Chronic Pain States Research Articles

Changes in GABAA Receptor Function Is Dependent on Osteoarthritis Pain State

Osteoarthritis pain is a heterogeneous pain state. Mid-stage osteoarthritis is associated with pain during joint use that abates during rest and can be managed with non-steroidal anti-inflammatory agents (NSAIDs). Advanced osteoarthritis is characterized by development of persistent ongoing pain that is resistant to NSAIDs. Mechanistic differences underlying these different osteoarthritis pain states are poorly understood. This study investigated the hypothesis that changes in spinal GABAA receptor signaling is dependent on the characteristics of the chronic pain state. A murine model of monosodium iodoacetate (MIA)-induced knee joint osteoarthritis (OA) in males and females was used. Mice with mid-stage OA demonstrate weight asymmetry without a persistent ongoing pain state. Mice with advanced OA develop both weight asymmetry and persistent ongoing pain. Control mice received intra-articular saline. Alterations in GABAA receptors were investigated using spinal administration of the GABAA agonist (muscimol) and antagonist (bicuculline). In mice with mid-stage OA, spinal muscimol normalized weight asymmetry whereas spinal bicuculline did not alter weight asymmetry. Conversely, in mice with advanced OA, spinal muscimol failed to alter weight asymmetry whereas bicuculline normalized weight bearing. Further, in mice with advanced OA, muscimol induced conditioned place aversion, indicated worsening of joint pain, whereas bicuculline induced conditioned place preference, indicating pain relief. Restoring KCC2 function through spinal administration of CLP290 reversed weight asymmetry in mice with advanced but not mid-stage OA. These data indicate that GABAA receptors induce net inhibition in mid-stage OA, a chronic pain state characterized by intermittent joint pain. In contrast, GABAA receptors induce net excitation in advanced OA, a chronic pain state characterized by persistent ongoing joint pain. This switch is likely mediated by diminished KCC2 function in the spinal cord. Grant support from NIH Centers of Biomedical Research Excellence (COBRE) Grant P20GM103643

Chronic Pain State Mediates Development of Hippocampal and Renal Inflammatory Responses

Chronic pain and related stress have been previously linked to the development of mood disorders and dysfunction of peripheral organs such as the kidney. While the underlying neurophysiological mechanisms remain elusive, here we examined the effects of chronic pain on activation of immune‐inflammatory responses in the brain and kidney. Male rats were exposed to chronic inflammatory pain for up to 42 days [multiple injections of Freund’s adjuvant (CFA) into the hind paw], which produced a state of chronic allodynia and enhanced behavioral emotionality. Biochemical analysis of the hippocampus, a limbic region that regulates mood and stress responses, showed that CFA evoked increases in expression of ionized calcium binding adaptor molecule 1 (IBA1) and NLRP3 inflammasome proteins, known markers of microglial activation and neuroinflammatory responses, respectively. An increase in the neutrophil gelatinase‐associated lipocalin (NGAL) and IL‐18 are recognized as early diagnostic injury and inflammatory biomarkers of kidney disease. NLRP3 is implicated in the pathogenesis of kidney diseases by regulation of renal inflammation. Analysis via immunocytochemistry demonstrated that CFA also evoked significant increases in NGAL, IL‐18 and NLRP3 protein levels in the renal glomeruli and tubules, suggesting that chronic pain and related stress effects induce renal inflammation and possibly a reduction in kidney function. Together, these findings provide new evidence to support a mechanistical understanding of a bidirectional relationship between chronic pain‐related stress and kidney dysfunction. Further understanding of this relationship could contribute to the identification of novel treatment strategies to diminish both mental health and renal physiological consequences of chronic pain.

Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic–pituitary–adrenal (HPA)‐axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA‐axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA‐axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA‐axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC2R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC2R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double‐labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA‐axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

Autonomic Nervous System Dysregulation and Osteoarthritis Pain: Mechanisms, Measurement, and Future Outlook.

