Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

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Introduction: Osteoarthritis (OA)-associated pain is often poorly managed, as our understanding of the underlying pain mechanisms remains limited. The known variability from patient to patient in pain control could be a consequence of a neuropathic component in OA. Methods: We used a rat monoiodoacetate model of the ankle joint to study the time-course of the development of pain-related behavior and pathological changes in the joint, dorsal root ganglia (DRG), and spinal cord, and to investigate drug treatments effects. Results: Mechanical hypersensitivity and loss of mobility (as assessed by treadmill) were detected from 4 weeks after monoiodoacetate. Cold allodynia was detected from 5 weeks. Using histology and x-ray microtomography, we confirmed significant cartilage and bone degeneration at 5 and 10 weeks. We detected increased nociceptive peptidergic and sympathetic fiber innervation in the subchondral bone and synovium at 5 and 10 weeks. Sympathetic blockade at 5 weeks reduced pain-related behavior. At 5 weeks, we observed, ipsilaterally only, DRG neurons expressing anti-activating transcription factor 3, a neuronal stress marker. In the spinal cord, there was microgliosis at 5 and 10 weeks, and astrocytosis at 10 weeks only. Inhibition of glia at 5 weeks with minocycline and fluorocitrate alleviated mechanical allodynia. Conclusion: Besides a detailed time-course of pathology in this OA model, we show evidence of contributions of the sympathetic nervous system and dorsal horn glia to pain mechanisms. In addition, late activating transcription factor 3 expression in the DRG that coincides with these changes provides evidence in support of a neuropathic component in OA pain.

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6063 Background: The primary aim of this study was to investigate the contribution of genetic predisposition to depression, through polygenic risk scores (PRS), on quality of life levels in patients with head and neck cancer (HNC) immediately post-treatment period (i.e., 3 months post-diagnosis). Methods: Prospective longitudinal study of 223 consecutive adult patients with HNC (72% participation) newly diagnosed with a first occurrence of primary HNC, including saliva samples analyzed using the Illumina PsychChip, psychometric measures, Structured Clinical DSM Interviews, and medical chart reviews. Results: Level of quality of life at 3 months on the FACT-G+H&N was predicted by (r2 = 0.51, r2 adj. = 0.33, p = 0.001) the polygenic risk score for depression (standardized b = -0.28, p = 0.01) and a previous history of suicidal ideation (standardized b = -0.25, p = 0.04). Other variables were non-significant in the analyses: sociodemographic (i.e., age, sex, education, living alone), psychosocial (i.e., SCID current and past diagnoses (trend), past history of abuse), and medical variables (i.e., cancer stage and site, HPV status, functional status/ECOG, treatment). Conclusions: Our results outline the importance of attending to genetic predisposition and past history of suicidal ideation as markers for quality of life compromise immediately post-treatment in patients with head and neck cancers. Strategies are needed to address psychosocial vulnerability early-on as part of pre-habilitation in the treatment of patients with head and neck cancer.