Neuropathic Pain: From Mechanisms to Treatment.

Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on α2δ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.

Neuropathic pain caused by miswiring and abnormal end organ targeting.

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

Navigating the complexity of pain in psoriatic arthritis and axial spondyloarthritis.

PURPOSE OF REVIEW: Pain is the most common and often most troublesome feature of chronic autoimmune diseases such as psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). A predominant concept is that the main source of pain is from disease-induced tissue inflammation and structural damage, activating peripheral nerve fibers which relay to the central nervous system. This mechanism is nociceptive pain and the presumption has been that controlling inflammation will be sufficient to reduce this form of pain. However, despite control of inflammation, patients may still have significant residual pain. RECENT FINDINGS: We are learning that there are additional pain mechanisms, neuropathic and nociplastic, that are often operative in patients with rheumatologic conditions, that can significantly influence pain experience, quantitation of disease activity, and may benefit from therapeutic approaches distinct from immunotherapy. Neuropathic pain arises from diseased or damaged nerve tissue and nociplastic pain reflects sensitization of the central nervous system due to multiple genetic, neurobiologic, neural network dysregulation, and psychosocial factors. Pain arising from these mechanisms influence assessment of disease activity and thus needs to be factored into decision-making about immunotherapy efficacy. SUMMARY: This review addresses the importance of accurately assessing the complex mechanisms of pain experience in patients with PsA and AxSpA to more appropriately manage immunomodulatory, neuromodulatory, and nonpharmacologic therapies.

Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain.

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.

Nerve Injury Triggers Time-dependent Activation of the Locus Coeruleus, Influencing Spontaneous Pain-like Behavior in Rats.

BACKGROUND: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, the authors explored the cellular cFos activity of the LC and its projections in conjunction with spontaneous pain-like behavior in neuropathic rats. METHODS: Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic approaches, as were its projections, in association with spontaneous pain-like behaviors. RESULTS: CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)-mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior. CONCLUSIONS: In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.

Sleep disturbance correlated with severity of neuropathic pain in sciatic nerve crush injury model.

The association between sleep and pain has been investigated widely. However, inconsistent results from animal studies compared with human data show the need for a validated animal model in the sleep-pain association field. Our study aims to validate common neuropathic pain models as a tool for evaluating the sleep-pain association. Electrodes electroencephalogram (EEG) and electromyogram (EMG) were surgically implanted to measure sleep. The von Frey test was used to measure pain sensitivity. Following the baseline data acquisition, two pain-modelling procedures were performed: sciatic nerve crush injury (SCI) and common peroneal nerve ligation (CPL). Post-injury measurements were performed on days 1, 5, 10, and 15 post-surgery. The results presented decreased paw withdrawal thresholds and reduced NREM sleep duration in both models on the first post-surgery day. In the SCI model, NREM sleep duration was negatively correlated with paw withdrawal thresholds (p = 0.0466), but not in the CPL model. Wake alpha and theta EEG powers were also correlated with the pain threshold. The results confirm that the SCI model shows disturbed sleep patterns associated with increased pain sensitivity, suggesting it is a reliable tool for investigating sleep disturbances associated with neuropathic pain.

Touch and tactile neuropathic pain sensitivity are set by corticospinal projections.

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain1-4. Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway5, a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal-cortical-spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain.

Analgesic Effect of Exercise on Neuropathic Pain via Regulating the Complement Component 3 of Reactive Astrocytes.

