Molecular Pain最新文献

The senescence-associated secretory phenotype (SASP) contributes to tissue degeneration and inflammation, yet its role in osteoarthritis (OA)-related pain remains poorly understood. We hypothesized that circulating SASP markers would be associated with distinct OA-pain phenotypes, defined by pain impact and radiographic OA (ROA) severity. A subset of middle-to-older-aged adults (45-85 years) from a larger multi-site study (n = 169) self-reported pain impact-defined as the extent to which pain interferes with daily functioning-and underwent knee radiography and blood collection. Hierarchical cluster analysis was used to empirically identify OA-pain phenotypes based on combined pain impact and Kellgren-Lawrence (KL) grade. Plasma levels of four SASP markers (GDF-15, activin A, osteopontin, and IL-15) were quantified from whole blood samples. Among 169 participants, 35.5% reported high-impact chronic knee pain and 27.8% exhibited moderate-to-severe radiographic OA. Cluster analysis identified five distinct ROA-pain phenotypes. GDF-15 levels were significantly elevated in non-Hispanic White females with early ROA and high-impact pain, with race- and sex-dependent differences. Activin A levels were higher in non-Hispanic Black participants without pain or ROA and varied by sex in early ROA/low-impact pain phenotypes. Osteopontin levels were elevated in males compared to females within the same phenotype group. IL-15 levels showed no association with ROA-pain phenotypes but were higher in males and positively correlated with age. SASP factors, particularly GDF-15, Activin A, and Osteopontin, demonstrated race- and sex-dependent associations with OA-pain phenotypes. These findings underscore the importance of demographic context in OA pathophysiology and support further investigation into SASP factors as potential biomarkers and therapeutic targets for OA-related pain.

Spinal cord injury (SCI) triggers a cascade of secondary insults-including vascular disruption, excitotoxicity, oxidative stress, inflammation, and apoptosis-that worsen neurological outcomes. Among the molecular mediators, transient receptor potential (TRP) channels have emerged as pivotal regulators of SCI pathology. Distinct subtypes contribute to diverse processes: TRPV1 and TRPA1 drive pain hypersensitivity and inflammation, TRPM2 and TRPM7 amplify oxidative injury and barrier breakdown, TRPC6 shapes astrocyte reactivity, while TRPML1 may confer neuroprotection via autophagy. Although these insights highlight TRPs as attractive therapeutic targets, clinical translation is hampered by widespread channel distribution, poor selectivity of available modulators, and systemic toxicity. Advancing SCI treatment will require innovative strategies to selectively modulate TRP signaling, exploit targeted delivery systems, and integrate TRP modulation into multimodal therapeutic approaches.

Inflammatory pain is a key component of acute traumatic pain and chronic rheumatic disease, which significantly reduces the quality of life of those who suffer from it and is often refractory to treatment. One contributor to the failure of current treatments is that the majority of pain testing has historically been performed in male subjects while the majority of pain patients are women. To better manage inflammatory pain, first the baseline sex differences in its experience must be assessed. Therefore, we evaluated C57BL/6J male and female mice for baseline sex differences in the formalin model of inflammatory pain, further investigating the observed significant sex differences through both assessing female mice at each phase of the estrous cycle and through examining the effects of gonadectomy (ovariectomy or castration) within the formalin model of inflammatory pain. Female mice in the metestrus or diestrus phase had decreased inflammatory pain relative to both male mice and female mice in the proestrus or estrus phase. Ovariectomy resulted in decreased pain, which was restored through treatment with estradiol (E2). Castration similarly reduced pain in male mice. Injection of the G-protein coupled estrogen receptor (GPER) agonist G1 resulted in significant antinociception in both female and male mice, in both mice that had received sham surgery or gonadectomy. These results establish baseline sex differences in the formalin model of inflammatory pain and support the need for further investigation into the interaction between estrogen, its receptors, and testosterone in the regulation of nociception.

