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BACKGROUND AND AIMS: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF1) agonist, cortagine. METHODS: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine. KEY RESULTS: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p

• Cerebrospinal fluid-contacting nucleus is present in the mouse brain and is involved in the regulation of acute thermal pain. • Targeted modulation of cerebrospinal fluid-contacting nucleus neurons can be achieved by the Cre/LoxP system. • NRG1-ErbB4 signaling is expressed in the cerebrospinal fluid-contacting nucleus in brain and interferes with thermal pain. The cerebrospinal fluid-contacting nucleus(CSF-contacting nucleus) is a pair of unique nuclei in the brain parenchyma which has long been demonstrated to play an important role in pain signal processing. However, the mechanisms by which the CSF-contacting nucleus intervenes in pain is unclear. The NRG1-ErbB4 signaling plays an important role in the nervous system and has been shown to be involved in the regulation of pain. Whether there is an involvement of NRG1-ErbB4 signaling in the regulation of pain in the CSF-contacting nucleus is currently unknown. Here, our works showed that c-Fos expression in the CSF-contacting nucleus was increased in response to incisional pain. The activation of the CSF-contacting nucleus by chemogenetics could induce thermal hyperalgesia in naive mice without effecting the pain in mice suffering from incision pain. The inhibition of the CSF-contacting nucleus alleviated incision pain, but had no effect on the pain response in naive mice. With immunofluorescence staining and Western blot, the NRG1-ErbB4 signaling in the CSF-contacting nucleus showed upregulated during the acute pain phase. And, activating NRG1-ErbB4 signaling in the CSF-contacting nucleus specifically by intracranial injection of drugs, the naïve mice displayed thermal hyperalgesia while inhibiting this signaling by intracranial injection could reverse the hyperalgesia caused by CSF-contacting nucleus activation, and execute an analgesic effect during the painful phase in mice. Our study suggested that the CSF-contacting nucleus plays a regulatory role in thermal pain in mice via NRG1-ErbB4 signaling. [ABSTRACT FROM AUTHOR]

Introduction: Acute lower back pain can lead to neuroplastic changes in the central nervous system, and symptoms of central sensitization after 12 weeks. While sensory sensitivity has been shown to predict symptoms of central sensitization, trait sensory profiles may be prognostic in the persistence of central sensitization symptoms in low back pain over time. Objective: To examine sensory profiles as prognostic symptoms of central sensitization in people with acute low back pain. Methods: A longitudinal type 2 prognostic factor research study was performed according to the PROGRESS framework. Baseline and 12-week follow-up measures were taken using the Adolescent/Adult Sensory Profile and the Central Sensitization Inventory measures. Study participants were consecutively included from primary care physiotherapy practices. Univariable, and multivariable regression analyses were performed to adjust sensory profiles based on previous history of low back pain, baseline Central Sensitization Inventory scores, level of pain, disability, age, and duration of low back pain. Results: After adjustment, the sensory profiles of Low Registration B = 0.44, 95%CI (0.18, 0.70), Sensation Seeking B = 0.38, 95%CI (0.19, 0.57), Sensory Sensitive B = 0.49, 95%CI (0.25, 0.74), Sensation Avoiding B = 0.40, 95% CI (0.15, 0.65) was significantly associated with the persistence of central sensitization symptoms (N = 103). Conclusion: Sensory profiles may predict symptoms of central sensitization after 12 weeks in people with acute low back pain. [ABSTRACT FROM AUTHOR]

Neurotransmitters and neuromodulators can be released via either action potential (AP)-evoked transient or AP-independent continuous neurotransmission. The elevated AP-evoked neurotransmission in the primary sensory neurons plays crucial roles in hyperalgesia. However, whether and how the AP-independent continuous neurotransmission contributes to hyperalgesia remains largely unknown. Here, we show that primary sensory dorsal root ganglion (DRG) neurons exhibit frequent spontaneous microdomain Ca2+ (smCa) activities independent of APs across the cell bodies and axons, which are mediated by the spontaneous opening of TRPA1 channels and trigger continuous neurotransmission via the cyclic adenosine monophosphate-protein kinase A signaling pathway. More importantly, the frequency of smCa activity and its triggered continuous neurotransmission in DRG neurons increased dramatically in mice experiencing inflammatory pain, inhibition of which alleviates hyperalgesia. Collectively, this work revealed the AP-independent continuous neurotransmission triggered by smCa activities in DRG neurons, which may serve as a unique mechanism underlying the nociceptive sensitization in hyperalgesia and offer a potential target for the treatment of chronic pain. [ABSTRACT FROM AUTHOR]

