Pain-related Changes Research Articles

Altered structure and functional connection of subcortical gray matter in female patients with classical trigeminal neuralgia.

The etiology of classical trigeminal neuralgia (CTN) is still unclear. A better understanding of the cerebral structural and functional changes in female patients with CTN may provide important novel insights into the pathophysiologic mechanisms of female CTN. A total 37 female CTN patients were included and referred to MRI scans, comprising with 19 left CTN and 18 right CTN patients. We analyzed the volume and shape of subcortical gray matter (GM), and the functional connectivity (FC) between the accumbens nucleus (NAc) and whole brain in right and left CTN patients respectively. We found left CTN patients had a reduced right NAc volume compared to controls, similarly, the right CTN had the decreased volume in the left NAc. Vertex-wise shapes of right NAc in left CTN patients showed significant regional shape deformation on the anterior, medial and ventroposterior aspects, in contrast, left NAc of right CTN patients showed significant regional shape deformation on the anterior and posterior aspect. Furthermore, patients with left CTN showed significantly lower FC between the right NAc and right orbitofrontal cortex than control subjects. The volume of NAc in all CTN was significantly related to the perception of present pain intensity. The CTN might be majorly caused by volume reduction in NAc. A greater understanding of the neurobiological basis of pain-related changes in NAc will provide the knowledge for the development of novel NAc based therapeutic targets for pain management or even prevention in CTN patients.

Resting-State Functional Connectivity of the Cerebellum in Patients with Chronic Low Back Pain.

Chronic low back pain (cLBP) affects nociceptive responses in the cerebellum, which leads to increased pain perception and sensorimotor control dysfunction. This study aimed to investigate altered functional connectivity in the anterior and posterior lobes of the cerebellum during cLBP. Twenty patients with cLBP and 18 healthy participants underwent 3.0 T resting-state functional magnetic resonance imaging. The bilateral lobule V of the anterior cerebellum and Crus I of the posterior cerebellum were selected as the region of interest for identifying the corresponding networks. The left lobule V had a greater intrinsic connectivity with the left insular cortex, left orbitofrontal cortex, and bilateral medial prefrontal cortex in patients with cLBP. In contrast, the right lobule V and bilateral Crus I had a significantly decreased connectivity with the contralateral multimodal cerebral networks, including the default mode network, salience network, and emotional network. The cerebellum had mechanistic implications in pain-related changes, which are involved in motor control, cognition, and emotion processing. These findings provide a novel perspective on the role of functional subregions in cLBP, which add to the growing body of evidence that the cerebellum can be a potential target for noninvasive brain stimulation for chronic pain treatment.

Pain-related changes in crSO2 among premature infants undergoing PICC insertion

Objective To evaluate the effectiveness of cerebral regional oxygen saturation (crSO2) values, measured using near-infrared spectroscopy (NIRS), in assessing pain associated with the peripherally inserted central catheter (PICC) in premature infants. Methods NIRS was used to measure the crSO2 levels of 48 premature infants with gestational age (GA) of < 32 weeks or a birth weight of < 1500 g. Premature infant pain profile (PIPP) scores, vital signs, transcutaneous oxygen tension (TcpO2), transcutaneous carbon dioxide tension (TcpCO2), and crSO2 values were monitored. One-way repeated measure analysis of variance was used to compare heart rate (HR), respiratory rate (RR), blood pressure (BP), peripheral oxygen saturation (SpO2), TcpO2, TcpCO2, and crSO2 values before (Time 1), during (Time 2), and after (Time 3) PICC insertion. The correlation between the PIPP scores at Time 2 and the fluctuations (values detected at Time 2 minus those at Time 1) of SpO2, TcpO2, and crSO2 were also analyzed. Results The PIPP score at Time 2 was significantly higher than those at Times 1 and 3. HR, RR, and BP values increased (p < .05), and SpO2 and crSO2 levels decreased at Time 2 (p < .05) compared with those at Time 1. Stratified analysis based on GA revealed significant differences in HR, RR, and crSO2 values between Times 1 and 2 in infants with a GA of ≥ 32 weeks. In infants with a GA < 32 weeks, significant differences were observed in HR, RR, SpO2, BP, and crSO2 values between Times 1 and 2. The fluctuation of the crSO2 level was strongly correlated with the PIPP score at Time 2 (r = −0.829, p < .001). A weak correlation was observed between the PIPP score at Time 2 and TcpO2 level fluctuation (r = 0.375, p = .009). No correlation was observed between the PIPP score at Time 2 and SpO2 level fluctuation (r = 0.242, p = .097). Conclusion The fluctuation of crSO2 levels strongly correlates with PICC procedural pain. Hence, crSO2 levels measured using NIRS may be used as an indicator for pain assessment in premature infants.

