Model Of Chronic Pain Research Articles

Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain

ABSTRACT Background Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. Methods Male Kunming mice (8–10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). Results Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. Conclusions The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.

Construction and validation of a nomogram prediction model for chronic low back pain after PKP for lumbar compression fractures.

The aim was to study the independent risk factors for chronic low back pain after lumbar compression fractures undergoing percutaneous kyphoplasty (PKP), and to establish a nomogram prediction model accordingly. Data were collected from patients with lumbar compression fractures from January 2017 to December 2021 at the Affiliated Hospital of Xinjiang Medical University. Univariate and multivariate logistic regression analyses were used to determine the independent risk factors for chronic low back pain after receiving PKP for lumbar compression fractures, and the corresponding nomogram was established. Receiver operating characteristic (ROC) curves were plotted and area under the curve (AUC) was calculated, and calibration curves and decision curve analysis (DCA) were plotted to evaluate the model performance. A total of 792 patients with lumbar compression fractures were included in the study, and 188 patients had chronic postoperative low back pain, with an incidence of 23.74%. After univariate and multivariate logistic regression analysis, a total of 5 variables were identified as independent risk factors for chronic low back pain after undergoing PKP for lumbar compression fractures, namely having diabetes (OR, 1.607; 95% CI, 1.157-3.205), preoperative T value < -2.5 SD (OR, 2.697; 95% CI, 1.417-5.021), multiple lumbar fractures (OR, 1.815; 95% CI, 1.415-3.201), lumbar compression ≥ 50% (OR, 2.854; 95% CI, 1.411-6.524), and bone cement leakage (OR, 2.911; 95% CI, 1.715-6.817). The nomogram for chronic low back pain after PKP for lumbar compression fractures constructed in this study has good predictive accuracy and helps orthopedic surgeons to intervene earlier in patients at high risk of chronic low back pain after undergoing PKP for lumbar compression fractures.

The potent analgesia of intrathecal 2R, 6R-HNK via TRPA1 inhibition in LF-PENS-induced chronic primary pain model

BackgroundChronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown.MethodsBased on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro.ResultsIntrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol.ConclusionsIn the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

Using a Whole Health Approach to Build Biopsychosocial-Spiritual Personal Health Plans for Veterans with Chronic Pain

Chronic pain affects over 50 million Americans per year and costs society billions of dollars annually. It is widely accepted that the biomedical model is outdated and research on the biopsychosocial model of chronic pain has increased in recent years, concurrent with investigations into self-management of chronic pain. The Veterans Health Administration (VHA) has incorporated both of these approaches into their Whole Health System. This work describes the VHA Whole Health System, reviews the literature on alignment between the Whole Health System's Circle of Health and chronic pain, and explains how the VHA Whole Health model may be used as a method for organizing self-management strategies within a personal health plan in the context of chronic pain. Given the infusion of nurses throughout the healthcare system, nurses are in a unique position to champion this biopsychosocial-spiritual approach to care.

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

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

Posttraumatic stress and distress tolerance in relation to opioid misuse and dependence among trauma-exposed adults with chronic pain.

Posttraumatic stress symptoms have been associated with opioid misuse and dependence among adults with chronic pain. Lower levels of perceived distress tolerance (i.e., perceived ability to withstand negative emotional states) have been independently associated with posttraumatic stress symptoms and opioid-related problems among nonchronic pain samples. However, there has not been a test of whether distress tolerance interacts with posttraumatic stress in terms of opioid misuse among trauma-exposed persons with chronic pain. Therefore, the present study examined the interaction between distress tolerance and posttraumatic stress symptoms in relation to opioid misuse and dependence among trauma-exposed adults with chronic pain who were using opioids (N = 289; 70.9% female, Mage = 37.75, SD = 10.83). Results indicated a significant negative interaction of distress tolerance with posttraumatic stress in terms of opioid misuse and dependence, as the relationship between posttraumatic stress symptoms and opioid misuse and dependence was diminished at higher levels of distress tolerance. The current findings help refine our understanding of the subgroups of persons with chronic pain distinguished by low distress tolerance and at the greatest risk for misusing opioids. Furthermore, current models of chronic pain and opioid misuse could be refined by integrating distress tolerance. These findings may help inform interventions for trauma-exposed persons with chronic pain who use opioids. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice

Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1–3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naïve mice at week 10 post-model induction. HDAC4 RNA reported in lower limb inflammatory pain models is not evident in the trigeminal models. Many other gene alterations persisting at week 10 in the trigeminal ganglia (TG) are restored to naïve levels in mice treated with LMK235. Important pain-related upregulated genes Hoxc8,b9,d8; P2rx4, Cckbr, growth hormone (Gh), and schlafen (Slfn4) are greatly reduced in LMK235-treated mice. Fold increase in axon regeneration/repair genes Sostdc1, TTr, and Folr1 after injury are doubled by LMK235 treatment. LMK235 reduces the excitability of trigeminal ganglia neurons in culture isolated from nerve injured mice compared to vehicle-treated controls, with no effect on neurons from naïve mice. Electrophysiological characterization profile includes a shift where ∼20% of the small neurons recorded under LMK235-treated conditions are high threshold, whereas none of the neurons under control conditions have high thresholds. LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PerspectiveData here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs.

Sensing the body matters: profiles of interoceptive sensibility in chronic pain adjustment.

Interoception is critical to health regulation and is often disrupted in individuals with chronic pain (ICPs). Interoceptive sensibility (IS)-the self-reported experience and relationship toward internal states-includes skills such as sensing, interpreting, and using bodily information for self-regulation. Current studies on IS and chronic pain (CP) adjustment are scarce, and how the interplay between different IS skills shapes CP adjustment remains unclear. This cross-sectional study aimed to identify profiles of IS skills among ICPs and examined their associations with pain outcomes and psychological and behavioral risk or protective processes. Individuals with chronic musculoskeletal pain (n = 173; 84.4% women) completed the Multidimensional Assessment of Interoceptive Awareness (MAIA), measures of CP adjustment (depression, anxiety, vitality, pain severity, interference, and physical function), psychological (self-efficacy, catastrophizing, and kinesiophobia), and behavioral processes (activity patterns). A cluster analysis identified 3 IS skills profiles: (1) high IS skills (n = 68), with the highest levels of attention regulation toward bodily sensations, body trust, listening for insight, and self-regulation; (2) low IS skills (n = 29), who distracted less and worried more about bodily sensations, and presented lower-body trust; and (3) mixed IS skills (n = 71), despite good body trust, attention regulation, and low worrying, showed lower awareness of body-mind connections. Interoceptive sensibility skills profiles differed in depression, vitality (fatigue), and psychological or behavioral processes, such as pain-related self-efficacy, catastrophizing, kinesiophobia, and activity pacing. These findings contribute to integrating body-mind connections more explicitly into current theoretical CP models and developing tailored interventions targeting specific IS skills to improve CP adjustment.

Soft Tissue Manipulation Alters RANTES/CCL5 and IL-4 Cytokine Levels in a Rat Model of Chronic Low Back Pain.

Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM), such as massage, has been shown to be effective in human subjects, but the molecular mechanisms underlying these findings are not well understood. In this paper, we evaluated potential changes in the soft tissue levels of more than thirty pro- or anti-inflammatory cytokines following instrument-assisted STM (IASTM) in rats with chronic, induced LBP using Complete Freund's Adjuvant. Our results indicate that IASTM is associated with reduced soft tissue levels of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES)/Chemokine (C-C motif) ligand 5 (CCL5) and increased soft tissue levels of Interleukin (IL)-4, which are pro-inflammatory and anti-inflammatory factors, respectively, by 120 min post-treatment. IASTM was not associated with tissue-level changes in C-X-C Motif Chemokine Ligand (CXCL)-5/Lipopolysaccharide-Induced CXC Chemokine (LIX)-which is the murine homologue of IL-8, CXCL-7, Granulocyte-Macrophage-Colony Simulating Factor (GM-CSF), Intercellular Adhesion Molecule (ICAM)-1, IL1-Receptor Antagonist (IL-1ra), IL-6, Interferon-Inducible Protein (IP)-10/CXCL-10, L-selectin, Tumor Necrosis Factor (TNF)-α, or Vascular Endothelial Growth Factor (VEGF) at either 30 or 120 min post-treatment. Combined, our findings raise the possibility that IASTM may exert tissue-level effects associated with improved clinical outcomes and potentially beneficial changes in pro-/anti-inflammatory cytokines in circulation and at the tissue level.