The autonomic nervous system is an important regulator of stress responses and exhibits functional changes in chronic pain states. This review discusses potential overlap among autonomic dysregulation, osteoarthritis (OA) progression, and chronic pain. From this foundation, we then discuss preclinical to clinical research opportunities to close gaps in our knowledge of autonomic dysregulation and OA. Finally, we consider the potential to generate new therapies for OA pain via modulation of the autonomic nervous system. Recent reviews provide a framework for the autonomic nervous system in OA progression; however, research is still limited on the topic. In other chronic pain states, functional overlaps between the central autonomic network and pain processing centers in the brain suggest relationships between concomitant dysregulation of the two systems. Non-pharmacological therapeutics, such as vagus nerve stimulation, mindfulness-based meditation, and exercise, have shown promise in alleviating painful symptoms of joint diseases, and these interventions may be partially mediated through the autonomic nervous system. The autonomic nervous system appears to be dysregulated in OA progression, and further research on rebalancing autonomic function may lead to novel therapeutic strategies for treating OA pain.

Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury.

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.

Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain.

Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.

Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study.

Aim: To evaluate the use of low-dose naltrexone (LDN) as a broad-spectrum analgesic. Methods: Retrospective cohort study from a single pain management practice using data from 2014 to2020. Thirty-six patients using LDN for ≥2months were matched to 42 controls. Pain scores were assessed at initial visit and at most recent/final documented visit using a 10-point scale. Results: Cases reported significantly greater pain reduction (-37.8%) than controls (-4.3%; p<0.001). Whole sample multivariate modeling predicts 33% pain reduction with LDN, with number needed to treat (for 50% pain reduction) of 3.2. Patients with neuropathic pain appeared to benefit even more than those with 'nociceptive'/inflammatory pain. Conclusion: LDN is effective in a variety of chronic pain states, likely mediated by TLR-4 antagonism.

Contextual control of conditioned pain tolerance and endogenous analgesic systems.

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment. To answer this question, we conditioned mice to associate distinct contexts with either repeated administration of a mild visceral pain stimulus (intraperitoneal injection of acetic acid) or vehicle injection over the course of 3 days. On the final day of experiments, animals received either an acid injection or vehicle injection prior to being placed into both contexts. In this way, contextual control of pain sensitivity and pain expectation could be tested respectively. When re-exposed to the noxious stimulus in a familiar environment, both male and female mice exhibited context-dependent conditioned analgesia, a phenomenon mediated by endogenous opioid signaling. However, when expecting the presentation of a painful stimulus in a given context, males exhibited conditioned hypersensitivity whereas females exhibited endogenous opioid-mediated conditioned analgesia. These results are evidence that pain perception and engagement of endogenous opioid systems can be modified through their psychological association with environmental cues. Successful determination of the brain circuits involved in this sexually dimorphic anticipatory response may allow for the manipulation of pain memories, which may contribute to the development of chronic pain states.

Functional connectivity and neurotransmitter impairments of the salience brain network in chronic low back pain patients: a combined resting-state functional magnetic resonance imaging and 1 H-MRS study.

Functional reorganisation of the salience network (SN) has been proposed as one of the key pathomechanisms associated with central nociceptive processing in the chronic pain state. Being associated with an altered functional connectivity within the SN, these processes have been hypothesized to result from a loss of inhibitory function leading to node hyperexcitability and spontaneous pain. Combined resting-state BOLD functional magnetic resonance imaging (MRI) and 1 H-MR spectroscopy was applied to chronic back pain patients and healthy subjects to assess deviations from functional integrity (weighted closeness centrality [wCC], derived from resting-state functional MRI), oscillatory BOLD characteristics (spectral power), and neurotransmitter levels (GABA + , glutamate+glutamine) in 2 key SN nodes, anterior insular (aIns R ) and anterior mid-cingulate cortices. In addition, examinations were repeated in chronic back pain patients after a 4-week interdisciplinary multimodal pain treatment and in healthy subjects after 4 weeks to explore longitudinal, treatment-mediated changes in target variables. The aIns R and, to a lesser extent, the anterior mid-cingulate of patients exhibited significantly reduced wCC accompanied by a spectral power shift from a lower to a higher frequency band, indicating a desynchronization of their neuronal activity within the SN, possibly because of increased spontaneous activations. Without revealing neurotransmitter differences, patients alone showed significant positive associations between local GABA + levels and wCC in aIns R , suggesting a stronger dependence of node synchronization on the inhibitory tone in the chronic pain state. However, this needs to be explored in the future using magnetic resonance spectroscopy techniques that are more sensitive to detecting subtle neurotransmitter changes and also allow multifocal characterization of neurotransmitter tone.