Pain Control and Sedation in Neuro Intensive Critical Unit

Neurocritical patients who can self-report pain use the 0-10 numerical rating scale (NRS, verbal or visual form). However, critically ill patients whose nervous systems cannot express pain use the behavioral pain scale (BPS) and the critical care pain observation tool (CPOT) behavioral pain assessment tools. These tools reveal pain-related changes in movement, facial expression, posture, and physiological indicators such as heart rate, blood pressure, and respiratory rate. In pain control, it is first essential to reduce unnecessary painkillers through non-drug therapy and maximize the effect of the administered analgesics. For nonneuropathic pain, narcotic analgesics such as fentanyl, hydromorphone, morphine, and remifentanil are administered intravenously. Gabapentin, pregabalin, and carbamazepine are recommended along with narcotic analgesics for neuropathic pain control. In addition, nonnarcotic analgesics for multi-modal analgesia are used to reduce the use of narcotic analgesics or the side effects of narcotic analgesics. In the intensive care unit (ICU), the sedation-agitation scale (SAS) and the Richmond agitation-sedation scale (RASS) are used to determine the depth of sedation to be maintained during shallow or deep sedation, considering the condition of the critically ill patient. When selecting sedatives for critically ill patients, preferentially consider nonbenzodiazepines such as propofol or dexmedetomidine rather than benzodiazepines such as midazolam or lorazepam. In addition, patients use painkillers or sedatives for over a week, and neurological changes or physiological dependence may occur. Therefore, clinicians should evaluate the critically ill patient’s condition, and sedatives and painkillers should be reduced or discontinued.

Pain and alcohol consumption in virtual reality.

Research suggests situational pain may motivate alcohol consumption, suggesting that pain may be an antecedent for problematic drinking behavior. In this pilot project, we assessed the effect of a painful thermal stimulus on drinking topography in a virtual reality bar environment using real alcohol-containing beverages. We also examined psychosocial factors that may account for individual differences in pain as an antecedent for alcohol use. Participants (N = 20, Mage = 25.65 years, 55% female, 15% Hispanic/Latino/a/x) completed a psychosocial screening battery before completing two counterbalanced alcohol self-administration sessions. In each, participants experienced either painful heat (44 °C) or nonnoxious warmth (38 °C). Sip interval (s) and sip volume (g) were measured. Effects of pain on drinking topography were assessed using multilevel models. Multilevel models assessed associations of pain-related changes in topography with hypothesized vulnerability factors. Analyses indicated a significant interaction of pain condition and sex on sip interval (b = -.16.96, p = .015, 95% CI [-30.75, -2.97]), such that painful heat significantly decreased sip interval in men (b = 16.38) but not women (b = -.45). No effect of pain on sip volume was detected (p > .49). Exploratory analyses indicated significant interactions such that the effect of the painful heat condition was stronger in individuals with higher levels of greater negative urgency but the opposite effect for pain catastrophizing. Results suggest acute pain has sex-contingent effects on drinking topography, such that men drank more rapidly while experiencing painful heat. Furthermore, analyses indicated that individuals with greater negative urgency, regardless of sex, may be at elevated risk for hazardous alcohol use when experiencing pain. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dog owners' recognition of pain-related behavioral changes in their dogs

