Abstract C57BL/6J-bg/bg (beige-J) mice have a blunted antinociceptive response to intracerebroventricularly (i.c.v.) injected morphine in the tail-flick test. Beije-J mice are also immunologically defective and exhibit the pathology of Chediak-Higashi syndrome (CHS). We trasferred by i.v. injection 2 × 10 7 mononuclear spleen cells, devoid of PMNs, obtained from beige-J mice to normal C57BL/6J-bg/ + littermates that do not exhibit CHS or a blunted antinociceptive response to morphine. After 8 days, the normal littermates demonstrated significant ( P < 0.05)_reduction in their analgesic responsiveness to morphine. This phenomenon was found to require B-cells and adherent cells in the adoptively transferred spleen cells. B-cells that had been purified by panning on anti-Ig-coated plates were sufficient to transfer the analgesic defect unless adherent cells were removed prior to immunocytoadherence. T-cells, in the presence or absence of adherent cells, failed to transfer the decreased sensitivity to morphine. These results demonstrate a novel neuroimmune interaction whereby B-lymphocytes and adherent cells, or a substrate derived from them, are able to affect the antinociceptive action of morphine.