The oral administration of Lotus corniculatus L. attenuates acute and chronic pain models in male rats

Ethnopharmacological relevanceLotus corniculatus L. (Fabaceae) traditionally used in Persian folk medicine to heal peritoneal inflammation and back pain. Aim of the studyTo explore the antinociceptive (acute pain) and anti-neuropathic (chronic pain) activities of Lotus corniculatus leaves essential oil (LCEO) in addition to uncovering the possible mechanisms of antinociception. Materials and methodsLCEO as well as the pure oleanolic acid (OA) compound, were assayed for their effects on acute (formalin induced paw licking test or FIPT) and chronic (cervical contusion injury models on the fifth cervical vertebra or CCS; 14-day intervals) pain. The possible involvements of NO-cGMP-K+ channel, TRPV, dopamine, cannabinoid, PPAR, adrenergic, and opioid mechanisms in the antinociceptive activity of LCEO have studied by formalin test. The levels of p53 and inflammatory markers were measured using a streptavidin biotin immune peroxidase complex and ELISA methods, respectively. ResultsThe LCEO and OA exerted antinociceptive activity in the first-phase of FIPT. Pretreatment with antagonists of TRPV1, dopamine D2, cannabinoid type1 and 2, and NO-cGMP-K+ channel blockers (glibenclamide, L-NAME and methylene blue) attenuated the antinociceptive effect of LCEO in FIPT. In addition, LCEO and OA meaningfully reduced hyperalgesia (days 6–14) and mechanical allodynia (days 2–14) in the CCS model. LCEO suppressed the apoptotic marker (p53) in CCS model and also ameliorated IL-2, TNF-α, and IL-1 in the spinal cord. ConclusionFinally, LCEO inhibited acute (possibly via the modulation of opioid, TRPV, dopamine, cannabinoid mechanisms as well as NO-cGMP-K+ channel) and chronic pain (via suppressing apoptotic and inflammatory markers) in male rats. The results also suggest that OA has analgesic activity against acute and chronic pain conditions.

Evaluation of novel epibatidine analogs in the rat nicotine drug discrimination assay and in the rat chronic constriction injury neuropathic pain model.

Nicotine is the primary psychoactive component responsible for maintaining tobacco dependence in humans. Chronic pain is often a consequence of tobacco-related pathologies, and the development of a dual therapeutic that could treat chronic pain and tobacco dependence would be advantageous. Epibatidine reliably substitutes for nicotine in the drug discrimination assay, and is a potent analgesic, but has a side-effect profile that limits its therapeutic potential. Thus, considerable efforts to produce epibatidine derivatives are underway. Here we tested three epibatidine derivatives, 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102; i.e., RTI-102), 2'-fluorodeschloroepibatidine (RTI-7527-36; i.e., RTI-36), and 3'-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76; i.e., RTI-76) in both the rat nicotine drug discrimination assay as well as in the rat chronic constriction injury (CCI) of the sciatic nerve neuropathic pain model. Male and female Sprague-Dawley rats were trained on a fixed-ratio 10 schedule to discriminate nicotine (0.32mg/kg base) from vehicle. All compounds dose-dependently substituted for nicotine, without significant decreases in response rates. In the discrimination assay the rank order potency was RTI-36 > nicotine > RTI-102 > RTI-76. Evidence suggests the α4β2* subtype is particularly important to nicotine-related abuse potential. Thus, here we utilized the antagonist dihydro-β-erythroidine (DHβE) to examine relative β2 subunit contribution. DHβE (3.2mg/kg, s.c.) antagonized the discriminative stimulus effects of nicotine. However, relative to antagonism of nicotine, DHβE produced less antagonism of RTI-102 and RTI-76 and greater antagonism of RTI-36. It is likely that at nicotinic receptor subunits RTI-102, RTI-76 and RTI-36 possess differing activity. To confirm that the full discriminative stimulus of these compounds was due to nAChR activity beyond the β2 subunit, we examined these compounds in the presence of the non-selective nicotinic receptor antagonist mecamylamine. Mecamylamine (0.56mg/kg, s.c.) pretreatment abolished nicotine-paired lever responding for all compounds. In a separate cohort, male and female Sprague-Dawley rats underwent CCI surgery and tested for CCI-induced mechanical allodynia via the von Frey assay. Each compound produced CCI-induced mechanical allodynia reversal. RTI-36 displayed higher potency than either RTI-102 or RTI-76. These novel epibatidine analogs may prove to be useful tools in the fight against nicotine dependence as well as novel neuropathic pain analgesics.

