Upregulation of synapse-associated protein 97 in the spinal dorsal horn exacerbates inflammatory pain through mediating GluA1-containing AMPARs membrane trafficking.

Rheumatoid Deformities of the Lesser Toes.

Discovery of novel HDAC6 inhibitors based on the diphenyl-1,2,4-oxadiazole scaffold with potential efficacy in alleviating inflammation- and chemotherapy- associated mechanical hypersensitivity.

Predicting psoriatic arthritis in new-onset psoriasis: development of multivariable prediction models from an inception cohort study.

Identification of pain-related biomarkers and the associated potential molecular regulation mechanism in pulpitis by bioinformatics method.

Pain remains a major clinical challenge, with current pharmacological treatments often limited by side effects, tolerance, and variable efficacy. The dorsal root ganglion (DRG) has emerged as a promising target for neuromodulation due to its pivotal role in pain signaling. In this study, we developed a miniaturized, semi-implantable cryo-neuromodulation device capable of delivering localized and reversible cooling to the lumbar DRG in awake, freely moving mice. Using a complete Freund's adjuvant (CFA)-induced inflammatory pain model, we demonstrated that DRG cooling at 29°C-but not 31.5°C-significantly reversed both mechanical and thermal hypersensitivity. The analgesic effect persisted for up to one hour post-cooling and exhibited cumulative improvement over repeated daily sessions, suggesting the induction of neuroplastic changes. Crucially, in a conditioned place preference test, CFA mice spent significantly more time in the chamber paired with DRG cooling, demonstrating that the pain relief is rewarding and motivationally salient. These findings establish DRG-targeted cryo-neuromodulation as a potent, non-pharmacological strategy for pain management, with implications for the development of precision neuromodulation therapies for pain.

Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.

Chronic pain and anxiety exhibit a high degree of comorbidity, in which these conditions can mutually exacerbate each other. The authors investigated whether glutamatergic neurons in the pedunculopontine tegmental nucleus (PPTg Glu ) and their projections to the central medial thalamic nucleus (CM) regulate nociceptive and anxiety-like behaviors in a complete Freund's adjuvant (CFA)-induced chronic pain model. The authors used c-Fos staining, chemogenetics, and optogenetics to assess the role of PPTg Glu and the PPTg Glu -CM pathway in regulating nociceptive and anxiety-like behaviors. Rabies-mediated retrograde tracing was used to map the anatomical connection from PPTg Glu to glutamatergic neurons in the CM (CM Glu ). Optogenetics combined with electrophysiologic recordings was used to verify the functional connectivity of this pathway. Plantar injection of CFA induced anxiety-like behaviors. This behavioral comorbidity was associated with the activation of glutamatergic neurons in the PPTg, as indicated by c-Fos staining. Chemogenetic inhibition of the PPTg Glu alleviated both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in CFA-treated mice. Conversely, optogenetic activation of these neurons was sufficient to elicit both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in naïve mice. To identify the underlying circuit, the authors first employed both anterograde and retrograde tracing to map the anatomical connectivity between the PPTg and the CM. The authors then verified the functional connectivity of this specific PPTg Glu -CM Glu pathway using optogenetics combined with electrophysiologic recordings. Finally, pathway-specific manipulations demonstrated that chemogenetic inhibition of the PPTg Glu -CM pathway relieved nociceptive and anxiety-like behaviors, whereas optogenetic activation of this pathway was sufficient to induce these behaviors in naïve mice. The CM receives excitatory input from PPTg Glu , and this PPTg Glu -CM pathway modulates nociceptive and anxiety-like behaviors.

Acute gout attacks are characterized by intense inflammatory activity and pain. This study aimed to evaluate changes in calculated serum osmolality during acute gout attacks compared with the inter-flare period and to investigate its associations with pain severity and systemic inflammatory markers. In this retrospective paired observational study, 79 patients with gout were evaluated during an acute attack and again in the inter-flare period. Calculated serum osmolality, inflammatory markers, pain visual analog scale (VAS) scores, and the number of involved joints were recorded. Paired comparisons, correlation analyses, linear mixed-effects models for paired acute/inter-flare comparisons, and multivariable linear regression analyses restricted to the acute attack period were performed. Calculated serum osmolality was significantly higher during acute gout attacks compared with the inter-flare period (296.6 ± 6.1 vs. 291.8 ± 5.1 mOsm/kg; p < 0.001), accompanied by significant increases in inflammatory markers and leukocyte indices. During acute attacks, calculated serum osmolality correlated with pain intensity, joint involvement, CRP, ESR, WBC count, and neutrophil count, but not with serum uric acid. In adjusted mixed-effects models, the acute attack period remained independently associated with higher calculated serum osmolality (β=+4.9 mOsm/kg; 95% CI 3.6-6.2; p < 0.001). In multivariable linear regression analyses restricted to the acute phase, higher calculated serum osmolality was associated with higher inflammatory marker levels. Elevated calculated serum osmolality during acute gout attacks was associated with higher inflammatory markers and greater pain severity. Further prospective studies are needed to clarify the clinical relevance and potential pathophysiological implications of this association.

