The distinctive clinical features of these conditions are borne out pharmacologically where drugs used with beneficial effects in one condition may exacerbate the other. This led us to investigate whether separate interacting/antagonistic receptor-mediated transduction systems may be affected in these conditions. Previous work in our laboratory indicated that the prostacyclin stimulation of adenylate cyclase in lymphocytes was significantly reduced in cluster headache but unaffected in migraine. Hence in this study, we investigated the polyphosphoinositide system which upon receptor activation gives rise to two second messengers, inositol trisphosphate and diacylglycerol. The chemotactic factor stimulation of inositol phosphate production in polymorphonuclear leucocytes (PMNs) was used as the assay system. The maximum response was obtained at approximately 0.1μM chemotactic factor (EC50=13nM for control subjects). Female migraineurs (9 non-smokers) were compared with a matched group of controls and found to have a significantly reduced PMN response to chemotactic factor stimulation (42% of control at 0.1 μM) while male cluster headache patients (7 smokers) showed a response slightly greater than a matched group of controls (male smokers). Interestingly, cluster headache patients undergoing lithium treatment showed a significantly reduced response (39% of the control response at 0.1 μM chemotactic factor). This indicates that lithium may have its beneficial effect in cluster headache by suppressing an overactive polyphosphoinositide system while being of little benefit in migraine where a substantial depression is already evident. Appropriate targetting of drugs to these transduction systems may offer a useful basis for treatment.