Mechanisms involved in the antinociceptive and anti-inflammatory effects of xanthotoxin.

Xanthotoxin (XAT) is a natural furanocoumarin clinically used in the treatment of skin diseases such as vitiligo and psoriasis. Recent studies have also investigated its effects on anti-inflammatory, anti-cognitive dysfunction, and anti-amnesia as a guideline for clinic application. However, little is known about its effects on pain relief. Here, we tested the analgesic effects of XAT in serious acute pain and chronic pain models. For acute pain, we used hot-, capsaicin- and formalin-induced paw licking. Nociceptive threshold was measured by mechanical stimuli with von Frey filaments. For chronic pain, we injected complete Freund's adjuvant (CFA) into the mice's plantar surface of the hind paw to induce inflammatory pain. Heat and mechanical hyperalgesia were evaluated by radiant heat and von Frey filament tests, respectively. To investigate the mechanisms underlying the analgesic effect of XAT, we used calcium imaging and western blot to assess transient receptor potential vanilloid 1 (TRPV1) activity and expression in isolated L4-L6 dorsal root ganglion (DRG) neurons. Haematoxylin and eosin (HE) staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine immune cell recruitment and proinflammatory factor release from skin tissue from paw injection sites. Our results demonstrated that XAT not only reduced acute pain behaviors generated by hot, capsaicin, and formalin but also attenuated CFA-induced heat and mechanical hyperalgesia. The analgesic activity of XAT may be achieved by controlling peripheral inflammation, lowering immune cell infiltration at the site of inflammatory tissue, reducing inflammatory factor production, and therefore inhibiting TRPV1 channel sensitization and expression.

The relationship between musicianship and pain. Is chronic pain and its management a problem for student musicians only?

The neuro-biological side of chronic pain research has presented reliable evidence of distinct cortical and spinal alteration compared to healthy individuals. Furthermore, research suggests that musicians are especially vulnerable to pain, and recent neurological investigations into musicians' brain plasticity support this hypothesis. However, chronic pain is not acute pain plus time, but a separate condition, and little is known about musicians' chronic pain-related emotions and behaviors. This knowledge, however, is a crucial step in understanding how chronic pain is processed by musicians. This study investigated pain catastrophizing as a critical pain-related behavior and emotional concept alongside six complementary variables: anxiety, depression, depersonalisation, burnout, coping strategies and professional identity. 103 under- and postgraduate students from various higher education institutions participated in an online survey. Students were allocated into three groups according to their main study subject and type of institution: music college musicians, university musicians and university non-musicians. A tree model confirmed the current chronic pain multifactorial model, suggesting a combination of several variables before catastrophizing pain. Group testing, however, showed that university non-musicians' pain catastrophizing was significantly worse especially when compared to music college musicians. Music college musicians and university musicians were less prone to maladaptive pain processes, despite perceiving pain for significantly longer. This novel finding indicates that chronic pain does not inevitably lead to dysfunctional pain processing for musicians and should be reflected accordingly to optimize pain-control. The biopsychosocio model of chronic pain provides a robust framework for future research in this population.

Effects of Early Exposure to Isoflurane on Susceptibility to Chronic Pain Are Mediated by Increased Neural Activity Due to Actions of the Mammalian Target of the Rapamycin Pathway.

Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests showed that early isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. Immunohistochemistry, Western blotting, and q-PCR indicated that isoflurane upregulated mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We concluded that early GA exposure, at least with isoflurane, alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.

A clindamycin acetylated derivative with reduced antibacterial activity inhibits articular hyperalgesia and edema by attenuating neutrophil recruitment, NF-κB activation and tumor necrosis factor-α production.

