Effect of high doses of morphine on Con-A induced lymphokine production in vitro

Morphine, a potent analgesic drug as well as the active metabolite derived from heroin, has been reported to affect a variety of immune functions. In vivo administration of high doses of morphine to animals has been shown to inhibit natural killer (NK) cell activity in the rat (Shavit et al., 1984) and splenic T cell mitogenic response in the mouse (Bryant et al., 1988). We report here on the effect of morphine sulfate (MS) (0.2-1.6 mM) on Concanavalin-A (Con-A) stimulated lymphokine production by mouse splenocytes in vitro. Twenty-four hour incubation of mouse splenocytes with MS, removal of the drug and activation with Con-A resulted in a significant (linear regression, P less than 0.001) dose-related inhibition of lymphokine production (IC50 = 0.8 mM) as measured by bioassay for interleukin-2 (IL-2)/interleukin-4 (IL-4). The inhibitory effect of MS on lymphokine production was not blocked by opiate antagonists nor was the inhibitory effect mimicked by equivalent concentrations of mu, delta or epsilon receptor-specific opiate agonists. Exposure to the concentrations of MS used did not reduce viability of mouse splenocytes as determined by Trypan Blue exclusion. Morphine did not inhibit protein synthesis or adenylate cyclase activity in a T cell clone under identical conditions, indicating that MS, in this concentration range, does not simply interfere with all cell functions in a nonspecific manner. These results suggest that (1) morphine directly inhibits splenocyte function, (2) the inhibitory effect is not mediated through classical opiate receptors, and (3) the inhibitory effect is not due to toxicity.