PAIN®最新文献

Abstract: Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

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.