Spinal acute opioid tolerance remains mechanistically undercharacterized. Expanded clinical use of direct spinal administration of opioids and other analgesics indicates that studies to further understand spinal mechanisms of analgesic tolerance are warranted. Rodent models of spinal administration facilitate this objective. Specifically, acute spinal opioid tolerance in mice presents a plasticity-dependent, rapid, and efficient opportunity for evaluation of novel clinical agents. Similarities between the pharmacology of acute and chronic spinal opioid tolerance, neuropathic pain, and learning and memory suggest that this model may serve as a high through-put predictor of bioactivity of novel plasticity-modifying compounds.