Pharmacokinetics and cytokine production in heroin and morphine-treated mice

The parallelism between serum levels of heroin and morphine (M) metabolites and the production of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2) , interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), transfor ming growth factor-beta 1 (TGF-beta 1), and interferon-gamma (IFN-gamma) fr om murine splenocyte cultures following s.c. injection with 20 mg/kg heroin or M in C57/BL mice is described. The pharmacokinetic profiles of M and in active morphine-3-glucuronide (M3G) in morphine-treated mice nearly overlap ped those in heroin-treated mice, with the only difference being the presen ce of 6-monoacetylmorphine (AM) in profiles of the latter group. Heroin and M significantly increased production of IL-1 beta, IL-2, TNF-alpha and IFN -gamma at 3, 20 and 40 min from treatment, peaking at 20 min, though the ef fect was very brief. At 24 h production was greatly inhibited, and this dep ressive effect lasted longer than the stimulatory effect. At 48 h only a pa rtial recovery was observed. Heroin and M also had a highly stimulatory eff ect on the release of anti-inflammatory cytokines such as TGF-beta 1 and IL -10, though this effect was observed after 120 min, peaking at 24 h and the n somewhat decreasing at 48 h. This study demonstrates that the more rapid and pronounced immune response to heroin treatment was due to the presence of AM. Both heroin and M produced a biphasic effect on cytokine production: the central opioid or non-opioid receptors are involved in exogenous opiod -induced stimulatory effects, whereas peripheral opioid or non-opioid recep tors are involved in depressive effects. Deficient or excess expression of these key mediators may predispose the host to aberrant defence mechanisms. (C) 2000 International Society for Immunopharmacology. Published by Elsevi er Science Ltd. All rights reserved.