Pain management in veterinary medicine has been drawing considerable attention in recent years. Although it is important to evaluate the daily behaviors of dogs while assessing chronic pain, there is scarce research available on owners' ability to assess behavioral changes related to pain in their dogs. This study aims to understand which behavioral changes and/or gestures are perceived by owners in their dogs. Dog owners were asked to fill out an online survey including three main parts: demographic information about the dog, pain-related behavioral changes, and pain-related ear and tail positions in dogs. In total, 124 dog owners participated in the study. Among 35 pain-related behavioral/postural changes, 13 of them were reported significantly more often by the owners of the dogs thought to be in pain. Most of the behavioral changes that were reported by the owners were related to movement-based behaviors observed in day-to-day activities. Owners were able to recognize changes in the ear and tail positions which can be related to pain during activity or positional changes (i.e., while standing up and jumping on /off couch). Most of the pain-related behavioral changes were reported in young adult dogs. In senior dogs, reduced general activity, resistance to walking and getting up, having difficulty turning onto both sides while lying down, and stiffness while walking were reported significantly more often in the dogs which were presumed to be in pain (P ≤ 0.05). This research is the first to show that owners are able to notice some of the pain-related behavioral changes in their dogs. They mostly report pain-related changes in behaviors and/or body language of their dogs during everyday contexts, in particular during activity/exercise and positional changes. Thus, it might be significant to pay more attention to those behavioral elements while developing reliable chronic pain scales for dogs in order to include owners' assessments. Pain scales that can be used by owners would help to detect chronic pain at early stages, and further to increase quality of life in dogs.

The Role of Amygdala Calcitonin Gene-related Peptide (CGRP) Receptors in the Development of Persistent Bladder Pain

The underlying mechanisms of visceral pain (e.g. bladder pain) are poorly understood, making it difficult to treat. The central amygdala (CeA) is known as a significant contributor to the pathology of chronic pain. While the CeA in the right hemisphere has been shown to increase bladder pain, the left CeA has been shown to reduce bladder pain. Recent evidence has shown that CeA activity is not only asymmetric, but also changes with time once somatic pain is induced. However, it is unknown whether time-dependent activation of the CeA contributes to the development of chronic bladder pain. We seek to study the hemispherical and temporal changes of the CeA in the context of bladder pain and identify cell-types that might be responsible for contributing to these changes. One interesting target that has been shown to produce asymmetric functions within the brain is calcitonin gene-related peptide (CGRP). In this study, we used a CGRP antagonist – CGRP8-37, to study the role of CeA CGRP receptors (CGRP-Rs) on bladder pain-related changes over time. The effects of CGRP8-37 were examined using a mouse model of bladder pain (100 mg/kg cyclophosphamide, 3 days). Two pain assays, abdominal von Frey and the voiding spot assay were conducted (2-14 days post-injury) in mice that received direct CeA injections (right CeA) of CGRP8-37 (1 uL of 100uM) or saline. Preliminary data indicate that animals that received saline displayed a decrease in 50% withdrawal threshold (bladder nociception) in the abdominal von Frey assay once treated with cyclophosphamide. Animals that received a direct injection of CGRP8-37 displayed an increase in 50% withdrawal threshold (less nociception) compared to saline treated animals. In the voiding assay, CGRP8-37 led to changes in voiding frequency. Collectively, these data support the study of cell-specific manipulation of the right CeA to produce pain relief. Grant support from 7R01DK115478-04 and 1F32DK128969.

Suvorexant and mirtazapine improve chronic pain-related changes in parameters of sleep and voluntary physical performance in mice with sciatic nerve ligation.

Both chronic pain and sleep disorders are associated with a reduction in the quality of life. They can be both a cause and a consequence of each other, and should therefore be simultaneously treated. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related changes in sleep parameters in a preclinical chronic pain mice model, by partial sciatic nerve ligation. We evaluated the quantity, duration, and depth of sleep by analyzing the electroencephalogram and voluntary activity by counting the number of wheel rotations to determine various symptoms of sleep disorders, including reduced total sleep time, fragmentation, low quality, and impaired activity in the daytime. Suvorexant and mirtazapine normalized the reduction in sleep time and fragmented sleep, further regaining the sleep depth at sleep onset in the chronic pain state in nerve-ligated mice. Mirtazapine also increased the percentage of rapid eye movement sleep in mice. Suvorexant decreased voluntary activity, which was prolonged after administration; however, mirtazapine did not decrease it. Although the effects of suvorexant and mirtazapine on sleep and activity are different, both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

Dynamic Pain-Related Changes in Pulse-Graph Measurements in Patients with Primary Dysmenorrhea before and after Electroacupuncture Intervention and Its Correlation with TCM Pattern.

