Pain
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Induced pluripotent stem cells (iPSCs) have enabled the generation of various difficult-to-access cell types such as human nociceptors. A key challenge associated with human iPSC-derived nociceptors (hiPSCdNs) is their prolonged functional maturation. While numerous studies have addressed the expression of classic neuronal markers and ion channels in hiPSCdNs, the temporal development of key signaling cascades regulating nociceptor activity has remained largely unexplored. ⋯ However, effective inhibition of forskolin-induced PKA-II activation by opioid receptor agonists required 70 days of in vitro differentiation. Our results identify a pronounced time difference between early expression of functionally important ion channels and emergence of regulatory metabotropic sensitizing and desensitizing signaling only at advanced stages of in vitro cultivation, suggesting an independent regulation of ionotropic and metabotropic signaling. These data are relevant for devising future studies into the development and regulation of human nociceptor function and for defining time windows suitable for hiPSCdN-based drug discovery.
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Observational Study
Fibromyalgia predicts increased odds of pain-related addiction exacerbation among individuals with pain and opioid use disorder.
Fibromyalgia and opioid use disorder (OUD) are highly impactful chronic illnesses with substantially overlapping psychosocial, biological, and clinical features. Little previous research has examined interactions between fibromyalgia and OUD. Limiting such research has been the previous requirement of a clinical examination to diagnose fibromyalgia. ⋯ Although all participants had pain, those with fibromyalgia demonstrated significantly greater odds of acknowledging pain-related OUD exacerbations. Pain-related OUD Exacerbation Scale was found to have a single-factor solution, strong internal consistency, and construct validity. This study provides first evidence of fibromyalgia as a risk factor for pain-related exacerbation of OUD and introduces a new scale with promising psychometric properties to measure pain-related OUD exacerbation.
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Debilitating pain affects the lives of patients with sickle cell disease (SCD). Current pain treatment for patients with SCD fail to completely resolve acute or chronic SCD pain. Previous research indicates that the cation channel transient receptor potential vanilloid type 4 (TRPV4) mediates peripheral hypersensitivity in various inflammatory and neuropathic pain conditions that may share similar pathophysiology with SCD, but this channel's role in chronic SCD pain remains unknown. ⋯ TRPV4 blockade also reduced the mechanical sensitivity of small, but not large, dorsal root ganglia neurons from mice with SCD. Furthermore, keratinocytes from mice with SCD showed sensitized TRPV4-dependent calcium responses. These results shed new light on the role of TRPV4 in SCD chronic pain and are the first to suggest a role for epidermal keratinocytes in the heightened sensitivity observed in SCD.