Probes for INS

Neuropathic pain is a leading cause of high impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14, and OSM in male and including CCL1, CCL21, PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Co-expression modules revealed enrichment in members of JUN-FOS signalling in males, and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light-mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino-ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)-positive neurons in the vLGN (vLGNPenk). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGNPenk neurons. In addition, activation of the projections from vLGNPenk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGNPenk-DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.

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