Effect of λ-carrageenan-induced inflammatory pain on brain uptake of codeine and antinociception

Abstract This study investigated the potential clinical implications of λ-carrageenan-induced inflammatory pain on brain uptake of a commonly used analgesic, codeine, in relation to the fundamental properties of the blood–brain barrier (BBB) correlated to its antinociceptive profile over a 168-h time course. BBB uptake of [ 14 C]sucrose (a membrane impermeant marker) and [ 3 H]codeine were investigated using an in situ brain perfusion model in the rat. Results demonstrated a significantly increased brain uptake of [ 14 C]sucrose at 1, 3, 6 and 48 h (139±9%, 166±19%, 138±13% and 146±7% compared with control, respectively) and [ 3 H]codeine at 3 and 48 h (179±6% and 179±12% compared with control, respectively). Capillary depletion analyses ensured that increased radioisotope associated with the brain was due to increased uptake rather than trapping in the cerebral vasculature. Antinociception studies using a radiant-heat tail flick analgesia method demonstrated that λ-carrageenan-induced inflammatory pain enhanced the in vivo antinociceptive profile of i.p.-administered codeine (7 mg/kg) at 3 and 48 h (144±11% and 155±9% compared with control, respectively). This study demonstrated that brain uptake and antinociception of codeine are increased during λ-carrageenan-induced inflammatory pain, suggesting that the presence of inflammatory pain may be an important consideration in therapeutic drug dosing, potential adverse effects and/or neurotoxicity.