham group (difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001; Cohen’s d, 0.58); and, also a significantly greater improvement in CPM-pressure in the knee (P = 0.01) and CPM-pain in the hand (P = 0.01). These effects were not sustained at follow-up. The intervention was well tolerated, with no severe adverse effects. ConclusionM1-SO tDCS is associated with a moderate effect size in reducing pain in elderly patients with KOA after 15 daily sessions of stimulation. This intervention has also shown to modulate the DPIS.

Neuropeptide W, an endogenous NPBW1 and NPBW2 ligand, produced an analgesic effect via activation of the descending pain modulatory system during a rat formalin test.

Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we examined whether NPW microinjected into the descending pain inhibitory system, such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM), produces an analgesic effect using a rat formalin test. Microinjections of NPW into the PAG ipsilateral and contralateral to the formalin-injected side, LC ipsilateral and contralateral to the formalin-injected side, and RVM produced an analgesic effect. In the RVM study, the analgesic effect was antagonized by WAY100135, a 5-HT1A antagonist, and enhanced by prazosin, an α1 antagonist, and SB269970, a 5-HT7 antagonist. Naloxone, an opioid antagonist, also antagonized the effect of NPW in the RVM study. In the ipsilateral LC study, the analgesic effect was antagonized by WAY100135, idazoxan, an α2 antagonist, and naloxone and was enhanced by prazosin and SB269970. In the contralateral LC study, the analgesic effect was antagonized by prazosin, idazoxan, SB269970, and naloxone. The analgesic effect was antagonized by WAY100135, SB269970, idazoxan, and naloxone in the ipsilateral and contralateral PAG studies. These findings strongly suggest that NPBW1/W2 activation by NPW microinjection into the RVM, LC, and PAG affect the descending pain modulatory system and produce anti-nociceptive and pro-nociceptive effects in the rat formalin test.

A Randomized Sham-Controlled Cross-Over Study on the Short-Term Effect of Non-Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects.

The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. Non-invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. Twenty-seven adult, healthy, and pain-free subjects participated in this double-blind cross-over study conducted at a university research center. They received 4minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. RIII reflex areas were 917.1±563.8µV×ms (mean±SD) before, 952.4±467.4µV×ms during and 929.2±484.0µV×ms immediately after nVNS and 858.4±489.2µV×ms before, 913.9±539.7µV×ms during and 862.4±476.0µV×ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66] =0.67, P=.574). There also were no effects of nVNS over sham on RIII reflex areas up to 60minutes after nVNS (F [1.7,37.4] =1.29, P=.283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4±2.4 (NRS 0-10) to 4.1±2.5 during nVNS compared to sham stimulation (F [1,22] =8.74, P=.007), but there were no longer lasting effects (5-60minutes after stimulation). The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components.