Pain
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Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. ⋯ Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.
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Pathophysiological mechanisms underlying pain associated with cancer are poorly understood. microRNAs (miRNAs) are a class of noncoding RNAs with emerging functional importance in chronic pain. In a genome-wide screen for miRNAs regulated in dorsal root ganglia (DRG) neurons in a mouse model of bone metastatic pain, we identified miR-34c-5p as a functionally important pronociceptive miRNA. Despite these functional insights and therapeutic potential for miR-34c-5p, its molecular mechanism of action in peripheral sensory neurons remains unknown. ⋯ Importantly, knocking down the expression of Cav2.3 specifically in DRG neurons led to hypersensitivity in mice. In summary, these results show that Cav2.3 is a novel mechanistic target for a key pronociceptive miRNA, miR-34c-5p, in the context of cancer pain and indicate an antinociceptive role for Cav2.3 in peripheral sensory neurons. The current study facilitates a deeper understanding of molecular mechanisms underlying cancer pain and suggests a potential for novel therapeutic strategies targeting miR-34c-5p and Cav2.3 in cancer pain.