Effect of lambda-carrageenan-induced inflammatory pain on brain uptake of codeine and antinociception.
This study investigated the potential clinical implications of lambda-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 [14C]sucrose (a membrane impermeant marker) and [3H]codeine were investigated using an in situ brain perfusion model in the rat. Results demonstrated a significantly increased brain uptake of [14C]sucrose at 1, 3, 6 and 48 h (139+/-9%, 166+/-19%, 138+/-13% and 146+/-7% compared with control, respectively) and [3H]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 lambda-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 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.
Hau
Vincent S
VS
Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Huber
Jason D
JD
Campos
Christopher R
CR
Davis
Ryan T
RT
Davis
Thomas P
TP
D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D002351:Carrageenan; D003061:Codeine / Q000493:pharmacokinetics*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D010146:Pain / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D010539:Permeability; D051381:Rats
D000701:Analgesics, Opioid; D002351:Carrageenan; D003061:Codeine