This study aimed to evaluate the therapeutic impact of Onabotulinumtoxin A (botulinum toxin) injections in patients suffering from chronic migraine and chronic tension-type headache, while assessing changes in salivary pain biomarkers-calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). A total of 45 subjects were recruited: 25 diagnosed with chronic migraine and 20 with chronic tension-type headache, based on criteria from the International Classification of Headache Disorders (ICHD-3 and ICHD-2 revisions, respectively). Diagnosis confirmation was supported by MRI or CT imaging to exclude other etiologies. Salivary CGRP and PACAP levels were measured before and after botulinum toxin administration using enzyme-linked immunosorbent assay (ELISA). In this open-label, uncontrolled design, results showed a statistically significant reduction (p < 0.05) in both biomarkers post-treatment across both patient groups. Onabotulinumtoxin A demonstrated apparent effectiveness as a prophylactic therapy, contributing to notable improvement in headache symptoms. Among all clinical parameters evaluated, orofacial pain showed the highest responsiveness to treatment.

Chronic itch is a debilitating symptom associated with many dermatological and systemic diseases. Rodent behavioral models that distinguish pain and itch responses remain limited. Our previous studies have examined behavioral responses of mice to chemicals delivered to the plantar glabrous skin and suggested that glabrous skin biting is associated with itch sensation whereas licking represents pain sensation, establishing a new mouse behavioral model to differentiate pain and itch responses in the glabrous skin. To provide further validation of this model, we here investigated behavioral responses following intraplantar injection of multiple pruritogens to examine if they can effectively evoke biting behavior. We show that most of the tested pruritogens induced dose-dependent responses. PAR2 peptide agonist SLIGRL selectively evoked licking, whereas deoxycholic acid (DCA) selectively induced biting. 5-HT triggered licking with a low concentration and both licking and biting with a higher concentration. IL-31 and allergen ovalbumin evoked both licking and biting. Importantly, morphine abolished capsaicin-induced licking but not biting induced by Bam8-22 or DCA, confirming that glabrous skin biting represents an itch-associated nocifensive behavior. Together, our results establish a robust model to differentiate between pain and itch and provide a platform for investigating mechanisms underlying glabrous skin itch.

The role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) is complex and shaped by biological and experimental factors, including sex, hormonal status, genetic background, and cancer model. This complexity has contributed to inconsistent findings among studies, limiting therapeutic progress. In this study, we investigate how T cells contribute to painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Adult male T cell-competent (RNU+/-) and T cell-deficient (RNU-/-) rats were subcutaneously inoculated with tumor cells and subsequently treated with intraperitoneal PTX (8 mg/kg total dose). Reflexive (mechanical, heat, cold) and non-reflexive (burrowing, gait) pain behaviors were assessed from baseline through Week 6. Immunohistochemistry (CD68, CX3CR1, CD206) and flow cytometry (CD163, CD86, CD11b/c, CD3, CD161a, CD45RA) were used to assess macrophage and lymphocyte populations. T cell-competent, but not -deficient, rats developed and maintained cold hypersensitivity following PTX. T cells also reduced the onset intensity of PTX-induced mechanical hypersensitivity. In T cell-competent rats, PTX reduced T and B cell counts and increased the CD4⁺/CD8⁺ T cell ratio across DRG, sciatic nerve, and spleen. PTX shifted macrophage polarization toward the M1 phenotype and reduced the M2/M1 ratio, independent of T cells. However, M2 macrophages (M2γ and M2a) increased specifically in the sciatic nerves of T cell-deficient rats. Additionally, natural killer (NK) cells decreased in PTX-treated, T cell-deficient rats but remained unchanged in T cell-competent rats. These findings highlight the complex role of T cells in PIPN. In PIPN, T cells play a critical role in driving PTX-induced cold hypersensitivity. A decrease in their number worsens pain intensity, possibly by altering the CD4⁺/CD8⁺ T cell balance. In contrast, NK cell reductions in T cell-deficient rats may contribute to hypersensitivity in the absence of T cells.

Most basic and clinical research on chronic pain has traditionally focused on the mechanisms and treatment of physical pain resulting from peripheral injuries in individual animals or humans. However, growing evidence highlights the importance of emotional pain, a form of distress that extends beyond the individual to include family members, partners, and friends affected by another's suffering. In this review, I summarize recent advances in animal models of empathic pain and explore cortical synaptic mechanisms underlying this form of social or emotional pain. I compare the cortical processes mediating physical pain and emotional pain, drawing on evidence from both human brain imaging and animal studies. Converging findings suggest that the anterior cingulate cortex (ACC) and insular cortex (IC) play central roles in the perception and persistence of emotional pain. Cortical potentiation appears to be a key synaptic mechanism driving long-term emotional pain, and cortical top-down modulation of spinal nociceptive transmission may help explain how emotional distress leads to abnormal somatosensory perception. Finally, the calcium-stimulated adenylyl cyclase subtype 1 (AC1) is discussed as a potential therapeutic target for the treatment of chronic pain and its associated emotional disorders.