Objective To explore the dynamic changes recorded in pulse graph related to the changes in the severity of pain before and after electroacupuncture (EA) intervention among young women suffering from primary dysmenorrhea (PD). Methods A total of 147 female college students were recruited in this study. Based on participants' symptoms associated with menstruation, they were divided into the PD group and the healthy control group. In addition, participants in the PD group were further sorted into the Cold Coagulation and Blood Stasis Pattern (CCBSP) and Qi Stagnation and Blood Stasis Pattern (QSBSP) based on TCM diagnoses and their pulses differences. Participants in the PD group received EA at maximal pain during menstruation. The primary acupuncture points selected were SP 6 and RN 3, additional RN 4 for CCBSP, and LR 3 for QSBSP. Four observation time points were 7–10 days before menstruation (T0), maximal pain during menstruation (T1), immediately after EA (T2), and 30 mins after EA (T3). The severity of pain was assessed by a visual analog scale (VAS) along with a pulse analyzer to record the variations of the pulse graph throughout the changes of pain level. Results (1) The average VAS score in the PD group decreased from 5.44 ± 1.46 at T1 to 1.72 ± 1.27 at T2 and 1.59 ± 1.30 at T3. The average VAS score in participants of CCBSP at T1, T2, and T3 was higher than that of QSBSP. (2) At T1, h2, h3, h4, and w1/t were all significantly increased, compared with those at T0. At T2, t and t5 were both significantly increased, and w1/t, t1, and t1/t were all significantly decreased, compared with those at T1. At T3, w1/t, t1, and t1/t were all significantly increased, and t and t5 were both significantly decreased, compared with those at T2. (3) Comparing the pulse graphs between the healthy control and the PD groups, h1 was significantly lower at T0; w1/t was significantly higher at T1; t was significantly higher at T2; and t1 and t1/t were both significantly higher at T3 in PD group. (4) When comparing the pulse graphs between QSBSP and CCBSP, t4/t5 was significantly higher at T0 and t1 was significantly higher at T1 in the CCBSP group. Conclusion EA is effective in relieving primary dysmenorrhea. Our results showed the opposite changing of the pulse graph recorded before the onset of pain to the maximum pain and that from maximum pain to pain relief. Indeed, there were differences in the recorded pulse graphs between CCBSP and QSBSP (two patterns of PD) as described in traditional Chinese pulses diagnosis. The study has been registered in the Chinese Clinical Trial Registry (registered number: ChiCTR2000040065; registered date: 2020/11/19).

“I Was Literally Just Not Myself”: How Chronic Pain Changes Multiple Frames of Identity

ABSTRACT Though experienced by more than 1 in 5 (50 million) American adults, chronic pain is invisible, subjective, difficult to communicate, and often stigmatized. When faced with a serious injury or ongoing illness, individuals create an “illness identity” by modifying their goals and expectations for the future, adapting to impairments, and understanding new emotional reactions. The current, two-phase study uses the communication theory of identity (CTI) to explore the process of illness identity adoption in the context of chronic pain, which may be different than for more understood, less stigmatized illnesses. A focus group was conducted (N = 6), from which interview protocol were created. Interview participants (N = 23) described specific differences between their pre- and post-pain selves within three identity frames: personal, relational, and enacted. Within each frame, several sub-themes of pain-related identity changes are identified, as well how they were communicated and how they subsequently influenced communication. Additionally, three pain-related identity gaps, or ways in which two identity frames contradict each other, were identified, all created explicitly because of the onset of chronic pain: personal-enacted, personal-relational, and personal-communal. Theoretical contributions include using CTI to outline the illness identity adoption process in the context of chronic pain, identifying unique identity gaps created by this relatively widespread condition. Practically, understanding pain-related identity outcomes can help pain patients make sense of and manage their situation, and de-stigmatize the chronic pain experience.