834 Whole-Brain Visualization of Single-Neuron Activity During the Development of Neuropathic Pain

INTRODUCTION: Chronic neuropathic pain is severely disabling and difficult to treat. The pathophysiological mechanisms behind the transition from an acute to chronic neuropathic pain state are not well defined. METHODS: TRAP2 mice are genetically engineered to express tdTomato under dual control of a c-Fos gene promoter and estrogen receptor activation. Seven adult TRAP2 mice underwent unilateral chronic constrictive injury (CCI) of the sciatic nerve, while another six underwent exposure of the nerve without constriction. The mice were administered 4-OHT (to “TRAP” active neurons) one week, three weeks, or six weeks post-injury and maintained for six days before transcardial perfusion. Tissue clarification and confocal imaging/processing allowed for active neuronal populations in distinct brain regions to then be quantified and compared between groups. RESULTS: Allodynia developed in only the CCI groups, as confirmed by paw withdrawal thresholds. Active neuronal populations in the medial thalamus became significantly increased from baseline in all CCI groups. The anterior insula, secondary somatosensory cortex, and lateral parabrachial nucleus demonstrated significantly increased activity from baseline at one week post-injury, but this activity decreased at three and six weeks post-injury. Neuronal activity in the ventral orbital cortex was significantly increased from baseline only at three weeks post-injury, while activity in the anterior nucleus of the periventricular thalamus increased with time and became significantly elevated from baseline at three and six weeks post-injury. CONCLUSIONS: Our model demonstrates a clear increase in the neuronal activity of pain-related medial thalamic and cortical structures in mice who develop a chronic neuropathic pain state. The TRAP model is an ideal method to study brain plasticity during the transition from an acute pain state to chronic pain condition - enhancing our understanding of the mechanisms responsible for central sensitization to chronic neuropathic pain.

126 Regulator of G Protein Signaling 4 (RGS4) Gene Expression is Upregulated in the Superficial Spinal Dorsal Horn and in Dorsal Root Ganglion Neurons in a Murine Model of Neuropathic Pain

INTRODUCTION: Regulator of G protein signaling 4 (RGS4), a potent negative regulator of G-protein coupled receptor signaling, is a key gene in the maintenance of mechanical and cold allodynia associated with chronic pain states in mice. RGS4 is abundantly expressed across the pain matrix, and is upregulated in response to peripheral inflammation and nerve injury. METHODS: To understand the dynamics of RGS4 gene expression after nerve injury, we perform the spared-nerve injury (SNI) model of neuropathic pain in C57BL/6. At 21 days (DRG) or 2.5 months (spinal cord) post-surgery (SNI vs sham), animals were sacrificed and specimens were harvested for tissue processing. RNAScope, an ultrasensitive RNA ISH method, was used to visualize and quantify single-molecule expression of RGS4, prodynorphin/PDYN (exclusively expressed by inhibitory dorsal horn interneurons), and somatostatin/SST (expressed by excitatory interneurons) within the cellular topography of the lumbar superficial dorsal horn. RESULTS: RGS4 expression increased significantly in the dorsal horn following spared-nerve injury (p = 0.0384). In sham-treated mice, there were no differences in cell-type-specific (PDYN vs. SST) RGS4 expression patterns in the dorsal horn (p = 0.4170). Cell-type-specific RGS4 expression in the dorsal horn was significantly different (F (2,27) = 8.353; p = 0.0015; one-way ANOVA) following SNI. SNI-induced RGS4 expression was significantly enriched in PDYN vs SST-expressing interneurons (p = 0.0300), and overall RGS4 expression was significantly downregulated in SST-expressing cells compared to all cells (p = 0.0012). In addition, neuronal-specific RGS4 expression was significantly increased in the DRG in SNI vs Sham-injured mice (p = 0.0050). CONCLUSION: Our data suggest that upregulation of RGS4 expression in the superficial dorsal horn and DRG may play a crucial role in maintenance of chronic pain following nerve injury.

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.

Neurohumoral Profiles and Childhood Adversity of Patients with Multisomatoform Disorder and Pain as the Leading Bodily Symptom.