BACKGROUND: Exercise has been proven to be an efficient intervention in attenuating neuropathic pain. However, the underlying mechanisms that drive exercise analgesia remain unknown. In this study, we aimed to examine the role of complement component 3 (C3) in neuropathic pain and whether antinociceptive effects are produced by exercise via regulating C3 in mice. METHODS: In this study, using a spared nerve injury (SNI)-induced neuropathic pain mice model, C57BL/6J mice were divided into 3 groups: Sham mice, SNI mice, and SNI + Exercise (Ex) mice with 30-minute low-intensity aerobic treadmill running (10 m/min, no inclination). Paw withdrawal threshold; thermal withdrawal latency; and glial fibrillary acidic protein, C3, tumor necrosis factor-α, and interlukin-1ß expression in the spinal cord were monitored. C3 knockout (KO) mice were further used to verify the role of C3 in neuropathic pain. RESULTS: von Frey test, acetone test, and CatWalk gait analysis revealed that treadmill exercise for 4 weeks reversed pain behaviors. In addition, exercise reduced astrocyte reactivity (SNI mean = 14.5, 95% confidence interval [CI], 12.7-16.3; SNI + Ex mean = 10.3, 95% CI, 8.77-11.9, P = .0003 SNI + Ex versus SNI) and inflammatory responses in the spinal cord after SNI. Moreover, it suppressed the SNI-induced upregulation of C3 expression in the spinal cord (SNI mean = 5.46, 95% CI, 3.39-7.53; SNI + Ex mean = 2.41, 95% CI, 1.42-3.41, P = .0054 SNI + Ex versus SNI in Western blot). C3 deficiency reduced SNI-induced pain and spinal astrocyte reactivity (wild type mean = 7.96, 95% CI, 6.80-9.13; C3 KO mean = 5.98, 95% CI, 5.14-6.82, P = .0052 C3 KO versus wild type). Intrathecal injection of recombinant C3 (rC3) was sufficient to produce mechanical (rC3-Ex mean = 0.77, 95% CI, 0.15-1.39; rC3 mean = 0.18, 95% CI, -0.04 to 0.41, P = .0168 rC3-Ex versus rC3) and cold (rC3-Ex mean = 1.08, 95% CI, 0.40-1.77; rC3 mean = 3.46, 95% CI, 1.45-5.47, P = .0025 rC3-Ex versus rC3) allodynia in mice. Importantly, exercise training relieved C3-induced mechanical and cold allodynia, and the analgesic effect of exercise was attenuated by a subeffective dose of intrathecal injection of C3. CONCLUSIONS: Overall, these results suggest that exercise suppresses neuropathic pain by regulating astroglial C3 expression and function, thereby providing a rationale for the analgesic effect of exercise as an acceptable alternative approach for treating neuropathic pain.

Effects of Computer-based Balance Exercises on Balance, Pain, Clinical Presentation and Nerve Function in Patients With Diabetic Peripheral Neuropathy: A Randomized Controlled Study.

OBJECTIVE: To evaluate the use of a computer-based biodex balance exercise system (BBS) on balance, neuropathic pain, clinical presentation and nerve function in patients with diabetic peripheral neuropathy (DPN). METHODS: A total of 32 participants with DPN were randomly assigned in a 1:1 ratio to an intervention group (IG) or control group (CG). The IG performed exercises using the BBS twice weekly for 8 weeks, while CG were informed regarding diabetes self-management. At baseline and after study completion, participants underwent balance (postural stability and fall risk) and neuropathic pain assessment (DN4 questionnaire) and were screened using the Michigan Neuropathy Screening Instrument and nerve conduction test. RESULTS: Among the baseline participants, 14 in the IG and 13 in the CG completed the study. Balance training improved postural stability (overall, p<0.001), fall risk (p<0.001), neuropathic pain (p=0.01) and symptoms (p<0.001), and clinical presentation (p=0.02), but not nerve function, within the IG. At follow-up, IG displayed significantly improved stability (p<0.001) and fall risk (p=0.02) and decreased neuropathic symptoms (p=0.01) compared to the CG. CONCLUSION: Computer-based balance exercises improve balance, pain, and clinical presentation of DPN, but not nerve function, in patients with DPN. CLINICALTRIALS: gov ID: NCT05255497.

Neuropathic Pain Component in Patients with Ankylosing Spondylitis and the Relationship of Neuropathic Pain and Disease Activity Parameters: A Cross-Sectional Study.

