When released in peripheral tissue, ATP causes pain by activating P2X receptors that are expressed in the membrane of sensory neurons in various mammals, from rodents to man. We have found that opioid and P2X receptors are functionally coupled in the sensory nerve fibers and neurons of rat. When examined in the skin-nerve preparation, the ATP-evoked discharges of nerve fibers belonging to n. saphenous were inhibited by various opiates in a naloxone-dependent manner. The functional coupling between opioid and purinergic receptors was studied in the neuronal cell bodies isolated from dorsal root and nodose ganglia. Both fast (mediated by P2X3 receptors) and slow (P2X2/3 heteromeric receptors) responses of sensory neurons to ATP were inhibited by opiates. The inhibition of slow responses developed in a characteristic biphasic manner: an initial short phase of potentiation (lasting for 300–400 sec) was followed by long-lasting inhibition of the response (for about 50 % when saturated). The effect is most probably due to the activation of m-opioid receptors: both phases of the response were initiated by the application of the highly selective ligand for m-receptors, endomorphin1 (30 nM). Intracellular GTPS itself caused a partial inhibition of the ATP responses and opioids were not effective against the residual response. Intracellular GDP eliminated the effect of opioids, while pertussis toxin (PTX) abolished only the inhibition phase. Thus, opioid receptors affect P2X receptors via multiple G-protein-dependent pathways.