PAIN®最新文献

Abstract: Mechanotransduction is vital for sensing various mechanical stimuli, including blunt force and dynamic light touch. The sensation of a punctate mechanical force is very different from that of a brush swept across the skin, yet both involve mechanical stimulation of the skin and embedded sensory afferent endings. However, the sensory neuron mechanisms contributing to punctate vs light touch somatosensation, and how they might become dysregulated in nerve injury to cause pain, remain unclear. Here, we use mice with sensory neuron-specific PIEZO1 deletion to demonstrate sensory neuron PIEZO1 is required for dynamic light mechanical touch, and possibly punctate mechanical force, in healthy animals. These mice are also protected from acute and chronic tibial spared nerve injury-induced dynamic light touch hypersensitivity. However, dorsal root ganglia neurons from uninjured mice with sensory neuron PIEZO1 deletion displayed evidence of developmental compensation, including sensitized mechanically evoked inward currents. Dorsal root ganglia from these mice also exhibit transcriptional and functional compensation of other ion channels, including PIEZO2, TRPV1, and TRPV4. Thus, the behavioral phenotype of mice with sensory neuron-specific PIEZO1 knockout likely reflects these and possibly other forms of genetic compensation resulting from PIEZO1 absence throughout development, in addition to functional sensory neuron PIEZO1 deletion. Research using this transgenic mouse model must account for these caveats to facilitate accurate data interpretation. Furthermore, this article serves as a call for researchers to critically investigate possible genetic compensation in their mice. Such scrutiny is crucial to prevent replication crises and for advancement of scientific knowledge more broadly.

Abstract: Orofacial pain (OFP) encompasses a complex spectrum of conditions that present significant diagnostic challenges. The International Classification of Orofacial Pain (ICOP), introduced in 2020, offers a comprehensive diagnostic framework encompassing nearly 200 distinct OFP conditions. However, its detailed structure can impede practical use in clinical settings. To address this, we developed the International Classification of Orofacial Pain Algorithm (ICOP-AL), a flowchart-based tool designed to simplify the diagnostic process by methodically guiding users through ICOP's hierarchical criteria. International Classification of Orofacial Pain Algorithm integrates well-established diagnostic standards, including those from the International Classification of Headache Disorders, 3rd edition and Diagnostic Criteria for Temporomandibular Disorders, to enhance clinical applicability and diagnostic precision. The algorithm's validity was assessed in a study with 100 anonymized patient cases and further evaluated by clinicians across varied experience levels. The results demonstrated substantial agreement between ICOP-AL-derived diagnoses and expert clinician diagnoses (Cohen's Kappa κ = 0.688, P < 0.001), with ICOP-AL outperforming nonexpert evaluators, thereby underscoring its reliability and potential to standardize diagnostic outcomes across clinical environments. International Classification of Orofacial Pain Algorithm represents a promising step toward improving OFP diagnosis, providing a structured and accessible approach for integrating ICOP into routine clinical practice. Although early results are encouraging, further refinement and real-world validation, particularly for more detailed diagnoses, are necessary to determine its full potential as a diagnostic and educational tool.

Abstract: Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain (CIPN) is a major neurotoxicity of cisplatin, a platinum-based drug widely used for lung, ovarian, and testicular cancer treatment. Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain causes drug discontinuation and severely affects life quality with no FDA-approved interventions. We previously reported that platinum-based drugs increase levels of sphingosine 1-phosphate (S1P) in the spinal cord and drive CIPN through activating the S1P receptor subtype 1 (S1PR1). However, the mechanisms engaged downstream of S1PR1 remain poorly understood. Using single-cell transcriptomics on male mouse spinal cord, our findings uncovered subpopulation-specific responses to cisplatin associated with CIPN. Particularly, cisplatin increased the proportion of astrocytes with high expression levels of S1pr1 ( S1pr1high astrocytes), specific to which a Wnt signaling pathway was identified. To this end, several genes involved in Wnt signaling, such as the fibroblast growth factor receptor 3 gene ( Fgfr3 ), were highly expressed in S1pr1high astrocytes. The functional S1PR1 antagonist, ozanimod, prevented cisplatin-induced neuropathic pain and astrocytic upregulation of the Wnt signaling pathway genes. Fibroblast growth factor receptor 3 gene belongs to the FGF/FGFR family which often signals to activate Wnt signaling. Intrathecal injection of the FGFR3 antagonist, PD173074, prevented the development of CIPN in male mice. These data not only highlight FGFR3 as one of the astrocytic targets of S1PR1 but raise the possibility that S1PR1-induced engagement of Wnt signaling in S1pr1high astrocytes may contribute to CIPN. Overall, our results provide a comprehensive mapping of cellular and molecular changes engaged in cisplatin-induced neuropathic pain and decipher novel S1PR1-based mechanisms of action.

