Pain Mechanisms Research Articles

Mechanism of Analgesia by Gabapentinoid Drugs: Involvement of Modulation of Synaptogenesis and Trafficking of Glutamate-Gated Ion Channels.

Gabapentinoids have clinically been used for treating epilepsy, neuropathic pain, and several other neurologic disorders for >30 years; however, the definitive molecular mechanism responsible for their therapeutic actions remained uncertain. The conventional pharmacological observation regarding their efficacy in chronic pain modulation is the weakening of glutamate release at presynaptic terminals in the spinal cord. While the α2/δ-1 subunit of voltage-gated calcium channels (VGCCs) has been identified as the primary drug receptor for gabapentinoids, the lack of consistent effect of this drug class on VGCC function is indicative of a minor role in regulating this ion channel's activity. The current review targets the efficacy and mechanism of gabapentinoids in treating chronic pain. The discovery of interaction of α2/δ-1 with thrombospondins established this protein as a major synaptogenic neuronal receptor for thrombospondins. Other findings identified α2/δ-1 as a powerful regulator of N-methyl-D-aspartate receptor (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) by potentiating the synaptic expression, a putative pathophysiological mechanism of neuropathic pain. Further, the interdependent interactions between thrombospondin and α2/δ-1 contribute to chronic pain states, while gabapentinoid ligands efficaciously reverse such pain conditions. Gabapentin normalizes and even blocks NMDAR and AMPAR synaptic targeting and activity elicited by nerve injury. SIGNIFICANCE STATEMENT: Gabapentinoid drugs are used to treat various neurological conditions including chronic pain. In chronic pain states, gene expression of cacnα2/δ-1 and thrombospondins are upregulated and promote aberrant excitatory synaptogenesis. The complex trait of protein associations that involve interdependent interactions between α2/δ-1 and thrombospondins, further, association of N-methyl-D-aspartate receptor and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor with the C-tail of α2/δ-1, constitutes a macromolecular signaling complex that forms the crucial elements for the pharmacological mode of action of gabapentinoids.

The Role of Red Blood Cell Vascular Adhesion Biomarkers in Understanding Sickle Cell Disease Associated Chronic Pain