Alterations in pain processing circuitries in episodic migraine

BackgroundThe precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli.MethodsFunctional magnetic resonance imaging was performed in 29 healthy controls and 25 migraineurs during the interictal and immediately (within 24-h) prior to migraine phases. We assessed activation of higher cortical areas during noxious orofacial heat stimulation using a thermode device and assessed whole scan and pain-related changes in connectivity.ResultsDespite similar overall pain intensity ratings between all three groups, migraineurs in the group immediately prior to migraine displayed greater activation of the ipsilateral nucleus accumbens, the contralateral ventrolateral prefrontal cortex and two clusters in the dorsolateral prefrontal cortex (dlPFC). Reduced whole scan dlPFC [Z + 44] connectivity with cortical/subcortical and brainstem regions involved in pain modulation such as the putamen and primary motor cortex was demonstrated in migraineurs. Pain-related changes in connectivity of the dlPFC and the hypothalamus immediately prior to migraine was also found to be reduced with brainstem pain modulatory areas such as the rostral ventromedial medulla and dorsolateral pons.ConclusionsThese data reveal that the modulation of brainstem pain modulatory areas by higher cortical regions may be aberrant during pain and these alterations in this descending pain modulatory pathway manifests exclusively prior to the development of a migraine attack.

Injectable, antioxidative, and neurotrophic factor-deliverable hydrogel for peripheral nerve regeneration and neuropathic pain relief

Although peripheral nerve system has intrinsic regeneration potential, recovery from peripheral nerve injury (PNI) is often far from optimal, leading to partial or complete loss of sensorimotor function and neuropathic pain. The failure for PNI repair can be due to multiple reasons. Excessively elevated oxidative stress in injured tissue is one of primary causes for poor nerve regeneration and pain by damaging neurons and myelin structure. In addition, deprivation in various neurotrophic factors (NTFs) in chronic nerve denervation will lose support for nerve regrowth. Here, we developed a multifunctional hyaluronic acid-phenylboronic acid-poly (vinyl alcohol) -heparin (HA-PVA-Hep) hydrogel by mixing cysteamine and phenylboronic acid modified hyaluronic acid, commercially available poly (vinyl alcohol) and maleimide functionalized heparin. This hydrogel is biocompatible, stable, injectable, antioxidative, anti-inflammatory, and capable of sustainably releasing NTFs (i.e. glial cell derived neurotrophic factor-GDNF in this study). The therapeutic effect of HA-PVA-Hep hydrogel to repair acute PNI was tested by using a mouse sciatic nerve crush model. We found the hydrogel effectively improved sensorimotor function during the recovery period and significantly prevented muscular atrophy, protected neurons from injury and promoted nerve regeneration as well as remyelination at 28 days post injury. In addition, the hydrogel could also alleviate PNI-induced pain as hydrogel treatment reversed pain-related changes induced by PNI, including increased expression of a proinflammatory modulator, TNF-α, at injured nerve, activation of microglia and upregulation of pain-sensor receptor, TRPA1 at ipsilateral spinal dorsal horn. Nevertheless, supplementing the hydrogel with GDNF interrupted the PNI recovery process and probably counteracted the pain alleviation effect of the hydrogel. Thus, therapeutic effect of GDNF through local administration on PNI treatment needs to be further determined. In summary, our work provides a hydrogel delivery system with inherent therapeutic effect for PNI therapy.

The Development of Mindful-Based Dance Movement Therapy Intervention for Chronic Pain: A Pilot Study With Chronic Headache Patients.