Abstract: Previous studies suggest a dysregulation of the inhibitory γ -aminobutyric acid (GABA) and the excitatory glutamate/glutamine (Glx) neurotransmitter systems in people living with chronic pain. Here, we test this hypothesis in people with HIV (PWH) on stable antiretroviral therapy, either with or without neuropathic pain (PWHpain and PWHnopain, respectively), and people without HIV and pain (Ctrl). Fourteen PWHpain (age, mean ± SD: 59 ± 6.5, 12 males), 13 PWHnopain (55 ± 9, 12 males), and 14 Ctrl (58 ± 10, 14 males) completed a 3T 1 H-magnetic resonance spectroscopy MEGA-PRESS scan quantifying GABA and Glx in the left posterior insula. Furthermore, temporal summation was evaluated using cuff pain algometry, applied on the participants' left calf for 120 seconds at a pressure calibrated to a subjective target pain rating of 40/100. In addition, we evaluated blood plasma levels of neurosteroids (ie, allopregnanolone) known to be endogenous modulators of GABA-A receptors. People with HIV with neuropathic pain exhibited increased temporal summation of cuff pain and decreased posterior insula GABA levels compared to Ctrl and PWHnopain ( P 's < 0.05). There were no statistically significant group differences in Glx. Lower GABA levels were associated with higher average cuff pain ratings (R = -0.44, P < 0.05) and temporal summation scores (R = -0.49, P < 0.01) in PWH. In addition, lower allopregnanolone levels were associated with higher insular Glx levels in PWHpain (R = -0.64, P < 0.05). Our results provide a link between decreased GABA levels and neuropathic pain in PWHpain. These results suggest that insufficient inhibitory metabolite levels, rather than excessive excitatory metabolite levels, may be linked to neuropathic pain in PWH.

Abstract: Pain has been suggested as an important risk factor for suicidality in adolescents. We examined the association between pain at age 11 years and suicidality until age 18 years. Second, we assessed whether psychiatric diagnoses might mediate this association. We used data from the Danish National Birth Cohort's 11-year follow-up (DNBC-11) and 18-year follow-up (DNBC-18). Self-reported head, stomach, neck, and back pain at age 11 years were examined as exposures. Outcomes were formed from data on self-reported suicidal ideation and suicide attempts from the DNBC-18 and hospital-recorded suicide attempts by age 18 years. We used multinomial logistic regressions and mediation analyses, adjusting for covariates and incorporating sampling weights. Among 28,465 eleven-year-olds, 13.5% reported any frequent pain, which was associated with increased risks of suicidal ideation (adjusted relative risk ratio [aRRR] = 1.6, 95% confidence interval [CI]: 1.5-1.7) and suicide attempts (aRRR = 2.4, 95% CI: 2.0-2.8). Individuals who had reported 3 or more pain sites at age 11 years had a higher risk of suicide attempt (aRRR = 6.4, 95% CI: 3.9-10.4) compared with those with no frequent pain. Pain-related functional interference and recurrent pain were associated with significantly elevated risks of suicidal ideation and suicide attempts. Affective and anxiety/stress-related disorders diagnosed between age 11 and 18 years significantly mediated the association between frequent pain and suicidal ideation (14%-16%), as well as between frequent pain and suicide attempts (37%-48%). Frequent pain is a common concern in 11-year-olds in Denmark and prospectively associated with an increased risk of suicidality by age 18 years. Suicide preventive strategies may consider targeting youth with frequent pain.

Abstract: The unprecedented disruption of the COVID-19 pandemic raises crucial questions about its impact on chronic pain levels in the US population. We present a comprehensive analysis of chronic pain (CP), high-impact chronic pain (HICP), and site-specific pain prevalence before, during, and after the pandemic, and investigate key contributing factors. We analyze a nationally representative sample of 90,769 community-dwelling adults aged 18 years and older from 3 cross-sectional waves of the National Health Interview Survey (2019, 2021, and 2023). Outcomes are CP and HICP; we also present findings for 6 site-specific pain measures. We include an extensive range of covariates (demographics, socioeconomic status, health behaviors, health conditions, mental health, and health insurance type); additional analyses also explore the role of long COVID. Chronic pain prevalence increased from 20.5% (95% confidence interval: 19.9%-21.2%) in 2019 to 20.9% (20.3%-21.6%) in 2021 and 24.3% (23.7%-25.0%) in 2023, representing an 18% increase over the study period. High-impact chronic pain prevalence, which was 7.5% (7.1%-7.8%) in 2019, declined to 6.9% (6.6%-7.3%) in 2021 before rising to 8.5% (8.1%-8.9%) in 2023, a 13% overall increase. The 2023 pain increases were widespread: they occurred for all examined body sites except tooth/jaw pain and all population subgroups. Long COVID accounted for approximately 13% of the observed 2019 to 2023 increase in both CP and HICP. In 2023, an estimated 60 million Americans experienced CP and 21 million experienced HICP, the highest prevalence ever recorded in the National Health Interview Survey. These findings suggest a significant escalation in the population burden of pain, with crucial implications for public health policy.