Background: Sickle cell disease (SCD) is characterized by repeated episodes of vaso-occlusion (VOC) that can lead to a host of complications including acute and chronic pain. Prior studies have demonstrated acute changes in RBC health biomarker flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and P-Selectin (FA-WB-Psel). Adhesive indices are significantly elevated during a proadhesive VOC. We examined whether individuals with SCD with and without chronic pain will exhibit differences in RBC health biomarkers between steady state and acute VOC pain. Methods: This was a 6-month, longitudinal, case-control cohort pilot study of FA-WB-VCAM and FA-WB-Psel indices collected in youth with SCD at Children's National Hospital in Washington, DC. SCD chronic pain patients (as defined per AAPT diagnostic criteria) were classified as “cases,” and SCD patients without chronic pain were “controls.” Controls were age (± 2 years), and genotype matched to cases. Both FA-WB-VCAM and FA-WB-Psel were collected at baseline and during acute VOC with assays performed by Functional Fluidics Inc. in Detroit, MI. Patient-reported outcomes were captured as pain scores and through completion of the centralized pain index survey to assess for centralized pain features of chronic pain. Statistical analysis included descriptive statistics and categorical analysis by t-test (GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 10 pediatric patients, 4 with chronic pain “cases” and 6 without chronic pain “controls” with FA-WB-VCAM and FA-WB-Psel assays performed at baseline and during an acute VOC episode. The average age of the cohort was 17.5 years with 70% females (n=7) and 30% males (n=3). Eighty percent (n=8) of the cohort were HgbSS and 20% (n=2) HgbSC genotype. Twenty-five percent (n=1) of the chronic pain patients were on disease-modifying therapy (DMT) with hydroxyurea (HU) at study initiation [all patients had been offered ≥ 1 FDA-approved DMT and previously discontinued DMT use due to intolerable side effects or personal choice], whereas 83% (n=5) of the control patients were on DMT with 50% (n=3) being on dual DMT therapy (HU + voxelotor or HU + crizanlizumab). The chronic pain cohort had a higher average number of ED visits/year than the control cohort (14 ± 7 vs. 4 ± 2 ED visits/year, p=0.11). The average baseline pain score for the chronic pain cohort was 7.25 versus 1.16 in the control cohort (p= 0.069). Centralized pain index survey responses were similar between both groups [median (IQR): 11.5 (7.25 - 15) vs. 9 (7-16), p=0.72)]. Figures 1A and 1B show a comparison of FA-WB-VCAM and FA-WB-Psel at baseline versus acute VOC for each chronic pain (P) “case” with their respective “controls (C).” The average baseline FA-WB-VCAM (P: 555.8 ± 605.3 vs. C: 435.3 ± 217 cells/mm2, p=0.905) and the average baseline FA-WB-PSel (P: 83.5 ± 64.5 vs. C: 57.33 ± 45.4, p=0.833) were similar between the cohort of chronic pain versus control subjects. Acute VOC FA-WB-VCAM (P: 722 ± 366.6 vs. C: 553.5 ± 309.6 cells/mm2, p=0.667) and FA-WB-PSel (P: 116.3 ± 66.6 vs. C: 98.7 ±96 cells/mm2, p=0.777) adhesion values were similar between cases and controls although adhesion values trended higher than baseline for both groups. All the cases had acute VOC adhesion indices above clinically established critical thresholds [Figure 1A and 1B]. The FA-WB-VCAM adhesion values increased from baseline in 75% (n=3) of the chronic pain patients (#3, #14, #16) during acute VOC. All the chronic pain patients (#3, #7, #14, #16) showed increased FA-WB-Psel adhesion from baseline during acute VOC [Figure 1A and 1B]. Fifty percent (n=3) of the control patients (#10, #12, #28) exhibited increased FA-WB-VCAM adhesion during acute VOC, and 60% (n=4) of the controls (#4, #5, #10, #28) exhibited increased FA-WB-Psel adhesion during acute VOC. Conclusions: We showed changes in RBC health vascular adhesion markers from baseline to acute VOC in patients with and without chronic pain. FA-WB-VCAM and FA-WB-Psel trended higher in the chronic pain cohort and all acute VOC values for the chronic pain cohort were above established critical thresholds. FA-WB-Psel adhesion increased from baseline with the onset of acute VOC episodes for most of the chronic pain cohort. Mechanistically, there is a need to understand differences in acute versus chronic pain, which may provide further insight into pro-adhesive versus non-vascular pain mechanisms.

Pathogenesis of Musculotendinous and Fascial Injuries After Physical Exercise - Short Review.

The identification of sports and physical exercises with injury risk is necessary to preserve the capacity of athletes and people who perform physical education and also to prevent the installation of functional deficiencies. We have selected the articles related to the pathogenic mechanisms involved in musculotendinous and fascial injuries produced as a result of physical exercise. The lesional pathogenesis is complex and incompletely clarified. Recent theories put in a new light the mechanisms of muscle pain and tendinopathy production. The accumulation of lactate anion, known to be a residue that induces fatigue and muscle pain, has been reconsidered by some authors. It appears that lactate anion is an excellent fuel for the myocardial fiber. Moreover, the accumulation of lactic acid after intense physical exercise could prevent the inexcitability of the sarcolemma induced by the increased concentration of interstitial K+. Most of the time, overuse injuries are not limited to muscles. They can cause myofascial, myotendinous or purely muscular injuries. The muscular fascia is more susceptible to injuries produced under the action of large external forces. Also, fascia is more sensitive to pain compared to muscle when external forces act eccentrically. Overloading the tendon and putting it under tension repeatedly is followed by ruptures of the tendon fibers. The regeneration of the degenerated tendon is defective in the context of the inflammation produced by the injury. Tendon fibers undergo a process of fibrosis, scarring, adhesion and heterogeneous calcification. Oxidative stress is responsible for inflammation, degeneration and apoptosis of tenocytes. The benefits brought by physical education and sports are indisputable, but their practice requires a coordinated program to prevent possible traumatic and overuse injuries.

