Endogenous opioids have been reported to elicit some of the pathophysiologic responses to endotoxic shock by binding to the δ-opiate receptor. We have previously reported the production of immunoreactive (ir)-endorphin by B lymphocytes treated with bacterial lipopolysaccharide (LPS). We postulated that this lymphocyte-derived ir-endorphin may be an extrapituitary source of the endogenous opioid component associated with the pathophysiology of endotoxic shock. To test this hypothesis, we chose to study the LPS-sensitive ( C3HeB FeJ) and -resistant ( C3H HeJ) inbred mouse model. We treated these mice with intraperitoneal injections of LPS or B-lymphocyte-derived ir-endorphin. The LPS-sensitive mice presented with a severe hypothermic and pathophysiologic response pattern when treated with LPS or with ir-endorphin. The LPS-resistant mice, which were unresponsive to the LPS, however, presented with the typical hypothermic and pathophysiologic responses to the ir-endorphin. Immunofluorescence on the splenic leukocytes in the LPS-treated mice showed significant ir-endorphin present only in the LPS-sensitive mice at a time point preceding onset of the pathophysiologic response pattern. Taken together, this evidence strongly suggests a role for B-lymphocyte-derived ir-endorphin in the pathophysiology of endotoxic shock. The implications of immune system regulation of neuroendocrine function are discussed. © 1987.