The at-risk-to-early continuum of enteropathic spondyloarthritis.

Objective Although axial spondyloarthritis (axSpA) is an inflammatory disease primarily affecting the spine, studies investigating cervical spine instability (CSI) are limited, and no research has comprehensively evaluated all forms of CSI. This study aimed to determine the frequency and associated factors of CSI in axSpA patients. Method This retrospective cross-sectional study, conducted in a single tertiary rheumatology unit, included adult axSpA patients with inflammatory back pain duration of > 10 years and receiving biological or targeted synthetic therapy. Patients with any concomitant disease that could affect the spine were excluded. CSI lesions were assessed using lateral neutral, full extension, full flexion, and open-mouth anteroposterior cervical radiographs. Radiographs were evaluated by two blinded rheumatologists. Results In total, 159 axSpA cases (ankylosing spondylitis: 89.3%; non-radiographic axSpA: 10.7%) were included in the study; 57.9% were male, mean age was 47 years, and mean disease duration was 17 years. A total of 33 CSI lesions was detected in 31 patients (19.5%); the most common was anterior atlantoaxial subluxation (54.5%), followed by subaxial (33.3%) and vertical subluxation (6.1%). In univariate logistic regression analysis; disease duration (p = 0.004), age at first symptom (p = 0.02), uveitis (p = 0.049), and sacroiliitis stage (p = 0.039) were associated with CSI. In multivariate analysis, disease duration was identified as a potential independent predictor of CSI (p = 0.027). Conclusion These results highlight the need for increased clinical awareness of CSI in axSpA, and support consideration of cervical imaging in patients with prolonged disease duration, severe sacroiliitis, or uveitis.

Orexinergic and opioidergic receptors interaction in the dentate gyrus of the hippocampus on modulation of formalin-induced inflammatory pain responses in the rat.

Benzothiazole derivatives are receiving considerable attention for their diverse pharmacological properties, particularly as anti-rheumatic agents. Rheumatoid arthritis is a common musculoskeletal disorder associated with chronic inflammation and joint degradation, necessitating the development of novel treatments. Due to its ability to modulate several biological targets involved in inflammatory pathways, benzothiazole, a heterocyclic scaffold, has emerged as a potential pharmacophore. Benzothiazole derivatives are well documented to display analgesic, antiinflammatory, and immunomodulatory effects, making them promising candidates for antirheumatic drugs. These compounds have been shown to inhibit key cytokines such as TNF-α and IL-6, as well as enzymes like cyclooxygenase (COX) and lipoxygenase (LOX) involved in the inflammation activation sequence. In addition, benzothiazole derivatives exhibit low cytotoxicity, which is advantageous for long-term therapy of chronic diseases. They also possess a wide range of medicinal properties, including antimicrobial, anticancer, anticonvulsant, and antioxidant effects, and can be applied in the treatment of rheumatism. Their chemical structures can be readily modified to enhance selectivity and potency at specific targets, highlighting their versatility. In conclusion, benzothiazole derivatives represent a promising class of compounds for antirheumatic drug development. Ongoing studies have increasingly demonstrated their therapeutic benefits in pain relief, inflammation control, and other pharmacological effects, making them valuable targets for further drug development in rheumatic and related diseases.