Upregulation of Calhm2 in the anterior cingulate cortex contributes to the maintenance of bilateral mechanical allodynia and comorbid anxiety symptoms in inflammatory pain conditions

Peripheral inflammation-induced chronic pain tends to evoke concomitant anxiety disorders. It's common knowledge that the anterior cingulate cortex (ACC) plays a vital role in maintaining pain modulation and negative emotions. However, the potential mechanisms of chronic inflammation pain and pain-related anxiety remain elusive. Here, it was reported that injecting complete Freund’s adjuvant (CFA) unilaterally resulted in bilateral mechanical allodynia and anxiety-like symptoms in mice via behavioral tests. In addition, CFA induced the bilateral upregulation and activation of calcium homeostasis modulator 2 (Calhm2) in ACC pyramidal neurons by quantitative analysis and double immunofluorescence staining. The knockdown of Calhm2 in the bilateral ACC by a lentiviral vector harboring ribonucleic acid (RNA) interference sequence reversed CFA-induced pain behaviors and neuronal sensitization. Furthermore, the modulating of ACC pyramidal neuronal activities via a designer receptor exclusively activated by designer drugs (DREADD)-hM4D(Gi) greatly changed Calhm2 expression, mechanical paw withdrawal thresholds (PWTs) and comorbid anxiety symptoms. Moreover, it was found that Calhm2 regulates inflammation pain promoting the upregulation of N-methyl-D-aspartic acid (NMDA) receptor 2B (NR2B) subunits. Calhm2 knockdown in ACC exhibited a significant decrease in NR2B expression. These results demonstrated that Calhm2 in ACC pyramidal neurons modulates chronic inflammation pain and pain-related anxiety symptoms, which provides a novel underlying mechanism for the development of inflammation pain.

Chronic Pain and Allostasis: Role of Glial Cells

Lesions or diseases affecting the somatosensory system cause neuropathic pain, a debilitating chronic pain condition. From our recent study using a mouse model of neuropathic pain, CD11c+ microglia that appear in the spinal cord after nerve injury are important cells required for the pain remission. In this article, we review the transition of microglial states after nerve injury and the allostatic control mechanisms of neuropathic pain by CD11c+ microglia.

COVID-19 and musculoskeletal pain: an overview of the current knowledge.

The Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has provoked billions of infections worldwide. Several meta-analyses have observed that up to 50% of individuals who had survived to a SARS-CoV-2 acute infection suffer from post-COVID symptoms lasting for weeks or months and up to one year after infection. The prevalence of post-COVID pain ranges between 10% to 20% when assessed with other overall post-COVID symptoms and can reach up to 50% to 60% when investigated specifically. The most common musculoskeletal manifestations of post-COVID-19 condition include fatigue, myalgia, arthralgia or back pain. Despite pain of musculoskeletal origin is one of the most prevalent post-COVID pain symptoms, the exact pathophysiological mechanisms of musculoskeletal post-COVID pain are not completely understood. Studies have reported the complexity of post-COVID pain including immune, biological, and psychological factors, and more recently, they have suggested that genetic and epigenetic factors may also play a potential role, highlighting the need for further investigation into these mechanisms. Its management is still controversial, as no specific guideline for treating musculoskeletal post-COVID pain has been proposed with only general consideration about the relevance of multidisciplinary and multimodal treatment approaches. In this paper we will highlight the clinical features, the mechanism, and the management possibilities of musculoskeletal post-COVID pain.

Roles of Neuronal Protein Kinase Cε on Endoplasmic Reticulum Stress and Autophagic Formation in Diabetic Neuropathy.

