Pain
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Pain is an unpleasant sensory and emotional experience. Both pain and emotions are warning signals against outside harm. Interoception, bodily sensations of emotions can be assessed with the emBODY tool where participants colour the body parts where they feel different emotions. ⋯ Patients and controls marked different body areas as sensitive to nociceptive and tactile stimulation, but there was no difference in sensitivity to hedonic touch. Our findings suggest that emotional processing changes when pain persists, and this can be assessed with these colouring tasks. BMoEs may offer a new approach to assessing pain.
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Neuropilin-1 (NRP-1) is a transmembrane glycoprotein that binds numerous ligands including vascular endothelial growth factor A (VEGFA). Binding of this ligand to NRP-1 and the co-receptor, the tyrosine kinase receptor VEGFR2, elicits nociceptor sensitization resulting in pain through the enhancement of the activity of voltage-gated sodium and calcium channels. We previously reported that blocking the interaction between VEGFA and NRP-1 with the Spike protein of SARS-CoV-2 attenuates VEGFA-induced dorsal root ganglion (DRG) neuronal excitability and alleviates neuropathic pain, pointing to the VEGFA/NRP-1 signaling as a novel therapeutic target of pain. ⋯ Following in vivo editing of NRP-1, lumbar dorsal horn slices showed a decrease in the frequency of VEGFA-mediated increases in spontaneous excitatory postsynaptic currents. Finally, intrathecal injection of a lentivirus packaged with an NRP-1 guide RNA and Cas9 enzyme prevented spinal nerve injury-induced mechanical allodynia and thermal hyperalgesia in both male and female rats. Collectively, our findings highlight a key role of NRP-1 in modulating pain pathways in the sensory nervous system.
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Opioid prescribing varies widely, and prescribed opioid dosages for an individual can fluctuate over time. Patterns in daily opioid dosage among patients prescribed long-term opioid therapy have not been previously examined. This study uses a novel application of time-series cluster analysis to characterize and visualize daily opioid dosage trajectories and associated demographic characteristics of patients newly initiated on long-term opioid therapy. ⋯ Time-series cluster analysis identified 2 clusters for each of the 3 baseline dosage categories <150 MME and 3 clusters for the baseline dosage category ≥150 MME. One cluster in each baseline dosage category comprised opioid dosage trajectories with decreases in dosage at the end of the follow-up period (80.7%, 98.7%, 98.7%, and 99.0%, respectively), discontinuation (58.5%, 80.0%, 79.3%, and 81.7%, respectively), and rapid tapering (50.8%, 85.8%, 87.5%, and 92.9%, respectively). These findings indicate multiple clusters of patients newly initiated on long-term opioid therapy who experience discontinuation and rapid tapering and highlight potential areas for clinician training to advance evidence-based guideline-concordant opioid prescribing, including strategies to minimize sudden dosage changes, discontinuation, or rapid tapering, and the importance of shared decision-making.
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Insight into nociceptive circuits will ultimately build our understanding of pain processing and aid the development of analgesic strategies. Neural circuit analysis has been advanced greatly by the development of optogenetic and chemogenetic tools, which have allowed function to be ascribed to discrete neuronal populations. Neurons of the dorsal root ganglion, which include nociceptors, have proved challenging targets for chemogenetic manipulation given specific confounds with commonly used DREADD technology. ⋯ We also demonstrated that our strategy can effectively silence inflammatory-like pain in a chemical pain model. Collectively, we have generated a novel tool that can be used to selectively silence defined neuronal circuits in vitro and in vivo. We believe that this addition to the chemogenetic tool box will facilitate further understanding of pain circuits and guide future therapeutic development.
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We have previously shown that intradermal injection of high-molecular-weight hyaluronan (500-1200 kDa) produces localized antihyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments, we studied the therapeutic effect of topical hyaluronan, when combined with each of 3 transdermal drug delivery enhancers (dimethyl sulfoxide [DMSO], protamine or terpene), in preclinical models of inflammatory and neuropathic pain. Topical application of 500 to 1200 kDa hyaluronan (the molecular weight range used in our previous studies employing intradermal administration), dissolved in 75% DMSO in saline, markedly reduced prostaglandin E 2 (PGE 2 ) hyperalgesia, in male and female rats. ⋯ The topical administration of a combination of hyaluronan with 2 other transdermal drug delivery enhancers, protamine and terpene, also attenuated CIPN hyperalgesia, an effect that was more prolonged than with DMSO vehicle. Repeated administration of topical hyaluronan prolonged the duration of antihyperalgesia. Our results support the use of topical hyaluronan, combined with chemically diverse nontoxic skin penetration enhancers, to induce marked antihyperalgesia in preclinical models of inflammatory and neuropathic pain.