MORPHINE SUPPRESSES THE ALLOANTIGEN-DRIVEN CTL RESPONSE IN A DOSE-DEPENDENT AND NALTREXONE REVERSIBLE MANNER

Previous studies have shown morphine (50.0 mg/kg, s.c.) suppresses cyt otoxic T lymphocyte (CTL) activity in alloimmunized mice. The present study was undertaken to assess the dose-dependent nature of the suppre ssive effect of subchronic morphine exposure on CTL activity in vivo. In alloimmunized ICR mice, morphine (10.0-100.0 mg/kg, s.c.) administe red,daily for 5 days significantly suppressed CTL activity (> 50%) in a dose-dependent and naltrexone (10.0 mg/kg, s.c.)-reversible fashion. The morphine-treated mice showed tolerance to the drug after daily ex posure over 5 days as determined by measuring tail flick latency durin g thermal application. CD4(+)- and CD8(+)-depletion studies showed tha t effector cells were predominately CD8(+) and mediated cytolysis thro ugh a Ca++-dependent pathway. Splenocytes obtained from the morphine ( 56.0-100.0 mg/kg)-treated, alloimmunized mice produced significantly l ess (30-40%) interferon-gamma but not interleukin-2 or interleukin-10 after antigen stimulation but not concanavalin A stimulation. Furtherm ore, this effect was dose- and time-dependent. In addition, there was a modest decrease (10%) in the interferon-gamma transcript level from the morphine (56.0-100.0 mg/kg)-treated, alloimmunized mice compared w ith vehicle-treated, alloimmunized mice as determined by quantitative reverse transcription-polymerase chain reaction. However, there were n o differences in the perforin transcript levels between morphine- and vehicle-treated mice. Collectively, these results suggest that subchro nic morphine exposure suppresses CTL activity in tolerized, alloimmuni zed mice through a pathway that may peripherally involve interferon-ga mma production.