In chronic diabetic neuropathy (DN), the cellular mechanisms of neuropathic pain remain unclear. Protein kinase C epsilon (PKCε) is an intracellular signaling molecule that mediates chronic pain. This paper addresses the long-term upregulated PKCε in DN associated with endoplasmic reticulum (ER) stress and autophagic formation and correlates to chronic neuropathic pain. We found that thermal hyperalgesia and mechanical allodynia course development were associated with PKCε upregulation after DN but not skin denervation. Pathologically, PKCε upregulation was associated with the expression of inositol-requiring enzyme 1α (IRE1α; ER stress-related molecule) and ubiquitin D (UBD), which are involved in the ubiquitin-proteasome system (UPS)-mediated degradation of misfolded proteins under ER stress. Manders coefficient analyses revealed an approximately 50% colocalized ratio for IRE1α(+):PKCε(+) neurons (0.34-0.48 for M1 and 0.40-0.58 for M2 Manders coefficients). The colocalized coefficients of UBD/PKCε increased (M1: 0.33 ± 0.03 vs. 0.77 ± 0.04, p < 0.001; M2: 0.29 ± 0.05 vs. 0.78 ± 0.04; p < 0.001) in the acute DN stage. In addition, the regulatory subunit p85 of phosphoinositide 3-kinase, which is involved in regulating insulin signaling, exhibited similar expression patterns to those of IRE1α and UBD; for example, it had highly colocalized ratios to PKCε. The ultrastructural examination further confirmed that autophagic formation was associated with PKCε upregulation. Furthermore, PKCεv1-2, a PKCε specific inhibitor, reverses neuropathic pain, ER stress, and autophagic formation in DN. This finding suggests PKCε plays an upstream molecule in DN-associated neuropathic pain and neuropathology and could provide a potential therapeutic target.

Sensory phenotypes of chronic pain in critically ill patients: a prospective observational study

INTRODUCTION: Determining sensory phenotypes that reflect underlying pain mechanisms may be relevant for critically ill patients with chronic pain. OBJECTIVE: To evaluate the intensity, localization and sensory phenotypes of chronic pain in critically ill patients. MATERIALS AND METHODS: The study included 99 critically ill patients. Inclusion criteria: age 18–75 years, length of stay in the ICU &gt; 3 days, duration of mechanical ventilation &gt; 48 hours, APACHE II score ≥ 7 points, obtaining informed consent. Localization, intensity, and qualitative characteristics of long-term (at least 6 months) pain associated with ICU stay were assessed using the Brief Pain Inventory and the PainDetect Questionnaire, and the severity of anxiety and depression on the HADS scale. Before discharge, all patients underwent thermal quantitative sensory testing (CST) with assessment of cold detection thresholds and warm detection thresholds, paradoxical thermal sensations, cold pain thresholds and heat pain thresholds, conditioned pain modulation. RESULTS: After 6 months chronic pain syndrome developed in 59 % of patients. Data were obtained on the intensity, localization, and severity of the neuropathic and dysfunctional components of pain. When assessing the thermal parameters of QST, a statistically significant difference in the distribution of values for the thresholds of sensitivity to cold and heat was obtained between the group of patients with chronic pain and the group without pain (p &lt; 0.0001) Hierarchical cluster analysis revealed a statistically significant relationship between changes in static and dynamic parameters of thermal sensory testing, the formation of an “irritated” and “deafferent” sensory phenotype depending on the duration of mechanical ventilation, stay in the ICU and assessment on the SOFA scale. CONCLUSIONS: sensory phenotypes make it possible to identify patients with dysfunction of small diameter fibers, impaired endogenous pain control mechanisms, which will allow selecting an individual program to pain relief.

Complex Regional Pain Syndrome Classification, Damage, Mechanisms, and Treatment: A Narrative Review

Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy syndrome, is a situation specified by persistent regional pain. The aberrant functioning of the neurological system is believed to be the root cause of an exaggerated reactivity to pain signals that are unable to switch off the sensation of pain. It is characterized by such symptoms as swelling, alterations in the color of the skin and tissues, along with edema. Although it most commonly affects the limbs, such as the arm, leg, hand, or foot, these symptoms can manifest themselves in any part of the body. The existence or nonexistence of nerve injury is used to classify patients into one of two subgroups, I or II, when referring to this illness. Since many medical professionals are unfamiliar with the diagnosis of CRPS and its etiology is not fully elucidated, the condition is frequently incorrectly diagnosed. The treatments available for CRPS focus on alleviating symptoms, regaining organ function, and cosseting a person's quality of life, despite the fact that no cure for the condition has been identified.