Introduction: It has well been documented that sex-related difference in the prevalence of migraine is widely accepted with more commonly seen in female patients. Although trigeminal ganglion (TG) neurons are the key players in the etiology of migraine, the underlying pathophysiology remains under debate so far.

Methods: Myelinated Ah-type TG neurons were identified by the waveform characters of action potential (AP) conjugated with pharmacological validation using whole-cell patch techniques.

Results: The results showed that AP duration and current derivative for repolarization were markedly increased by 3 µM Yoda1 along with the increased firing frequency of repetitive discharge that could be abolished by 3 µM GsMTx4. Although Yoda1 concentration-dependently increased the peaks of Ca²⁺ currents, the blocker for Ca²⁺ channel ω-Conotoxin did not alter the AP waveform characters and discharge profiles, whereas Yoda1-mediated changes in AP waveform trajectory and repetitive discharge could be completely reversed by 1.0 µM Iberiotoxin, a selective KCa1.1 blocker, suggesting that Piezo1-induced Ca²⁺ influx can activate KCa1.1 via presumably channel coupling. Additionally, Ah-type TG neurons functionally expressed Nav1.9/Nav1.8 in all tested neurons and their peaks were significantly increased by 3 µM Yoda1 and completely blocked by 3 µM GsMTx4.

Conclusion: These datasets have demonstrated Piezo1-mediated neuroexcitation of female-specific subpopulation of myelinated Ah-type TG neurons due at least to the coupling between N-type Ca²⁺ channel and KCa1.1 and functional upregulation of Nav1.9, which uncovers an additional insights for higher incidence of migraine in woman.

When conventional drug-based Western medicine proves ineffective, complementary and alternative medicine (CAM), including herbal medicine and acupuncture, often gains prominence. Phytochemicals, plant-derived compounds synthesized for self-protection against environmental stressors like ultraviolet radiation and insects, have also shown numerous physiological benefits in humans. Among these, flavonoid compounds - abundant in fruits and vegetables - have garnered significant research interest due to their reported biological activities, such as antioxidant, anti-inflammatory, and anticancer effects. Recent in vitro studies have provided substantial evidence that flavonoids modulate the activity of various ion channels. These channels are crucial for the generation and conduction of activation and action potentials in excitable cells, including those involved in pain transmission. These findings strongly suggest that flavonoids could serve as novel therapeutic agents for pain relief, potentially replacing existing local anesthetics. This paper discusses recent in vivo neurophysiological findings which reveal the potential of flavonoids to substitute existing local anesthetics in nociceptive and inflammatory pain. We explore the possibility of developing new drugs with fewer side effects by focusing on the common chemical structure of flavonoids, addressing the shortcomings of current anesthetics, and outlining future prospects.

Background: Chronic Back Pain (CBP) may lead to a reorganization of brain function, which can be observed through the indicator of degree centrality (DC). Traditional pain research has predominantly focused on static measurements of brain function within classical frequency bands, which may not fully capture the complexities of chronic pain. This study not only employed static frequency division but also incorporated dynamic analyses to capture the evolving nature of brain activity in chronic pain conditions.

Methods: This study included a total of 31 patients with CBP and 33 age- and gender-matched healthy controls. Spontaneous brain activity was investigated by traditional DC, DC in subfrequency bands (slow-5, slow-4) and dynamic DC (dDC). Differences in brain regions between the two groups were obtained using two-sample t-tests. The association of abnormal brain regions with pain intensity and psychological tests were analyzed in parallel.

Results: Compared to classical frequency band, the number of brain regions with changes in DC values in the slow-5 frequency band is greater. The right angular gyrus was found in both the slow-5 frequency band and the classical frequency band, while the left putamen was only found in the slow-5 frequency band. The dDC values were changed in left hippocampus, and right putamen, which were all different from the brain regions that the static DC (sDC) value altered.

Conclusion: This study demonstrates that incorporating frequency and dynamic analysis in addition to traditional DC metrics can better understand the functional characteristics of the brain in CBP.