As the most frequent clinical problem, intervertebral disc degeneration (IVDD) and associated inflammatory pain are still a big challenge, thus there is a need for improved and more lasting therapeutic approaches. In this study, a lipidic prodrug of diclofenac, Diclofenac Lauryl Ester (L-DCF), was synthesized and formulated into nanoparticles (Nanofenac-L) using the ethanol injection method followed by microfluidization. The encapsulation efficiency of Nanofenac-L was > 97% with sustained drug release, releasing around 65% of the diclofenac in 48h. The therapeutic potential of Nanofenac-L was evaluated in rat intervertebral disc-derived nucleus pulposus cells.Nanofenac-L was found to be more effective than free Diclofenac Sodium (DCF-Na) in terms of anti-inflammatory activity, which was confirmed with significant suppression of COX-2 and Substance P. Furthermore, Nanofenac-L increased the expression of antioxidant genes in cells, such as SOD1, GPX1 and PRDX1. Preventive treatment was found to have shown therapeutic value whereas the curative treatment yielded a significant therapeutic effect indicating the possibility of Nanofenac-L to alleviate inflammation as well as to slow down disease progression. Altogether, these results suggest that Nanofenac-L could represent a promising long-lasting anti-inflammatory, pain relieving and antioxidant nanotherapeutic. Comprehensive preclinical and clinical evaluation is essential to translate these findings into viable therapies.

ABSTRACTIntroductionPreclinical evidence suggests that dysregulation of the ceramide‐sphingosine‐1‐phosphate (S1P) axis may have analgesic properties. However, currently approved S1PR1 modulators such as fingolimod are hindered for this indication as they induce lymphopenia. The aim of the current study was to evaluate whether the novel, selective S1PR1 agonist TRV045 has analgesic effects in a validated evoked pain test battery in healthy volunteers.MethodsIn this randomized, double‐blind, double‐dummy, placebo‐controlled, four‐way cross‐over study, 25 male or female healthy volunteers were randomized to receive either placebo or TRV045 50, 150 or 300 mg at separate occasions. The primary endpoint was heat pain detection threshold on UVB‐induced inflammatory pain. Secondary endpoints included analgesic reduction of capsaicin‐induced allodynia and pain detection and tolerance thresholds to evoked cold, electrical, pressure and heat pain. Furthermore, safety, tolerability and pharmacokinetics were monitored throughout the study. Data analyses included a repeated‐measures mixed‐effects model.ResultsTRV045 was well tolerated, without serious adverse events. Compared to placebo, TRV045 did not reduce heat pain detection thresholds on UVB‐exposed skin, but significantly reduced the secondary area of capsaicin‐induced pain for the higher dose levels: 150 mg: −304.10 mm2 (95% CI: −494.78 to −113.43, p = 0.002); 300 mg: −298.51 mm2 (−486.83 to −110.20, p = 0.002). No effects on peripheral lymphocyte count were observed.ConclusionTRV045 is a well‐tolerated S1PR1 modulator with analgesic properties in healthy volunteers as measured by the capsaicin‐induced pain model, which provides initial clinical evidence that selective S1PR1 modulation may be an appropriate novel target for the treatment of neuropathic pain.Significance StatementSelective S1PR1 modulation produced analgesic effects in a validated human experimental pain model. This study provides clinical proof‐of‐concept for S1PR1 as a promising therapeutic target for neuropathic pain.

The serotonin 5-HT7 receptor (5-HT7R), a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs), is highly expressed in the central nervous system (CNS) and represents a promising target for treating CNS disorders such as sleep disturbances, migraine, neuropsychiatric conditions, and neuropathic pain. Because of its therapeutic potential, extensive efforts have focused on developing selective 5-HT7R ligands. In the last decades, biased signaling has emerged as a key concept in GPCR pharmacology as biased ligands can stabilize specific active states of the receptor and trigger selective activation of downstream signaling pathways. In this context, we recently identified two biased 5-HT7R ligands, Serodolin and MOA51, from different chemical series. Here, we aimed to compare the pharmacological and safety profiles of these ligands and assess their effect on pain-related behaviors and spinal neuroinflammation. In inflammatory pain models (acid acetic writhing, formalin, and CFA tests), both Serodolin and MOA51 effectively attenuated pain responses to a similar extent. Furthermore, in neuropathic pain models, spinal nerve injury (SNI) and the Cuff model, both ligands reversed mechanical allodynia. Interestingly, unlike pregabalin, a clinically used reference drug, neither Serodolin nor MOA51, induced apparent development of tolerance after 10 consecutive days of administration. Treatment with these 5-HT7R ligands also reduced spinal microglial activity and attenuated neuronal hyperactivity in the spinal cord. Altogether, these findings highlight the potential of 5-HT7R-biased ligands as promising analgesic candidates capable of modulating neuroinflammatory processes and mitigating both inflammatory and neuropathic pain.