Background: Interventional therapy of trigeminal neuropathic pain has been well documented; however, intraoperative monitoring and management of pain hypersensitivity remains barely reported, which may pose a great challenge for pain physicians as well as anesthesiologists. Case presentation: A 77-year-old Han Chinese male, who suffered from severe craniofacial postherpetic neuralgia, underwent pulsed radiofrequency of trigeminal ganglion in the authors' department twice. The authors successfully placed a radiofrequency needle through the foramen ovale during the first procedure with local anesthesia and intravenous sedation (dexmedetomidine). The patient reported about 50% pain reduction postoperatively, and the second procedure was performed 1 week later. However, the intraoperative administration of sedative agents was suspended owing to hemodynamic instability during the second session. As a result, the patient displayed hypersensitivity to the percutaneous operation under local anesthesia and the authors failed to place the needle inside the Meckel's cave for uncontrollable breakthrough pain. The patient still needed to take oral medication for pain control, oxycodone (10–20 mg, every 12 hours) and pregabalin (75 mg, two times a day) in the last follow-up at 1.5 years after discharge. Conclusion: The authors report a failure case of percutaneous puncturing operation with trigeminal neuropathic pain, potentially caused by intraoperative sensitization. It is essential to monitor and prevent hypersensitivity to both innoxious and noxious stimuli in patients with neuropathic pain syndrome, especially at surgical sites close to the area of nerve injury. [ABSTRACT FROM AUTHOR]

Background: Low back pain (LBP) is a leading cause of disability worldwide, often driven by distinct pain mechanisms: nociceptive, neuropathic, and central sensitization. Accurate classification of these mechanisms is critical for guiding effective, targeted treatments. Methods: A scoping review was conducted following the Joanna Briggs Institute methodology and reported according to PRISMA-ScR guidelines. A comprehensive literature search was performed in MEDLINE, Cochrane CENTRAL, Scopus, PEDro, and Web of Science. Eligible studies included adults with LBP and focused on clinical criteria for classifying pain mechanisms. Data on study methods, population characteristics, and outcomes were extracted and synthesized. Results: Nine studies met the inclusion criteria. Nociceptive pain was characterized by localized symptoms proportional to mechanical triggers, with no neurological signs. Neuropathic pain was associated with burning sensations, dysaesthesia, and a positive neurodynamic straight leg raise (SLR) test. Central sensitization featured widespread pain, hyperalgesia, and disproportionate symptoms. Tools such as painDETECT, DN4, and the Central Sensitisation Inventory (CSI) were validated for neuropathic and central sensitization pain. Central sensitization and neuropathic pain were linked to greater disability and psychological distress compared to nociceptive pain. Conclusions: This review aims to provide a historical perspective on pain mechanism classifications and to explore how previous frameworks have influenced current diagnostic concepts in physiotherapy practice. By synthesizing key clinical criteria used to differentiate between nociceptive, neuropathic, and central sensitization pain, this review proposes a practical framework to improve the accuracy of pain classification in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is prevalent among patients receiving paclitaxel chemotherapy, which results in sensory abnormality as well as neuropathic pain. Conventional medications lack effectiveness on PIPN. Clinical trials identified beneficial effects of acupuncture on PIPN among patients receiving chemotherapy. Here we explored the mechanisms underlying how acupuncture might alleviate PIPN. Methods: A mouse model of PIPN was established by repeated paclitaxel application. Electroacupuncture (EA) was applied at ST36 and BL60 acupoints of model mice. Immunostaining, flow cytometry, behavioral assay, in vivo imaging were utilized for effects determination and mechanism exploration. Results: EA ameliorated mechanical and cold pain hypersensitivities, reduced sensory neuron damage and improved loss in intra-epidermal nerve fibers (IENFs) in model mice. Macrophages infiltration were detected in DRG and sciatic nerve of model mice, which was reduced by EA. EA affected M1-like pro-inflammatory macrophage infiltration in DRG, whereas it did not affect M2-like macrophages. DRG neurons released chemoattractant CCL2 that recruited macrophages via CCR2 to DRG. EA reduced CCL2 overproduction by DRG neurons and reduced macrophage infiltration. Blocking CCR2 mimicked EA's anti-allodynic effect, whereas exogenously applying recombinant CCL2 reversed the ameliorative effect of EA on macrophage infiltration and abolished EA's anti-allodynia on model mice. EA ameliorated other signs of PIPN, including sensory neuron damage, sciatic nerve morphology impairment and IENFs loss. In mice inoculated with breast cancer cells, EA didn't affect paclitaxel-induced antitumor effect. Conclusions: These findings suggest EA alleviates PIPN by reducing CCL2/CCR2 mediated-pro-inflammatory macrophage infiltration into sensory ganglia as well as the sciatic nerve. Our study supports EA could be used as a potential non-pharmacological therapy for PIPN. [ABSTRACT FROM AUTHOR]