Chronic pain is of significant global concern. There is growing evidence that body–mind therapies and psychological approaches can contribute toward changing chronic pain perceptions. This is the first model described in the literature that combines a mindfulness-based approach with dance movement therapy and explores the potential psychological and pain-related changes for this client population. In this paper, the results from the pilot study are presented involving patients with chronic headache recruited in an outpatient rehabilitation setting.Methods: In this pilot study, 29 patients (n = 29) with chronic headache were randomized to either the Mindful-Based Dance Movement Therapy (MBDMT) group or the waiting list control group (treatment as usual, TAU). The MBDMT group was offered 10 sessions in a clinical outpatient rehabilitation setting for 5 weeks. Data were collected pre- and post-intervention and 16 weeks after the intervention was finished. The Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire−9 (PHQ-9), Five Facet Mindfulness Questionnaire (FFMQ), and Numeric Rating Scale (NRS) were used as outcome measures.Results: The working model of MBDMT identifies nine therapeutic mechanisms (safe therapeutic environment, mindfulness skills, body awareness, relaxation/releasing, distancing and staying with discomfort, meaning making, self-regulation, acceptance and integration, creative process). Per-protocol analysis reveals statistically significant reduction of pain intensity and depression scores in favor of the MBDMT group, and these improvements were maintained in the follow-up assessment.Conclusions: The results suggest that MBDMT is a feasible and promising therapy approach for chronic pain patients. The pilot study offered sufficient information and preliminary results in the desirable direction to enable the researchers to move to a randomized controlled trial (RCT) stage in order to establish the efficacy of the intervention.Clinical Trial Registration: The study was registered in the www.researchregistry.com, registry (5483).

Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats

Neuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

Rigid head-neck responses to unpredictable perturbations in patients with long standing neck pain does not change with treatment.

In a previous study we have shown that patients with long standing non-specific neck-pain display more rigid neck movement behavior than controls in response to unpredictable perturbations. In the present study we investigated head/neck motor control in patients with neck-pain during a course of physiotherapy intervention and the associations with pain, neck disability and kinesiophobia. In this longitudinal observational study, 72 patients with non-specific neck-pain were exposed to unpredictable horizontal rotations by means of an actuated chair in three conditions; with a visual reference, and without vision with and without a cognitive task before first consultation with physiotherapist, after 2 weeks and 2 months of intervention. The neck movements were analyzed in the frequency domain to cover voluntarily and reflex controlled responses. Questionnaires encompassed Neck Disability Index, Tampa Scale of Kinesiophobia, and the Numerical Rating Scale for current pain. The results showed that the response pattern for the amplitudes of movement between head and trunk across frequencies did not change over time, whereas some changes in timing were found for some frequencies. Pain, neck disability, and kinesiophobia improved after intervention, but were not significantly associated with neck movement responses to perturbations across time or condition. Although physiotherapy intervention improved self-reported function, the rigid responses to unpredictable perturbations remained unchanged. This indicates altered function in reflex mediated control mechanisms, i.e., the vestibulocollic and the cervicocollic reflex systems that control the head in space and on the trunk. Future research should further investigate pain related changes in reflex systems and whether alterations in these systems are modifiable.

Oxytocin prevents neuronal network pain-related changes on spinal cord dorsal horn in vitro

Recently, oxytocin (OT) has been studied as a potential modulator of endogenous analgesia by acting upon pain circuits at the spinal cord and supraspinal levels. Yet the detailed action mechanisms of OT are still undetermined. The present study aimed to evaluate the action of OT in the spinal cord dorsal horn network under nociceptive-like conditions induced by the activation of the N-methyl-d-aspartate (NMDA) receptor and formalin injection, using calcium imaging techniques. Results demonstrate that the spontaneous Ca2+-dependent activity of the dorsal horn cells was scarce, and the coactivity of cells was mainly absent. When NMDA was applied, high rates of activity and coactivity occurred in the dorsal horn cells; these rates of high activity mimicked the activity dynamics evoked by a neuropathic pain condition. In addition, although OT treatment increased activity rates, it was also capable of disrupting the conformation of coordinated activity previously consolidated by NMDA treatment, without showing any effect by itself. Altogether, our results suggest that OT globally prevents the formation of coordinated patterns previously generated by nociceptive-like conditions on dorsal horn cells by NMDA application, which supports previous evidence showing that OT represents a potential therapeutic alternative for the treatment of chronic neuropathic pain.