Objective Patients suffering from chronic pain often present with multifactorial underlying conditions, sometimes without concrete pathological physical findings. Functional somatic syndromes (FSS) and somatoform disorders show a high prevalence of 8-20% and are often associated with adverse childhood experiences (ACE) and chronic stress. As many different FSS have overlapping symptoms, the concept of multisomatoform disorder (MSD) has been introduced as an encompassing concept. We hypothesize that a common neurohumoral profile is present in patients with MSD that is distinct from gender- and age-matched controls and thus provides insight into possible common underlying mechanisms. Design In 151 patients with MSD (138 females) and 149 matched controls (131 females), we determined ACE by the Childhood Trauma Questionnaire (CTQ) and chronic stress by the Trier Inventory for Chronic Stress (TICS). Furthermore, the serum levels of leptin, FSH, LH, cortisol, DHEA-S, and IGF-1 have been assessed. Results There were significant differences in the levels of leptin, FSH, IGF-1, and cortisol between patients and controls, mainly driven by female participants. Levels of leptin were significantly correlated with BMI in patients, in controls, and in the female subgroup. This correlation was exaggerated in female patients when compared to female controls. Both CTQ and TICS predicted MSD directly and indirectly through the levels of leptin. Conclusion There is evidence of a distinct neurohumoral profile in female patients with MSD when compared to matched healthy controls, similar to what has been demonstrated in other chronic pain states. The observed profile can be taken as possible evidence for a dysregulated response to chronic stress and metabolic balance as well as a state of hypocortisolism and HPA-axis dysfunction. ACE and chronic stress play a major role in the development of MSD and altered neurohumoral profile.

Pulsed Radiofrequency Increases Nestin and Matrix Metalloproteinase-2 Expression in Porcine Lumbar Dorsal Root Ganglion.

BackgroundPulsed radiofrequency (PRF) has been used for the treatment of chronic lumbar radicular pain and other chronic pain states. The dorsal root ganglion (DRG) consists of primary afferent somatic and visceral nerve cell bodies that transduce sensory signals from the periphery to the central part of the nervous system. It is a very important part of acute nociception, as well as the development and maintenance of chronic pain.MethodsA total of seven domestic pigs were investigated. All pigs underwent a PRF procedure while under general anesthesia and with X-ray imaging. Four lumbar DRGs were randomly treated. We used the opposite side of the DRGs as controls. The lumbar region of the spine was placed in 10% formaldehyde for one month. After this fixation, DRG samples were prepared for slide analysis.ResultsNestin (Nes, code-Nr. AB 5968, dilution 1:250, rabbit, Abcam, United Kingdom) and matrix metallopeptidase 2 (MMP-2, code-Nr. DUB 03, dilution 1:100, goat) expressions were detected by immunohistochemical staining. The cell numbers with Nes (28.4 ± 3.3 vs. 16.1 ± 3.4; P < 0.05) and MMP-2 (26.2 ± 3.2 vs. 14.1 ± 2.3; P < 0.05) expressions were larger on the PRF side compared to the control side. The glial cells in the spinal ganglia on both sides showed immunoreactivity.ConclusionsThe increase of MMP-2-containing gangliocytes one month after PRF procedures highlights active neural cell proliferation. Increased Nes factor expression in spinal gangliocytes of the lumbar region indicates neural remodeling and regeneration.

Electrophysiological characterization of ectopic spontaneous discharge in axotomized and intact fibers upon nerve transection: a role in spontaneous pain?

Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.

A nigra-subthalamic circuit is involved in acute and chronic pain states.

The basal ganglia modulate somatosensory pain pathways, but it is unclear whether a common circuit exists to mitigate hyperalgesia in pain states induced by peripheral nociceptive stimuli. As a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) may be a candidate for this role. To test this possibility, we optogenetically modulated SNr GABAergic neurons and examined pain thresholds in freely behaving male mice in inflammatory and neuropathic pain states as well as comorbid depression in chronic pain. We observed that stimulation of either SNr GABAergic neurons or their projections to the subthalamic nucleus (STN) significantly alleviated nociceptive responses in all pain states on the contralateral side and comorbid depression in chronic pain, and that this analgesic effect was eliminated when SNr-STN GABAergic projection was blocked. However, SNr modulation did not affect baseline pain thresholds. We also found that SNr-STN GABAergic projection was attenuated in pain states, resulting in disinhibition of STN neurons. Thus, impairment of the SNr-STN GABAergic circuit may be a common pathophysiology for the maintenance of hyperalgesia in both inflammatory and neuropathic pain states and the comorbid depression in chronic pain; compensating this circuit has potential to effectively treat pain related conditions.

