Carprofen and buprenorphine delivery using micropipette-guided drug administration (MDA) in mice

Refined, non-invasive analgesic delivery methods are essential for improving animal welfare and ethical standards in laboratory rodent research. Here, we evaluated whether the micropipette-guided drug administration (MDA) method, which promotes voluntary consumption using a sweetened condensed milk vehicle, achieves therapeutically relevant plasma and brain concentrations of two widely used analgesics, carprofen and buprenorphine, in male and female C57BL/6 N and BALB/c mice. Carprofen administered via MDA at 5, 15, and 30 mg/kg produced dose-response relationships and plasma exposure comparable to those observed following conventional subcutaneous (SC) injection of the same doses, with plasma concentrations exceeding the recommended therapeutic threshold ( ~ 25 μg/mL) in a dose-dependent manner. In contrast, the administration route substantially influenced plasma and brain concentrations of buprenorphine, which was administered at higher doses for MDA (0.5, 1.0, and 2.0 mg/kg) than for SC injection (0.05, 0.1, and 0.2 mg/kg) to compensate for presystemic first-pass metabolism. Specifically, SC injections of buprenorphine produced higher plasma concentrations early after administration, whereas MDA caused a dose-dependent delay in peak plasma levels and led to higher plasma concentrations of the major metabolite, buprenorphine-3-glucuronide. Although plasma concentrations of buprenorphine did not reach the recommended therapeutic threshold (1 ng/mL) for either administration route, brain concentrations exceeded proposed efficacy thresholds (3-5 ng/g) at 8 h post-treatment across all MDA buprenorphine doses. Together, our findings demonstrate that MDA provides an effective alternative to parenteral injection for analgesic treatment, while underscoring the importance of evaluating central drug exposure in addition to plasma concentrations.