The transition from acute to chronic pain: dynamic epigenetic reprogramming of the mouse prefrontal cortex up to 1 year after nerve injury.

Chronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive, and emotional information and in conditioned pain modulation. We previously reported widespread epigenetic reprogramming in the PFC many months after nerve injury in rodents. Epigenetic modifications, including DNA methylation, can drive changes in gene expression without modifying DNA sequences. To date, little is known about epigenetic dysregulation at the onset of acute pain or how it progresses as pain transitions from acute to chronic. We hypothesize that acute pain after injury results in rapid and persistent epigenetic remodelling in the PFC that evolves as pain becomes chronic. We further propose that understanding epigenetic remodelling will provide insights into the mechanisms driving pain-related changes in the brain. Epigenome-wide analysis was performed in the mouse PFC 1 day, 2 weeks, 6 months, and 1 year after peripheral injury using the spared nerve injury in mice. Spared nerve injury resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed between spared nerve injury and sham-operated control mice at all time points. Hundreds of differentially methylated genes were identified, including many with known function in pain. Pathway analysis revealed enrichment in genes related to stimulus response at early time points, immune function at later time points, and actin and cytoskeletal regulation throughout the time course. These results emphasize the importance of considering pain chronicity in both pain research and in treatment optimization.

New insights into pain-related changes in muscle activation revealed by high-density surface electromyography

High-density surface electromyography (HDEMG) is an electrophysiological technique that can be used to quantify the spatial distribution of activity within muscles. When pain-free individuals perform sustained or repetitive tasks, different regions within a muscle become progressively more active; this is thought to reflect a strategy to redistribute the load to different regions, thus limiting localised muscle fatigue. The use of HDEMG has revealed that when people with musculoskeletal pain perform the same tasks, the distribution of activity within the same muscle is usually different, and the same muscle region tends to be active throughout the whole task without progressive activation of different muscle regions. This potentially results in a focal overload of a muscle region, and may contribute to fatigue, localised muscle pain and potentially pain persistence and/or recurrence over time. Interestingly, not all patients with musculoskeletal pain present with this regional alteration in muscle activation, reflecting the heterogeneity of patient presentations. This article will briefly review the technique of HDEMG followed by a review of studies demonstrating spatial redistribution of muscle activity in asymptomatic people during both isometric and dynamic conditions, including functional tasks. Lastly, the article will provide a review of HDEMG studies with a focus on changes in the behaviour of the lumbar erector spine and upper trapezius in people with spinal pain. These studies have revealed subtle changes in the distribution of muscle activity in people with spinal pain, which may have relevance for onset, persistence or recurrence of symptoms and could become a target of novel therapeutic approaches.

Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.

Chronic noncancer pain is not associated with accelerated brain aging as assessed by structural magnetic resonance imaging in patients treated in specialized outpatient clinics.

Chronic pain is often associated with changes in brain structure and function, and also cognitive deficits. It has been noted that these chronic pain-related alterations may resemble changes found in healthy aging, and thus may represent accelerated or premature aging of the brain. Here, we test the hypothesis that patients with chronic noncancer pain demonstrate accelerated brain aging compared with healthy control subjects. The predicted brain age of 59 patients with chronic pain (mean chronological age ± SD: 53.0 ± 9.0 years; 43 women) and 60 pain-free healthy controls (52.6 ± 9.0 years; 44 women) was determined using the software brainageR. This software segments the individual T1-weighted structural MR images into gray and white matter and compares gray and white matter images with a large (n = 2001) training set of structural images, using machine learning. Finally, brain age delta, which is the predicted brain age minus chronological age, was calculated and compared across groups. This study provided no evidence for the hypothesis that chronic pain is associated with accelerated brain aging (Welch t test, P = 0.74, Cohen's d = 0.061). A Bayesian independent-samples t test indicated moderate evidence in favor of the null hypothesis (BF01 = 4.875, ie, group means were equal). Our results provide indirect support for recent models of pain-related changes of brain structure, brain function, and cognitive functions. These models postulate network-specific maladaptive plasticity, rather than widespread or global neural degeneration.