(A) A timeline of sustained i.t. siRNA delivery, chronic morphine administration, and assessments of pain behavior and gene expression is shown. CXB7/ByJ mice receiving antisense siRNA exhibit analgesia following morphine administration and cessation, and fail to exhibit (B) decreased paw withdrawal thresholds, or increased responses to (C) repeated presentation of an innocuous or (D) noxious mechanical stimulus. In contrast, mice receiving sense siRNA or sham exhibited analgesia following morphine administration, which was then followed by allodynia/hyperalgesia on days 5–7. (E) CXB7/ByJ mice receiving antisense siRNA exhibit decreased MOR-1K gene expression levels in the spinal cord as compared to those receiving sense siRNA. For all behavioral graphs, blue background indicates a decrease in pain sensitivity (analgesia), and red background indicates an increase in pain sensitivity (allodynia/hyperalgesia). Panels B-D: N = 6-9/group. Data expressed as mean ± SEM.****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 different from Sham. Panel E: N = 3-4/group. **p<0.01 different from Sense.