Time-Dependent Changes in Protein Composition of Medial Prefrontal Cortex in Rats with Neuropathic Pain.

Chronic pain is associated with time-dependent structural and functional reorganization of the prefrontal cortex that may reflect adaptive pain compensatory and/or maladaptive pain-promoting mechanisms. However, the molecular underpinnings of these changes and whether there are time-dependent relationships to pain progression are not well characterized. In this study, we analyzed protein composition in the medial prefrontal cortex (mPFC) of rats at two timepoints after spinal nerve ligation (SNL) using two-dimensional gel electrophoresis (2D-ELFO) and liquid chromatography with tandem mass spectrometry (LC–MS/MS). SNL, but not sham-operated, rats developed persistent tactile allodynia and thermal hyperalgesia, confirming the presence of experimental neuropathic pain. Two weeks after SNL (early timepoint), we identified 11 proteins involved in signal transduction, protein transport, cell homeostasis, metabolism, and apoptosis, as well as heat-shock proteins and chaperones that were upregulated by more than 1.5-fold compared to the sham-operated rats. Interestingly, there were only four significantly altered proteins identified at 8 weeks after SNL (late timepoint). These findings demonstrate extensive time-dependent modifications of protein expression in the rat mPFC under a chronic neuropathic pain state that might underlie the evolution of chronic pain characterized by early pain-compensatory and later aberrant mechanisms.

Facilitatory Effect of Intermittent Repetitive Transcranial Magnetic Stimulation on Perceptual Distortion of the Face

Orofacial pain patients often report that the painful facial area is “swollen” without clinical signs - known as perceptual distortion (PD). The neuromodulatory effect of facilitatory repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals was investigated, to provide further support that the primary somatosensory cortex (SI) is involved in facial PD. Participants were allocated to active (n = 26) or sham (n = 26) rTMS group in this case-control study. PD was induced experimentally by injecting local anesthesia (LA) in the right infraorbital region. PD was measured at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. Intermittent theta-burst stimulation (iTBS) as active rTMS and sham rTMS was applied to the face representation area of SI at 10 min after LA. The magnitude of PD was compared between the groups. The magnitude of PD significantly increased immediately after iTBS compared with sham rTMS (P = .009). The PD was significantly higher immediately after iTBS compared to 6 min after LA (P = .004) in the active rTMS group, but not in the sham rTMS group (P = .054). iTBS applied to a somatotopic-relevant cortical region appears to facilitate facial PD further supporting the involvement of SI in the processing of one´s own face and PD. PerspectiveThis study provides information on neural substrate responsible for processing of perceptual distortion of the face which is speculated to contribute to the chronification of orofacial pain. The findings of this study may aid in mechanism-based management of the condition in orofacial pain disorders and possibly other chronic pain states.

Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation.

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

Pain in focus in patients with osteoarthritis

Introduction. Peripheral joint osteoarthritis is the leading cause of musculoskeletal pain and functional limitation. Osteoarthritis has a high prevalence and incidence and, therefore great socioeconomic importance. Clinical presentation. Pain in osteoarthritis results from a complex interaction of sensory, affective, and cognitive processes that include numerous abnormal cellular mechanisms at the affected joints and different levels of the nervous system involved in the pathophysiological mechanisms of chronic pain (spinal and supraspinal). In chronic pain states, central nervous system factors are particularly prominent. Although there are several ways to determine pain sensitivity, data suggest that assessing pressure pain threshold (i.e., tenderness to palpation) is the most reliable and reproducible method for identifying individuals with a centralized pain state. Conclusion. Significant advances in our understanding of pain pathophysiology and pain biomarkers are finally making the vision of ?personalized analgesia?. Clinicians can identify the sub-sets of individuals with what were once considered purely ?peripheral? pain syndromes and treat these patients with approaches directed more centrally than peripherally.