An international consensus on gaps in mechanisms of forced-based manipulation research: findings from a nominal group technique

ABSTRACT Force-Based Manipulation (FBM) including light touch, pressure, massage, mobilization, thrust manipulation, and needling techniques are utilized across several disciplines to provide clinical analgesia. These commonly used techniques demonstrate the ability to improve pain-related outcomes; however, mechanisms behind why analgesia occurs with these hands-on interventions has been understudied. Neurological, neuroimmune, biomechanical, neurovascular, neurotransmitter, and contextual factor interactions have been proposed to influence response; however, the specific relationships to clinical pain outcomes has not been well established. The purpose of this study was to identify gaps present within mechanism-based research as it relates to FBM. An international multidisciplinary nominal group technique (NGT) was performed and identified 37 proposed gaps across eight domains. Twenty-three of these gaps met consensus across domains supporting the complex multisystem mechanistic response to FBM. The strength of support for gaps within the biomechanical domain had less overall support than the others. Gaps assessing the influence of contextual factors had strong support as did those associating mechanisms with clinical outcomes (translational studies). The importance of literature investigating how FBM differs with individuals of different pain phenotypes (pain mechanism phenotypes and clinical phenotypes) was also presented aligning with other analgesic techniques trending toward patient-specific pain management (precision medicine) through the use of pain phenotyping.

Pain and itch coding mechanisms of polymodal sensory neurons

Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch.

Predictors of Placebo Response to Local (Intra-Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta-Analysis.

We undertook this study to evaluate potential predictors of placebo response with intra-articular (IA) injections for knee/hip osteoarthritis (OA) using individual participant data (IPD) from existing trials. Randomized placebo-controlled trials evaluating IA glucocorticoid or hyaluronic acid published to September 2018 were selected. IPD for disease characteristics and outcome measures were acquired. Potential predictors of placebo response included participant characteristics, pain severity, intervention, and trial design. Placebo response was defined as at least a 20% reduction in baseline pain. Logistic regression models and odds ratios were computed as effect measures to evaluate patient and pain mechanisms and then pooled using a random effects model. Generalized mixed-effect models were applied to intervention and trial characteristics. Of 56 eligible trials, 6 shared data, and these were combined with the existing 4 OA Trial Bank studies, yielding 10 studies with IPD of 621 placebo participants for analysis. In the total placebo population, at short-term follow-up, the use of local anesthetic and ultrasound guidance were associated with reduced odds of placebo response. At midterm follow-up, mid- to long-term trial duration was associated with increased odds of placebo response, and worse baseline function scores were associated with reduced odds of a placebo response. The administration of local anesthetics or ultrasound guidance may reduce IA placebo response at short-term follow-up. At midterm follow-up, participants with worse baseline function scores may be less likely to respond to IA placebo, and mid- to long-term trial duration may enhance the placebo response. Further studies are required to corroborate these potential predictors of IA placebo response.

BMP7 alleviates trigeminal neuralgia by reducing oligodendrocyte apoptosis and demyelination

BackgroundBMP7 has been shown to have neuroprotective effects and to alleviate demyelination. However, its role in trigeminal neuralgia (TN) has not been well investigated. The current study aims to determine whether BMP7 plays a role in demyelination, its effects on pain behaviors and mechanism of action in rats with TN.MethodsWe used an infraorbital-nerve chronic-constriction injury (ION-CCI) to establish a rat model of TN. Adeno-associated viruses (AAVs) were injected into the rats to upregulate or downregulate BMP7. The mechanical withdrawal thresholds (MWT) of the injured rats were detected using Von Frey filaments. The changes in expression levels of BMP7 and oligodendrocyte (OL) markers were examined by western blotting, quantitative real-time PCR, immunofluorescence, and transmission electron microscopy.ResultsThe ION-CCI induced mechanical allodynia, demyelination, and loss of OLs with a reduction of BMP7. Short-hairpin RNA (shRNA)-BMP7 that inhibited BMP7 expression also caused mechanical allodynia, demyelination, and loss of OLs, and its mechanism may be OL apoptosis. Overexpressing BMP7 in the trigeminal spinal subnucleus caudalis(VC) with AAV-BMP7 relieved all three phenotypes induced by the CCI, and its mechanism may be alleviating OLs apoptosis. Two signal pathways associated with apoptosis, STAT3 and p65, were significantly downregulated in the VC after CCI and rescued by BMP7 overexpression.ConclusionBMP7 can alleviate TN by reducing OLs apoptosis and subsequent demyelination. The mechanism behind this protection could be BMP7-mediated activation of the STAT3 and NF-κB/p65 signaling pathway and subsequent decrease in OL apoptosis. Importantly, our study presents clear evidence in support of BMP7 as a possible therapeutic target for the treatment of TN.

