In this study, we investigated how bevacizumab influences morphine antinociception and dissected the underlying molecular mechanisms within the mPFC. We hypothesized that VEGF-A inhibition disrupts neuronal autophagy by reducing TSC1 expression and activating mTOR, thereby compromising morphine analgesic signaling. We further examined whether genetic or pharmacological interventions targeting this axis could restore morphine efficacy under VEGF-A blockade. Through integrated behavioral, proteomic, molecular, ultrastructural, and in vivo calcium-imaging analyses, we identified a mechanistic link between VEGF-A blockade and impaired opioid function, and explored potential therapeutic strategies to mitigate this interaction in clinical settings where anti-VEGF therapy is employed.