Buprenorphine administration is recommended following certain surgical procedures in laboratory animals. Although this opioid analog is thought to reduce post-operative discomfort, little research has been undertaken to assess the effects that buprenorphine may have on neuronal and behavioural function, especially in stroke research. This study assessed the effects of buprenorphine administration on survival, histological and functional outcome after cortical stroke. Sprague-Dawley rats (n=73) underwent endothelin-1 (ET-1) forelimb motor cortex stroke under 2% isoflurane anesthesia and were pseudorandomized into one of three experimental conditions that received either 3 (Bupe-3), or 1 (Bupe-1) injection(s) of buprenorphine (0.04 μg/kg, s.c.) or vehicle (Saline). Lidociane injections (2%) and Xylocaine gel (1%) were applied prior to incisions and at wound closure in all animals. Buprenorphine significantly increased core temperature (~0.5o C) for 3 hours immediately post-stroke, but only in the Bupe-1 animals. An overall wellness score consisting of post-operative weight gain, sensory reactivity, respiration rate, etc. revealed that Saline treated animals recovered more quickly than Bupe-3 animals (p<0.025). Buprenorphine resulted in a decrease in skilled reaching in the Montoya staircase test (~10%) and increased infarct volume (~20%) and neuroinflammation (~45%), although neither of these results attained statistical significance. Further, buprenorphine significantly increased the mortality rate compared to the Saline group. Based on these results it may be difficult to compare studies where investigators use different drugs and dosing regimens to control pain and discomfort, thereby posing a challenge to successful translation of preclinical research findings.