The clinical management of chronic pain has long relied on conventional medications, including drugs such as opioids, anti-inflammatory drugs and anticonvulsants, which are universally associated with inadequate efficacy and prominent adverse effects. This highlights an urgent need for novel therapeutic strategies targeting the underlying mechanisms of pain. Recent studies have demonstrated that T-type calcium channels play a pivotal role in the pathogenesis and progression of neuropathic and inflammatory pain, with their expression and function being significantly up-regulated in neurons of the dorsal root ganglion (DRG) and spinal dorsal horn neurons, emerging as a highly promising yet clinically unvalidated analgesic target. However, the development of blockers directly targeting the Cav3.2 subtype is still confronted with major translational challenges, such as low subtype selectivity, as well as adverse effects in the central nervous system and cardiovascular system. Repeated clinical setbacks of candidate drugs like ABT-639 have highlighted the gap between preclinical potential and clinical efficacy, and to date, no ideal clinical candidate has been identified. This review integrates structural biology insights, lessons from clinical failures and pharmacological advances to guide the research and development of safe, highly selective Cav3.2-targeted analgesic agents.

Recombinant dimeric PICK1 peptide inhibitors for long-term relief of chronic pain by AAV therapeutics.

To compare demographic, clinical, functional, and therapeutic characteristics of patients with axial spondyloarthritis (axSpA) across 3 Latin American regions using data from the Registro de Espondiloartritis Axial de America (ESPALDA) registry between January 2019 and December 2024. This cross-sectional study included 418 patients diagnosed with axSpA who fulfilled the Assessment of SpondyloArthritis international Society classification criteria. Participants were recruited from 3 Latin American regions: northern (Mexico), Andean (Colombia, Ecuador, Peru, Venezuela), and southern (Argentina, Chile, Paraguay, Uruguay). Collected data included demographic characteristics, HLA-B27 status, extraarticular manifestations, disease activity, radiographic damage, and treatments. The northern region showed the highest prevalence of HLA-B27 (81%) and uveitis (36.3%), along with lower frequencies of peripheral involvement and fewer patients with magnetic resonance imaging-defined sacroiliitis (7.3%; all P ≤ 0.003). In contrast, the southern region reported a later onset of inflammatory back pain (median 39 vs 22 years; P = 0.01), higher Bath Ankylosing Spondylitis Functional Index scores (median 4.6 vs 3.3, P = 0.005), and a lower response to nonsteroidal antiinflammatory drugs (59.8% vs 79%; P = 0.001). Use of biologic disease-modifying antirheumatic drugs was lowest in the northern region (34.7%) compared with the Andean (57.9%) and southern (53.8%) regions (P ≤ 0.002 for northern vs other regions). The median diagnostic delay was 40.9 (IQR 12.0-121.1) months, with no significant regional differences. Two clinical phenotypes of axSpA appear to exist in Latin America: a predominantly axial, HLA-B27-positive phenotype in the northern region, and a second phenotype in the Andean and southern regions characterized by greater peripheral involvement and, in the southern region, later symptom onset and worse functional status.

The spinoparabrachial tract is a major ascending pathway that transmits nociceptive signals from the spinal cord to the brain, but whether electroacupuncture (EA) relieves pain-anxiety comorbidity by modulating this pathway remains unclear. Here, we investigated the effects of EA on mechanical allodynia and anxiety-like behaviors in Complete Freund's adjuvant (CFA)-induced inflammatory pain mice using von Frey testing, the open field test, and the elevated plus maze, combined with chemogenetic manipulation of glutamatergic projections from the spinal dorsal horn (SDH) to the lateral parabrachial nucleus (LPBN). EA attenuated CFA-induced mechanical allodynia and anxiety-like behaviors and reduced c-Fos expression in both the SDH and LPBN. Chemogenetic inhibition of LPBN glutamatergic neurons mimicked the analgesic and anxiolytic effects of EA, whereas their activation abolished these effects. Activation of either ipsilateral or contralateral SDH→LPBN glutamatergic projections induced pain- and anxiety-like phenotypes that depended on intact LPBN glutamatergic output. Moreover, selective activation of spinoparabrachial glutamatergic terminals was sufficient to block the therapeutic efficacy of EA. These findings indicate that EA alleviates CFA-induced pain-anxiety comorbidity by inhibiting the SDH-LPBN glutamatergic circuit, identifying a key ascending pathway through which peripheral EA signals modulate central pain and affective processing.