OBJECTIVE: It is known that neuropathic pain frequently accompanies rheumatological diseases. In this study, neuropathic pain in Ankylosing Spondylitis(AS) and its relationship with disease activity were investigated. METHODS: Forty patients with AS were included. Laboratory data and disease status parameters were recorded. Neuropathic pain questionnaires were administered. Electrophysiological examination was performed on all patients. The relationship between neuropathic pain and disease activity parameters was investigated. RESULTS: According to the Pain Detect and LANSS questionnaire results, the rate of neuropathic pain was 57.5% and 42.5%. ASQoL, BASDAI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the PainDetect (p:0.018, p:0.04, p:0.028). MASES, ASQoL, BASDAI, BASFI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the LANSS (p:0.004, p:0.005, p: 0.001, p:0.005, p:0.02). Disease activity is higher in patients with neuropathic pain for both scales. Peripheral neuropathy is detected in nine patients. There is a positive correlation between disease activity parameters and neuropathic pain scales. A strong positive correlation was detected between ASQoL and BASDAI parameters and the Pain Detect questionnaire (r:0.533, r:0.606). CONCLUSIONS: The majority of patients with AS have a neuropathic pain. This condition is associated with high disease activity and adversely affects the patient's quality of life.

Neuropathic pain has sex-specific effects on oxycodone-seeking and non-drug-seeking ensemble neurons in the dorsomedial prefrontal cortex of mice.

Approximately 50 million Americans suffer from chronic pain, and nearly a quarter of chronic pain patients have reported misusing opioid prescriptions. Repeated drug seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone-seeking behaviour and that the pain state would differentially increase intrinsic excitability in dmPFC drug-seeking ensemble neurons. TetTag mice self-administered intravenous oxycodone. After 7 days of forced abstinence, a drug-seeking session was performed, and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between the first and second seeking session. Following the second seeking session, we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug-seeking ensemble and non-ensemble neurons. SNI had no impact on sucrose seeking or intrinsic excitability of dmPFC neurons from these mice. In females, SNI increased oxycodone seeking and intrinsic excitability of non-ensemble neurons. In males, SNI had no impact on oxycodone seeking or neuron excitability. Data from females are consistent with clinical reports that chronic pain can promote drug craving and relapse and support the hypothesis that chronic pain itself may lead to neuroadaptations which promote opioid seeking.

Advances in the Treatment of Neuropathic Pain by Sympathetic Regulation.

PURPOSE OF REVIEW: To explore the mechanism and therapeutic effect of sympathetic nerve regulation on neuropathic pain. RECENT FINDINGS: A comprehensive search was conducted in the PubMed and CNKI libraries, using the following keywords: stele ganglion block, neuropathic pain, sympathetic nerve block, sympathetic chemical destruction, and sympathetic radiofrequency thermocoagulation. We selected and critically reviewed research articles published in English that were related to sympathetic modulation in the treatment of neuropathic pain. The collected literature will be classified according to content and reviewed in combination with experimental results and clinical cases. Neuropathic pain was effectively treated with sympathetic regulation technology. Its mechanism includes the inhibition of sympathetic nerve activity, regulation of the inflammatory response, and inhibition of pain transmission, which greatly alleviates neuropathic pain in patients. Stellate ganglion blocks, thoracic and lumbar sympathectomies, chemical destruction, and radiofrequency thermocoagulation have been widely used to treat neuropathic pain. Sympathetic regulation can effectively relieve pain symptoms and improve the patient's quality of life by inhibiting sympathetic nerve activity, reducing the production and release of pain-related mediators, and inhibiting pain transmission. CT-guided radiofrequency thermocoagulation of the thoracic and lumbar sympathetic nerves is effective and durable, with few complications, and is recommended as a treatment for intractable neuropathic pain.

The Complexity of Neuropathic Pain and Central Sensitization: Exploring Mechanisms and Therapeutic Prospects.

Neuropathic pain is a common pain syndrome, which seriously affects the quality of life of patients. The mechanism of neuropathic pain is complex. Peripheral tissue injury can trigger peripheral sensitization; however, what really plays a key role is the sensitization of the central nervous system. Central sensitization is a key factor in the perception of chronic pain. Central sensitization refers to the increased sensitivity of the central nervous system to pain treatment, which is related to the change of the functional connection mode of the neural network. The current study aims to reveal the basic molecular mechanisms of central sensitization, including the involvement of P2 purine X4 receptor and brain-derived neurotrophic factor. In terms of treatment, although there are drugs and physical therapy, the accuracy of targeting is limited and the efficacy needs to be further improved. Future therapeutic strategies may involve the development of new drugs designed to specifically inhibit the central sensitization process. This article focuses on the effector molecules involved in central sensitization, aiming to elucidate the pathogenesis of neuropathic pain and provide a basis for the development of more effective treatment models.