Hyperalgesia is a condition marked by an abnormal increase in pain sensitivity, often occurring in response to tissue injury, inflammation, or prolonged exposure to certain medications. Inflammatory mediators, such as cytokines IL-1β, IL-6, and TNF-α, play a central role in this process, amplifying pain perception. Developing effective treatments that address the underlying mechanisms of hyperalgesia is an active field of research. Apis mellifera syriaca venom demonstrated potential immunomodulatory activity associated with cytokine release in vivo. Therefore, the aim of this study is to evaluate the effect of Apis mellifera syriaca bee venom (AmsBV) on pain sensitivity in a formalin-induced hyperalgesia mice model and to evaluate the potential role of cytokines associated with the nociception of pain. The hotplate test, used to measure pain latency, showed that hypersensitivity to pain was induced in formalin-injected male mice only, with no changes in females, suggesting a sex-based response to formalin. When applied, AmsBV reduced pain sensitivity in males, suggesting pain relief potential. At the molecular level, AmsBV was able to reduce pro-inflammatory interleukin IL-4 and cytokine IFN-γ, emphasizing its immunomodulatory potential. Interestingly, the venom restored anti-inflammatory IL-10 levels that were significantly decreased in hyperalgesia males. Together, these findings highlight the therapeutic potential for AmsBV in managing inflammation and reducing pain, particularly hyperalgesia. [ABSTRACT FROM AUTHOR]

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement of several neurochemical systems in DNIC/CPM and point to a major contribution of the noradrenergic, serotonergic, and opioidergic systems. Here, we thoroughly review the latest data on the monoaminergic and opioidergic studies, focusing particularly on pre-clinical models of chronic pain. We also conduct an in-depth analysis of these systems by integrating the available data with the descending pain modulatory circuits and the neurochemical systems therein to bring light to the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic effects but also hyperalgesic effects. This duality might be explained by the underlying circuitry and the receptor subtypes involved therein. Acknowledging this duality might contribute to validating the prognostic nature of the paradigm. Additionally, DNIC/CPM may serve as a robust paradigm with predictive value for guiding pain treatment through more effective targeting of descending pain modulation. [ABSTRACT FROM AUTHOR]

The course and outcome of infection with the parasitic protozoa Leishmania major depends on the host immune response which, itself, depends mainly on the cytokine milieu, especially early in the infection. It is widely accepted that INF-γ, TNF-α, and IL-12 usually favor a protective response, while IL-4, IL-5, IL-10, and IL-13 favor a pathogenic one. These and other cytokines also play a major role in Leishmania-induced hyperalgesia via two possible pathways, one involving prostaglandins and the other sympathetic amines as final mediators, preceded by a cascade of cytokines, among which TNF-α seems to play a pivotal role via a still unclear mechanism of action. This study investigates the effects of anti-TNF-α antibody (Infliximab) on L. major-induced hyperalgesia in susceptible BALB/c mice using the hot plate and tail flicks tests, as well as the levels of many cytokines in the infected paws of mice using the ELISA technique. In addition, the parasite burden was assessed using the serial dilution method. Our results show that Infliximab can reduce the induced hyperalgesia, up-regulate TNF-α, IL-1β, and keratinocyte-derived chemokine (KC), and down-regulate IL-10 and IL-17 in the paws of infected mice. Infliximab may also have beneficial effects on the prognosis of cutaneous leishmaniasis by reducing the parasite burden. [ABSTRACT FROM AUTHOR]