Effects of progressive intensity resistance training on the impact of fibromyalgia: protocol for a blinded randomized controlled trial

BackgroundFibromyalgia guidelines indicate that exercise is critical in the management of fibromyalgia, and there is evidence that patients with fibromyalgia can perform resistance training at moderate and high intensities. However, despite the biological plausibility that progression of intensity provides greater benefit to individuals, no studies have compared different intensities (progressive versus constant intensities) of the same exercise in this population.ObjectiveTo compare the effect of 24 sessions of resistance training (progressive vs. constant intensity) on impact of fibromyalgia, sleep quality, anxiety, depression, pain, walking ability, and musculoskeletal capacity.MethodsA protocol for a blinded randomized controlled trial. The sample will be randomized into three groups: group 1 (progressive intensity, experimental), group 2 (constant intensity, control A), and group 3 (walking, control B). Group 1 will perform resistance training at moderate intensity (50% of maximum dynamic strength), previously determined by the 1 repetition maximum (1-RM) test in the proposed exercises. The strength of each individual will be reassessed every 4 weeks (by 1-RM) and the intensity of each exercise will be positively adjusted by 20% of the value observed in kg (i.e., first month 50%; second month 70%; third month 90% of the maximum dynamic strength). Group 2 will perform the same procedure, but the intensity will be maintained at 50% of the maximum dynamic strength throughout the treatment (i.e., constant intensity from the first to the third month). Group 3 will perform a 40-minute treadmill walk at low intensity, defined by a walking speed corresponding to 60-70% of the maximum heart rate, which we will control with a heart rate monitor. All groups will receive a 45-minute pain education session prior to the exercise program, covering the pathophysiologic mechanisms of chronic pain, strategies for coping with pain, avoiding hypervigilance, and deconstructing beliefs and myths about chronic pain.DiscussionThe results of the present study may help health care professionals adjust the intensity of resistance training and thus plan the most effective intervention (progressive or constant intensity) to reduce the impact of fibromyalgia on patients’ lives.Trial registrationBrazilian Registry of Clinical Trials (ReBEC) ID: RBR-9pbq9fg, date of registration: October 06, 2022.

Gut-Brain Crosstalk and the Central Mechanisms of Orofacial Pain.

Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.

Effectiveness of different percutaneous electrolysis protocols in the endogenous modulation of pain: A Double-Blinded Randomized Clinical Trial

ObjectiveThis randomized clinical trial investigated if the application of percutaneous electrolysis (PE) enhances endogenous pain mechanisms (EPM) when compared with a simple needle application (acting as sham). MethodsForty-six asymptomatic subjects, aged 18–40 years, were randomized into three groups receiving a single ultrasound-guided PE intervention consisting of a needle insertion on the lateral epicondyle: sham (without electrical current), low-intensity (0.3 mA, 90s), or high-intensity (three pulses of 3 mA, 3s) PE. Widespread pressure pain thresholds (PPT), conditioned pain modulation (CPM), and temporal summation (TS) were bilaterally assessed in the lateral epicondyle, bicipital groove, transverse process of C5 and tibialis anterior muscle. Outcomes were obtained by an assessor blinded to the treatment allocation of the subjects. ResultsNo significant changes in CPM were observed in either group (omnibus ANOVA all, P > .05). A significant bilateral increase in PPT in the lateral epicondyle in the high intensity group as compared with the sham group was observed (P < .01). A significant decrease of TS in both low (P = .002) and high (P = .049) intensity groups on the right, but not on the left, tibialis anterior was also observed when compared with the sham group. ConclusionsOne session of PE is able to slightly stimulate modulatory pathways related to nociceptive gain, particularly pressure pain sensitivity and temporal summation but not conditioning pain modulation, when compared with a sham needle intervention, with changes even contralaterally. No significant differences were found between low- and high-intensity doses of percutaneous electrolysis.

Functional and anatomical analyses of active spinal circuits in a mouse model of chronic pain.

