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

This study investigated the potential clinical implications of X-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 [C-14]sucrose (a membrane impermeant marker) and [H-3]codeine were investigated using an in situ brain perfusion model in the rat. Results demonstrated a significantly increased brain uptake of [C-14] sucrose at 1, 3, 6 and 48 h (139 9%, 166 +/- 19%, 138 +/- 13% and 146 +/- 7% compared with control, respectively) and [H-3]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 X-carrageenan-induced inflammatory pain enhanced the in vivo antinociceptive profile of i.p.-administered codeine lambda 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 lambda-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. (C) 2004 Elsevier B.V All rights reserved.