Probes for INS

Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3+ T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis.

Knee osteoarthritis (KOA) is the most common cause of musculoskeletal pain (MSK), constituting a major public health burden. Sleep is among the multiple factors contributing to KOA-related pain, as sleep disturbance increases risk for worse pain-related outcomes in KOA. In addition, our lab found that brain cortical structure mediated the relationship between sleep qualities and pain severity in older adults with MSK. Further, using a machine-learning-based brain-aging biomarker (brain-PAD; brain-predicted age minus chronological age), we also found that individuals with high-impact KOA pain showed greater brain aging than their low-impact pain counterparts. Considering this, we examined whether brain-PAD mediated the relationship between KOA pain and sleep problems. KOA participants (mean age 57.9 years) were classified into low-impact (n=87), and high-impact (n=60) pain. Demographic, pain and sleep assessments were followed by a T1-weighted anatomical scan. Exploratory Spearman and Pearson partial correlations, controlling by age, sex and race, were used to determine associations of brain-PAD with clinical pain and sleep measures. We then tested if brain-PAD mediated the sleep-pain association using PROCESS 3.5 on SPSS 28. Brain-PAD correlated with the affective domain of the McGill Pain Questionnaire (MPQ) (r=0.215, p=0.010) and MPQ total score (r=0.181, p=0.033). Moreover, Brain-PAD significantly mediated (bootstrapped 95% CIs p

Younger age is a risk factor for worse outcomes following breast cancer surgery, including acute pain, development of persistent post-surgical pain, physical symptoms (arm disability), and greater psychological distress (depression). The biopsychosocial model of pain emphasizes the importance of considering the psychosocial context of pain experience, in addition to biological factors (age). Potentially, younger women's worse psychosocial adjustment after breast cancer surgery may explain their greater pain-related functional disability. We investigated the longitudinal relationship between age and pain-related functioning three months post-surgery among women with breast cancer. Further, we examined whether early postoperative psychosocial distress, reported two weeks postoperatively, mediated the association between age and subsequent pain-related functioning. This prospective, observational longitudinal study recruited women (N:161, age:54, range: 26-81) undergoing breast cancer surgery. Validated psychosocial assessments (anxiety, depression, sleep disturbance) were assessed two weeks postoperatively, and impact of surgical pain on cognitive/emotional and physical functioning was assessed three months postoperatively. Bivariate correlations tested associations among age, psychosocial factors, and pain-related functioning. Parallel mediation analyses tested whether the relationship between age and pain-related functioning three months postoperatively was mediated by psychosocial factors reported two weeks postoperatively. Younger age was significantly associated with greater impact of pain on cognitive/emotional and physical functioning. Younger age was associated with greater severity of depressive and anxiety symptoms, and greater sleep disturbance (ps