This study compared the degree of secondary hyperalgesia and somatosensory threshold changes induced by topical capsaicin between spinal and trigeminal innervation. This crossover clinical trial included 40 healthy individuals in which 0.25 g of 1% capsaicin cream was randomly applied for 45 minutes to a circular area of 2 cm2 to the skin covering the masseter muscle and forearm in 2 different sessions, separated by at least 24 hours and no more than 72 hours (washout period). The main outcome variables were the area of allodynia and pinprick hyperalgesia, as well as electrical and mechanical pain thresholds within the area of pinprick hyperalgesia. Mixed ANOVA models and McNemar tests were applied to the data (p = 0.050). The occurrence of allodynia and pinprick hyperalgesia was higher in the forearm than in the masseter (p < 0.050). Additionally, the areas of pinprick hyperalgesia and allodynia were larger in the forearm compared to the masseter (p < 0.050). The electrical and mechanical pain thresholds demonstrated a loss of somatosensory function following capsaicin application to the masseter (p < 0.050). However, no significant somatosensory threshold changes were observed at the forearm after capsaicin (p > 0.050). In conclusion, these findings indicate potential differences compatible with central sensitization related to secondary hyperalgesia between trigeminal and spinal innervation. [ABSTRACT FROM AUTHOR]

Background: Migraine is a painful neurological syndrome characterized by attacks of throbbing headache, of moderate to severe intensity, which is associated with photo- and phono- sensitivity as well as nausea and vomiting. It affects about 15% of the world's population being 2–3 times more prevalent in females. The calcitonin gene-related peptide (CGRP) is a key mediator in the pathophysiology of migraine, and a significant advance in the field has been the development of anti-CGRP therapies. The trigeminal ganglion (TG) is thought to be an important site of action for these drugs. Moreover, experimental migraine can be induced by CGRP injection in the TG. The signaling pathway induced by CGRP in the TG is not fully understood, but studies suggest that voltage-gated calcium channels contribute to CGRP effects relevant to migraine. Objective: We hypothesised that CGRP injection in the TG enhances CaV3.2 T-type calcium channel currents to contribute to the development of periorbital mechanical allodynia. Results: A Co-Immunoprecipitation assay in tsA-201 cells revealed that CaV3.2 channels form a complex with RAMP-1, a component of the CGRP receptor. Constitutive CGRPR activity was able to inhibit CaV3.2 channels and induce a depolarizing shift in both activation and inactivation curves. Incubation of TG neurons with CGRP increased T-type current density by ~ 3.6 fold, an effect that was not observed in TG neurons from CaV3.2 knockout mice. Incubation of TG neurons with Z944, a pan T-type channel blocker, resulted in an approximately 80% inhibition of T-type currents. In vivo, this treatment abolished the development of periorbital mechanical allodynia induced by CGRP in male and female mice. Likewise, CaV3.2 knockout mice did not develop periorbital mechanical allodynia after intraganglionic CGRP injection. Finally, we demonstrated that the CGRP effect depends on the activation of its canonical GPCR, followed by protein kinase A activation. Conclusion: The present study suggests that CGRP modulates CaV3.2 in the TG, an effect possibly mediated by the canonical CGRP receptor and PKA activation. The increase in T-type currents in the TG may represent a contributing factor for the initiation and maintenance of the headache pain during migraine. [ABSTRACT FROM AUTHOR]

Background: To improve perioperative pain management, several interventions have been suggested for the prevention of increased pain sensitivity caused by opioids (called opioid-induced hyperalgesia). It is currently unclear which intervention is the most effective or appropriate in preventing opioid-induced hyperalgesia. Remifentanil is the most investigated opioid causing opioid-induced hyperalgesia. Thus, to guide future research, we conducted a systematic review and a network meta-analysis of preclinical trials investigating pharmacological interventions for remifentanil-induced hyperalgesia. Methods: To identify relevant articles, electronic database searches were conducted in Embase, PubMed, Web of Science, and Google Scholar. Study characteristics were extracted, and the risk of bias was evaluated. Studies were included in the network meta-analysis if they shared similar characteristics with at least one other study. The interventions were ranked based on P-scores. Results: Overall, the 62 eligible trials tested 86 individual interventions and 6 combination interventions. Thirty-five studies eligible in the network meta-analysis formed five groups which were further divided into subgroups based on the quantitative sensory tests used. The best-ranked interventions within the subgroups were Anxa12-26, MRS2179, salicylaldehyde isonicotinoyl hydrazone (SIH), ANA-12, TDZD-8, ketamine, dexmedetomidine, JWH015, and the combination of KN93 and ketamine. Discussion: The current literature is too heterogeneous to produce a clear answer on which intervention is the most effective in preventing remifentanil-induced hyperalgesia. Future research in this field should prioritise finding the most effective intervention over testing the efficacy of new options. The results of our work can be used in planning which comparisons should be included in new trials. [ABSTRACT FROM AUTHOR]