Decades of efforts in elucidating pain mechanisms, including pharmacological, neuroanatomical, and physiological studies have provided insights into how nociceptive information transmits from the periphery to the brain and the locations receiving nociceptive signals. However, little is known about which specific stimulus-dependent activated neurons, amongst heterogeneous neural environments, discriminatively evoke the cognate pain behavior. We here shed light on the population of neurons in the spinal cord activated by a painful stimulus to identify chronic pain-dependent activated neuronal subsets using Fos2A-iCreER (TRAP2) mice. We have found a large number of neurons activated by a normally nonpainful stimulus in the spinal cord of spinal nerve-ligated mice, compared with sham. Neuronal activation was observed in laminae I and II outer under heat hyperalgesia. A large number of neurons in laminae II inner were activated in both mechanical allodynia and heat hyperalgesia conditions, while mechanical allodynia tends to be the only stimulus that activates cells at lamina II inner dorsal region. Neuroanatomical analyses using spinal cell markers identified a large number of spinal inhibitory neurons that are recruited by both mechanical allodynia and heat hyperalgesia. Of interest, spinal neurons expressing calretinin, calbindin, and parvalbumin were activated differently with distinct pain modalities (ie, mechanical allodynia vs heat hyperalgesia). Chemogenetic inhibition of those activated neurons significantly and specifically reduced the response to the pain stimulus associated with the stimulus modality originally given to the animals. These findings support the idea that spinal neuronal ensembles underlying nociceptive transmission undergo dynamic changes to regulate selective pain responses.

Phenotyping Pain in Patients With Fibrous Dysplasia/McCune-Albright Syndrome.

Pain is a poorly managed aspect in fibrous dysplasia/McCune-Albright syndrome (FD/MAS) because of uncertainties regarding the clinical, behavioral, and neurobiological underpinnings that contribute to pain in these patients. Identify neuropsychological and neurobiological factors associated with pain severity in FD/MAS. Prospective, single-site study. Twenty patients with FD/MAS and 16 age-sex matched healthy controls. Assessments of pain severity, neuropathic pain, pain catastrophizing (pain rumination, magnification, and helplessness), emotional health, and pain sensitivity with thermal quantitative sensory testing. Central nervous system (CNS) properties were measured with diffusion tensor imaging, structural magnetic resonance imaging, and functional magnetic resonance imaging. Questionnaire responses, detection thresholds and tolerances to thermal stimuli, and structural and functional CNS properties. Pain severity in patients with FD/MAS was associated with more neuropathic pain quality, higher levels of pain catastrophizing, and depression. Quantitative sensory testing revealed normal detection of nonnoxious stimuli in patients. Individuals with FD/MAS had higher pain tolerances relative to healthy controls. From neuroimaging studies, greater pain severity, neuropathic pain quality, and psychological status of the patient were associated with reduced structural integrity of white matter pathways (superior thalamic radiation and uncinate fasciculus), reduced gray matter thickness (pre-/paracentral gyri), and heightened responses to pain (precentral, temporal, and frontal gyri). Thus, properties of CNS circuits involved in processing sensorimotor and emotional aspects of pain were altered in FD/MAS. These results offer insights into pain mechanisms in FD/MAS, while providing a basis for implementation of comprehensive pain management treatment approaches that addresses neuropsychological aspects of pain.

Peripheral Mechanism of Cancer-Induced Bone Pain.

Cancer-induced bone pain (CIBP) is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis. CIBP constitutes a specific pain state with distinct characteristics; however, it shares similarities with inflammatory and neuropathic pain. At present, although various therapies have been developed for this condition, complete relief from CIBP in patients with cancer is yet to be achieved. Hence, it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs. Herein, we focused on the peripheral mechanism associated with the initiation of CIBP, which involves tissue injury in the bone and changes in the tumor microenvironment (TME) and dorsal root ganglion. The nerve-cancer and cancer-immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis, ultimately leading to CIBP. The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

Chronic pelvic pain in endometriosis: from therapeutic Abstraction to clinical definition: A review

Currently, endometriosis is one of the most common and relevant gynecological conditions. It is characterized by a wide range of symptoms, with highly heterogeneous pain being one of the most typical. The unifying concept of the algological patterns of endometriosis is chronic pelvic pain, which contributes to a pronounced decrease in patients' quality of life. Therefore, it is necessary to analyze the key pathogenetic mechanisms of pelvic pain associated with endometriosis and to determine a personalized therapeutic approach based on them.