We recently demonstrated that clindamycin exhibits activities in acute and chronic models of pain and inflammation. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced in mice by intraarticular (i.a.) injection of zymosan or lipopolysaccharide (LPS). Clindamycin or CAD were administered via the intraperitoneal route 1h before zymosan or LPS. Paw withdrawal threshold, joint diameter, histological changes, neutrophil recruitment, tumor necrosis factor-α (TNF-α) production and phosphorylation of the IκBα and NF-κB/p65 were evaluated. In vitro assays were used to measure the antibacterial activity of clindamycin and CAD and also their effects on zymosan-induced TNF-α production by RAW264.7 macrophages. Clindamycin exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains at much lower concentrations than CAD. Intraarticular injection of zymosan or LPS induced articular hyperalgesia, edema and neutrophil infiltration in the joints. Zymosan also induced histological changes, NF-κB activation and TNF-α production. Responses induced by zymosan and LPS were inhibited by clindamycin (200 and 400mg/kg) or CAD (436mg/kg). Both clindamycin and CAD inhibited in vitro TNF-α production by macrophages. In summary, we provided additional insights of the clindamycin immunomodulatory effects, whose mechanism was associated with NF-κB inhibition and reduced TNF-α production. Such effects were extended to a clindamycin derivative with reduced antibacterial activity, indicating that clindamycin derivatives should be investigated as candidates to drugs that could be useful in the management of inflammatory and painful conditions.

Urokinase-type Plasminogen Activator-induced Mouse Back Pain Model.

A model of persisting lower back pain can be induced in mice with the simple methodology described herein. Step-by-step methods for simple, rapid induction of a persisting back pain model in mice are provided here using an injection of urokinase-type plasminogen activator (urokinase), a serine protease present in humans and other animals. The methodology for induction of persisting lower back pain in mice involves a simple injection of urokinase along the ligamentous insertion region of the lumbar spine. The urokinase inflammatory agent activates plasminogen to plasmin. Typically, the model can be induced within 10 min and hypersensitivity persists for at least 8 weeks. Hypersensitivity, gait disturbance, and other standard anxiety- and depression-like measures can be tested in the persisting model.Back pain is the most prevalent type of pain. To improve awareness of back pain, the International Association for the Study of Pain (IASP) named 2021 the "Global Year about Back Pain" and 2022 the "Global Year for Translating Pain Knowledge to Practice." One limitation of the therapeutic advancement of pain therapeutics is the lack of suitable models for testing persistent and chronic pain. Thefeatures of this modelare suitable for testing potential therapeutics aimed at the reduction of back pain and its ancillary characteristics, contributing to IASP's naming 2022 as the Global Year for Translating Pain Knowledge to Practice.

Development and Validation of a Predictive Model for Chronic Postsurgical Pain After Arthroscopic Rotator Cuff Repair: A Prospective Cohort Study.

Chronic pain management continues to present a significant challenge following arthroscopic shoulder surgery. Our purpose was to detect chronic postsurgical pain (CPSP) in patients who had undergone arthroscopic rotator cuff repair (ARCR) and develop a nomogram capable of predicting the associated risk. We collected the demographic and clinical data of 240 patients undergoing ARCR in our hospital from January 2021 to May 2022. The pain level was monitored and evaluated three months after ARCR. LASSO regression was used to screen out pain-predictingfactors, which were subsequently used to construct a nomogram. Internal validation was carried out using Bootstrap resampling. The data of 78 patients who underwent ARCR in our hospital from August 2022 to December 2022 were also collected for external verification of the nomogram. The predictive model was evaluated using the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Age, duration of preoperative shoulder pain (DPSP), C-reactive protein (CRP), number of tear tendons, and American Shoulder and Elbow Surgical Score (ASES) were screened by LASSO regression as predictive factors for CPSP. These factors were then used to construct a chronic pain risk nomogram. The area under the curve (AUC) of the predictive and validation models were 0.756 (95% CI: 0.6386-0.8731) and 0.806 (95% CI: 0.6825-0.9291), respectively. Furthermore, the calibration curves and decision curve analysis (DCA) for both models indicated strong performance, affirming the reliability of this predictive model. The CPSP risk model that has been developed exhibits strong predictive capabilities and practical utility. It offers valuable support to clinical healthcare professionals in making informed treatment decisions, reducing the unnecessary use of analgesic drugs, and optimizing the allocation of medical resources.