Background: Chronic pain poses a clinical challenge due to its associated costly disability and treatment needs. Determining how pain transitions from acute to chronic is crucial for effective management. Upregulation of the chemokine C-X-C motif ligand 12 (CXCL12) in nociceptive pathway is associated with chronic pain. Our previous study has reported that elevated plasma CXCL12 mediates intracerebral neuroinflammation and the comorbidity of cognitive impairment in neuropathic pain, but whether it is also involved in the pathogenesis of pathologic pain has not been investigated. Methods: Intravenous or intrathecal injection (i.v. or i.t.) of recombinant mouse CXCL12, neutralizing antibody (anti-CXCL12) or AMD3100 [an antagonist of its receptor C-X-C chemokine receptor type 4 (CXCR4)] was used to investigate the role of CXCL12 signaling pathway in pain chronicity. Two behavioral tests were used to examine pain changes. ELISA, immunofluorescence staining, Western blot, quantitative Real Time-PCR and Cytokine array were applied to detect the expressions of different molecules. Results: We found that increased plasma CXCL12 was positively correlated with pain severity in both chronic pain patients and neuropathic pain model in mice with spared nerve injury (SNI). Neutralizing plasma CXCL12 mitigated SNI-induced hyperalgesia. A single i.v. injection of CXCL12 induced prolonged mechanical hyperalgesia and activation of the nociceptive pathway. Multiple intravenous CXCL12 caused persistent hypersensitivity, enhanced structural plasticity of nociceptors and up-regulation of the CXCL12/CXCR4 axis in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH). However, intrathecal blocking of CXCL12/CXCR4 pathway by CXCL12 antibody or CXCR4 antagonist AMD3100 significantly alleviated CXCL12-induced pain hypersensitivity and pathological changes. Conclusions: Our study provides strong evidence that a sustained increase in plasma CXCL12 contributes to neuropathic pain through a positive feedback loop that enhances nociceptor plasticity, and suggests that targeting CXCL12/CXCR4 axis in plasma or nociceptive pathways has potential value in regulating pain chronicity. Highlights: 1) Plasma CXCL12 in neuropathic pain states were positively correlated with pain severity. 2) A sustained increase in plasma CXCL12 contributes to pain chronicity. 3) Elevated plasma CXCL12 enhances spinal synaptic structural plasticity of pain through positive feedback. [ABSTRACT FROM AUTHOR]

Lacrimal hyperalgesia is a rare type of periorbital neuralgia triggered by tear production. Two female patients in their mid-forties underwent orbital surgery and, several weeks following their procedures, developed pain when they produced tears. The symptom was described as a sharp, debilitating, and transient periocular pain. A possible mechanism for this lacrimal hyperalgesia is through the formation of an artificial synapse along the superolateral aspect of the orbit. Two mechanisms for this type of hyperalgesia are described herein, which include potential mechanical compression or direct disruption of the normal nerve pathways and microvascular disruption causing ischemic nerve injury. Currently, there is no accepted treatment for this aberrant neuropathic pain caused by lacrimation. Gabapentin therapy was trialed in one of these two patients, who experienced partial improvement with nightly use. In this case series, we describe the clinical and radiographic features associated with this unique type of neuralgia, emphasizing the importance of recognizing it as a complication following orbital surgery. [ABSTRACT FROM AUTHOR]

Background/Objectives: Fibromyalgia syndrome (FMS) is a multifactorial pain syndrome not only characterized by widespread pain as the primary symptom but also accompanied by physical, psychological, and cognitive manifestations. Impairments in conditioned pain modulation (CPM) are common in this population; however, there is significant heterogeneity in the CPM response among women with FMS. The Left/Right Judgment Task (LRJT) is a validated method for studying motor imagery in chronic pain patients. Previous scientific evidence has not yet thoroughly investigated the relationship between CPM alterations and motor imagery processes in FMS patients. The aim of this study was to investigate the relationship between CPM and motor imagery. Methods: This is a secondary analysis of a cross-sectional study. Pain intensity (NPRS), disability (FIQ), mechanical hyperalgesia (PPT), descending pain modulation (CPM), and laterality discrimination (LRJT) were assessed in 30 women diagnosed with FMS. Participants were divided into two groups, responder and non-responder, according to their response to the CPM test. Results: Findings showed that the FMS subgroup of non-responders to CPM, performed worse in motor imagery processes (LRJT). Additionally, older age and higher mechanical hyperalgesia were also associated with poorer functioning of the inhibitory system. Conclusions: Women with FMS who are non-responders to CPM exhibit a reduced ability to perform motor imagery processes. Additionally, the non-responder group shown significant differences, such as older age and greater initial mechanical hyperalgesia compared to the responder group. [ABSTRACT FROM AUTHOR]