Quantitative Sensory Testing in Spinal Cord Stimulation: A Narrative Review.

OBJECTIVES: Quantitative sensory testing (QST) has been used for decades to study sensory abnormalities in multiple conditions in which the somatosensory system is compromised, including pain. It is commonly used in pharmacologic studies on chronic pain but less so in conjunction with neuromodulation. This review aims to assess the utility of QST in spinal cord stimulation (SCS) protocols. MATERIALS AND METHODS: For this narrative review, we searched PubMed for records of studies in which sensory testing has been performed as part of a clinical study on SCS from 1975 onward until October 2023. We focused on studies in which QST has been used to explore the effect of SCS on neuropathic, neuropathic-like, or mixed pain. RESULTS: Our search identified 22 useful studies, all small and exploratory, using heterogeneous methods. Four studies used the full battery of validated German Research Network on Neuropathic Pain QST. There is emerging evidence that assessment dynamic mechanical allodynia (eight studies), and mechanical/thermal temporal summation of pain (eight studies) may have a role in quantifying the response to various SCS waveforms. There also were sporadic reports of improvement of sensory deficits in a proportion of patients with neuropathic pain that warrant further study. CONCLUSIONS: We recommend the adoption of QST into future clinical research protocols, using either the full QST protocol or a less time-demanding short-form QST.

Dorsal Root Ganglion Stimulation Relieves Chronic Neuropathic Pain Along With a Decrease in Cortical γ Power.

BACKGROUND: Stimulation of dorsal root ganglion (DRG) is an ideal neuromodulative intervention, providing pain relief in localized chronic pain conditions because γ-band oscillations reflect the intensity of ongoing chronic pain in patients affected. OBJECTIVE: We aimed to observe the role of cortical γ-band power associated with the relief of chronic neuropathic pain through DRG stimulation (DRGS). MATERIALS AND METHODS: We examined nine patients (two women, mean age 56.8 years; range, 36-77 years) diagnosed with chronic neuropathic pain who underwent DRGS therapy. We used the numeric rating scale (NRS) on the painful limb and simultaneously recorded the electroencephalography to assess the broadband γ power. Assessments were conducted on the first day and on the seventh day after implantation of the DRGS system and then compared and correlated with the results of the NRS. RESULTS: The NRS scores showed a significant decrease from the first day to the seventh day (p = 0.007). The resting-state γ power revealed a significant decrease (p = 0.021) between 30 and 45 Hz, recorded through the central electrode contralateral to the painful limb from the first day (mean [M] = 0.46, SD = 0.25) to the seventh day (M = 0.31, SD = 0.12) after DRGS. There was no significant change in the resting-state γ-band power recorded through the central electrode ipsilateral to the painful limb. However, we found a positive correlation in the γ-band power (rs = 0.628, p = 0.005) with the NRS rating. CONCLUSIONS: A lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system.

Unraveling the Connection: Pain and Endoplasmic Reticulum Stress.

Pain is a complex and multifaceted experience. Recent research has increasingly focused on the role of endoplasmic reticulum (ER) stress in the induction and modulation of pain. The ER is an essential organelle for cells and plays a key role in protein folding and calcium dynamics. Various pathological conditions, such as ischemia, hypoxia, toxic substances, and increased protein production, may disturb protein folding, causing an increase in misfolding proteins in the ER. Such an overload of the folding process leads to ER stress and causes the unfolded protein response (UPR), which increases folding capacity in the ER. Uncompensated ER stress impairs intracellular signaling and cell function, resulting in various diseases, such as diabetes and degenerative neurological diseases. ER stress may be a critical universal mechanism underlying human diseases. Pain sensations involve the central as well as peripheral nervous systems. Several preclinical studies indicate that ER stress in the nervous system is enhanced in various painful states, especially in neuropathic pain conditions. The purpose of this narrative review is to uncover the intricate relationship between ER stress and pain, exploring molecular pathways, implications for various pain conditions, and potential therapeutic strategies.

Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain.

BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Phenotypical characterization of exteroceptive sensation and pain symptoms on diabetic patients.

BACKGROUD: Diabetic neuropathy (DN) is one of the most common complications of diabetes, affecting about half of individuals with the disease. Among the various symptoms of DN, the development of chronic pain stands out and manifests as exacerbated responses to sensorial stimuli. The conventional clinical treatments used for general neuropathy and associated painful symptoms, still brings uncomplete and unsatisfactory pain relief. Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities which difficult the correct diagnosis of sensory comorbidities and consequently, the appropriate chronic pain management. AIMS: Herein, we aimed to demonstrate the existence of different sensory profiles on diabetic patients by investigating epidemiological and clinical data on the symptomatology of a group of patients with DN. METHODS: This is a longitudinal and observational study, with a sample of 57 volunteers diagnosed with diabetes from outpatient day clinic of Hospital Universitário of the University of São Paulo-Brazil. After being invited and signed the Informed Consent Form (ICF), patients were submitted to clinical evaluation and filled out pain and quality of life questionnaires. They also performed quantitative sensory test (QST) and underwent skin biopsy for correlation with cutaneous neuropathology. RESULTS: Data demonstrate that 70% of the studied sample presented some type of pain, manifesting in a neuropathic or nociceptive way, what has a negative impact on the life of patients with DM. We also demonstrated a positive association between pain and anxiety and depression, in addition to pain catastrophic thoughts. Three distinct profiles were identified in the sample, separated according to the symptoms of pain: (i) subjects without pain; (ii) with mild or moderate pain; (iii) subjects with severe pain. We also identified through skin biopsy that diabetic patients presented advanced sensory impairment, as a consequence of the degeneration of the myelinated and unmyelinated peripheral fibers. This study characterized the painful symptoms and exteroceptive sensation profile in these diabetic patients, associated to a considerable level of sensory degeneration, indicating, and reinforcing the importance of the long-term clinical monitoring of individuals diagnosed with DM, regarding their symptom profiles and exteroceptive sensitivity.

Cannabinoid CB2 receptors are upregulated via bivalent histone modifications and control primary afferent input to the spinal cord in neuropathic pain.

Type-2 cannabinoid receptors (CB2, encoded by the Cnr2 gene) are mainly expressed in immune cells, and CB2 agonists normally have no analgesic effect. However, nerve injury upregulates CB2 in the dorsal root ganglion (DRG), following which CB2 stimulation reduces neuropathic pain. It is unclear how nerve injury increases CB2 expression or how CB2 activity is transformed in neuropathic pain. In this study, immunoblotting showed that spinal nerve ligation (SNL) induced a delayed and sustained increase in CB2 expression in the DRG and dorsal spinal cord synaptosomes. RNAscope in situ hybridization also showed that SNL substantially increased CB2 mRNA levels, mostly in medium and large DRG neurons. Furthermore, we found that the specific CB2 agonist JWH-133 significantly inhibits the amplitude of dorsal root-evoked glutamatergic excitatory postsynaptic currents in spinal dorsal horn neurons in SNL rats, but not in sham control rats; intrathecal injection of JWH-133 reversed pain hypersensitivity in SNL rats, but had no effect in sham control rats. In addition, chromatin immunoprecipitation-qPCR analysis showed that SNL increased enrichment of two activating histone marks (H3K4me3 and H3K9ac) and diminished occupancy of two repressive histone marks (H3K9me2 and H3K27me3) at the Cnr2 promoter in the DRG. In contrast, SNL had no effect on DNA methylation levels around the Cnr2 promoter. Our findings suggest that peripheral nerve injury promotes CB2 expression in primary sensory neurons via epigenetic bivalent histone modifications and that CB2 activation reduces neuropathic pain by attenuating nociceptive transmission from primary afferent nerves to the spinal cord.

Neuropathic Pain: Mechanism-Based Therapeutics.

Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.