Pain
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Alterations in amygdala activity are apparent in women who report a history of early life stress (ELS) and those diagnosed with chronic pain disorders. Chronic stress in adulthood induces visceral hypersensitivity by alterations in glucocorticoid receptor (GR) and corticotropin-releasing factor (CRF) expression within the central amygdala (CeA). Here, we hypothesized that unpredictable ELS, previously shown to induce visceral hypersensitivity in adult female rats, alters GR and CRF expression in the CeA. ⋯ Knockdown of GR increased visceral sensitivity in all rats but revealed an exaggerated visceral hypersensitivity in females with a history of predictable or unpredictable ELS compared with that of controls. Knockdown of CRF expression or antagonism of CRF1R in the CeA attenuated visceral hypersensitivity after unpredictable ELS. This study highlights a shift in GR and CRF regulation within the CeA after ELS that underlies the development of visceral hypersensitivity in adulthood.
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Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. ⋯ The effect was reversible with local naloxone administration. We quantified β-endorphin secretion from HSC-3 cells and showed that HSC-3 cells transfected with OPRM1 secreted significantly more β-endorphin than control HSC-3 cells. These findings indicate that nonviral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and nonviral gene delivery is a potential treatment for cancer pain.