Introduction: Radiation‐induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life‐long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation‐induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. Methods: Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham‐radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham‐radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain‐related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8‐week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. Results: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non‐radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. Conclusions: A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation‐induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition. [ABSTRACT FROM AUTHOR]

The present study examined the medium‐ and long‐term effects of early environmental enrichment (EE) on neuromotor, nociceptive, cognitive, behavioral, and neurochemical parameters in newborn rats repeatedly exposed to morphine. The study employed 90 Wistar rats: 10 adult nulliparous females and 80 male pups. Litter was split into standard and EE housing. Following, half of each litter received saline (S) or morphine (M) injections, resulting in four groups: SC + S, EE + S, SC + M, and EE + M. EE was applied from PND1 to PND21, while morphine or saline was given daily (5 μg/s.c.) from PND8 to PND14. Neuromotor development was similar between groups. In the OF test, morphine reduced outer and total crossings, whereas EE increased inner crossings and rearings. Adult rats showed a decrease in outer and total crossings and grooming and an increase in rearing. EE increased the number of protected and unprotected head dipping. Adult rats showed an increase in protected head dipping. Adult rats showed a lower recognition index, and, when exposed to EE, a lower anxiety index and analgesia. EE increased brainstem and hippocampal BDNF levels. Adult rats had increased hypothalamus, spinal cord, and brainstem BDNF levels, an increase in the spinal cord, and decreased hypothalamus TNF‐α levels. This study demonstrated that early‐life EE raises BDNF levels in the brainstem and hippocampus of rats and modifies their behaviors (such as nociception, exploration, and anxiety) in a state‐dependent manner (morphine and age). [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have key roles in the pathological processes of neuropathic pain. Here, our aim was to elucidate the function of miR‐200a‐3p as well as its related regulatory mechanism in neuropathic pain. An animal model of neuropathic pain was established by chronic constriction injury (CCI) induction. The knockdown experiments are performed by injecting a lentiviral construct intrathecally. MiR‐200a‐3p and bromodomain‐containing protein 3 (BRD3) expression in rat spinal cord was determined using RT‐qPCR. The mechanical, thermal, and cold responses in animals were assessed at the indicated time after surgery. The levels of inflammatory cytokines in rat spinal cord were measured by ELISA. The changes in NF‐κB signaling‐related molecules in rat spinal cord were determined using western blot and immunofluorescence. MiR‐200a‐3p was underexpressed in CCI rats in a time‐dependent manner. Overexpression of miR‐200a‐3p decreased mechanical hyperalgesia and thermal sensitivity to attenuate neuropathic pain in rats. BRD3 was targeted by miR‐200a‐3p. Additionally, downregulation of BRD3 inhibited neuropathic pain progression. Moreover, overexpression of BRD3 rescued the effect of miR‐200a‐3p on NF‐κB signaling and neuropathic pain in CCI rats. MiR‐200a‐3p attenuates neuropathic pain via downregulating BRD3 to block NF‐κB signaling. [ABSTRACT FROM AUTHOR]

Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia. [ABSTRACT FROM AUTHOR]

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100 mg/kg), acetaminophen (100 and 300 mg/kg) and codeine (3 and 10 mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a critical source of comorbidity following spinal cord injury (SCI) that can be exacerbated by immune-mediated pathologies in the central and peripheral nervous systems. In this article, we investigate whether drug-free, biodegradable, poly(lactide- co -glycolide) (PLG) nanoparticle treatment mitigates the development of post-SCI neuropathic pain in female mice. Our results show that acute treatment with PLG nanoparticles following thoracic SCI significantly reduces tactile and cold hypersensitivity scores in a durable fashion. Nanoparticles primarily reduce peripheral immune-mediated mechanisms of neuropathic pain, including neuropathic pain-associated gene transcript frequency, transient receptor potential ankyrin 1 nociceptor expression, and MCP-1 (CCL2) chemokine production in the subacute period after injury. Altered central neuropathic pain mechanisms during this period are limited to reduced innate immune cell cytokine expression. However, in the chronic phase of SCI, nanoparticle treatment induces changes in both central and peripheral neuropathic pain signaling, driving reductions in cytokine production and other immune-relevant markers. This research suggests that drug-free PLG nanoparticles reprogram peripheral proalgesic pathways subacutely after SCI to reduce neuropathic pain outcomes and improve chronic central pain signaling.

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.

The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTMs underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes.