A single methadone treatment reverses the reduced antinociception produced by the methadone/NTB cocktail.

<p>A) Proposed model of reduced analgesia produced by the MOR/DOR heteromer in mice treated with methadone/NTB cocktail, where DOR/MORs are anti-analgesic and contribute to poor antinociception. B) Proposed model of a single methadone exposure on the trafficking of MOR and DOR/MOR heteromers after induction of poor antinociception. MOR on day 6 will be activated, internalized and recycled back to the plasma membrane in response to the methadone treatment. Normal cycling will keep the MOR ready for further activation. DOR/MOR on day 6 will be activated, internalized and degraded as a consequence of the methadone treatment. C) Antinociception to escalating doses of methadone on day 7, in the same mice previously shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058362#pone-0058362-g002" target="_blank">Figure 2C & D</a> (closed squares for methadone group: ED₅₀ and 95% confidence intervals: 4.5 (3.4–6.7) mg/Kg, and closed triangles for cocktail group: ED₅₀ and 95% confidence intervals: 3.8 (3.5–4.2) mg/Kg). Open circles show antinociception to methadone on day 6 in the cocktail group: ED₅₀ and 95% confidence intervals: 8.6 (5.4–12.4) mg/Kg. Data represents mean ± SEM; n = 20 mice per group.