Sound-induced analgesia cannot always be observed in adult mice.

Music seems promising as an adjuvant pain treatment in humans, while its mechanism remains to be illustrated. In rodent models of chronic pain, few studies reported the analgesic effect of music. Recently, Zhou et al. stated that the analgesic effects of sound depended on a low (5dB) signal-to-noise ratio (SNR) relative to ambient noise in mice. However, despite employing multiple behavioral analysis approaches, we were unable to extend these findings to a mice model of chronic pain listening to the 5dB SNR.

The impact of sciatic nerve injury and social interactions testing on glucocorticoid receptor expression in catecholaminergic medullary cell populations

Paradoxically, while acute pain leads to transiently elevated corticosterone, chronic pain does not result in persistently elevated corticosterone. In the sciatic nerve chronic constriction injury (CCI) model of chronic pain, we have shown that the same nerve injury produces a range of behavioural outcomes, each associated with distinctive adaptations to the HPA-axis to achieve stable plasma corticosterone levels. We also demonstrated that CRF and GR expression in the paraventricular hypothalamus (PVH) was increased in rats that showed persistent changes to their social behaviours during Resident-Intruder testing (‘Persistent Effect’ rats) when compared to rats that showed no behavioural changes (‘No Effect’ rats). In this study, we investigated whether these changes were driven in part by altered sensitivity of the brainstem catecholaminergic pathways (known to regulate the PVH) to glucocorticoids. GR expression in adrenergic (C1,C2) and noradrenergic (A1,A2) cells was determined using immunohistochemistry in behaviourally tested CCI rats and in uninjured controls. We found no differences between Persistent Effect and No Effect rats in (1) the glucocorticoid sensitivity of these cells, or (2) the numbers of adrenergic and noradrenergic cells in each region. However, we discovered an overall reduction in GR expression in the non-catecholaminergic cells of these regions in both experimental groups when compared to uninjured controls, most likely attributable to the repeated Resident-Intruder testing. Taken together, these data suggest strongly that brainstem mechanisms are unlikely to play a key role in the rebalancing of the HPA-axis triggered by CCI, increasing the probability that these changes are driven by supra-hypothalamic regions.

Predictors of Psychosocial and Functional Outcomes in Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia: Application of the Fear-Avoidance Model

Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD), which affects up to 4.3% of individuals, is a distressing and poorly understood condition characterized by persistent, unwanted, and often painful sensations of genito-pelvic arousal (eg, throbbing) in the absence of sexual desire. PGAD/GPD is associated with significant negative impacts on psychosocial well-being and daily functioning. Recent research has indicated that PGAD/GPD shares many similarities with other forms of chronic genito-pelvic pain. This study applied the fear-avoidance model of chronic pain to PGAD/GPD to identify cognitive and behavioral factors associated with psychosocial and functional outcomes. A total of 263 individuals with PGAD/GPD symptoms completed a cross-sectional online survey of symptom intensity, cognitive and behavioral predictors (symptom catastrophizing, hypervigilance to symptoms, symptom fear and avoidance, self-efficacy), depression symptoms, and role functioning. Symptom catastrophizing, fear of symptoms, avoidance of symptoms, and hypervigilance to PGAD/GPD symptoms were significantly correlated with poorer psychosocial and functional outcomes, whereas higher self-efficacy was significantly associated with lower depression and better role functioning. Two serial parallel mediation models examined the fear-avoidance pathway from PGAD/GPD symptom intensity to depression symptoms and role functioning. In both models, the pathway through symptom catastrophizing, fear of symptoms, and symptom avoidance was significant, but the pathway through symptom catastrophizing, fear of symptoms, and symptom hypervigilance was not. The results of this study provide support for the applicability of the fear-avoidance model to PGAD/GPD. Interventions targeting fear-avoidance factors may help to reduce PGAD/GPD symptom intensity, distress, and increase psychological well-being and daily functioning. PerspectiveThis article provides support for the applicability of the fear-avoidance model of chronic pain to Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). These results suggest that interventions targeting fear-avoidance cognitions and behaviors (catastrophizing, fear, avoidance, hypervigilance) may help to reduce PGAD/GPD symptom intensity and improve psychological well-being and daily functioning.