We have shown that in the lamprey a specific opioid-sensitive region, located rostrolateral to the trigeminal motor nucleus and termed the paratrigeminal respiratory group (pTRG), contains respiratory neurons and plays a pivotal role in respiratory rhythm generation. The present study was performed on in vitro lamprey brainstem preparations to investigate the respiratory effects of neurokinins (NKs) possibly through an action on the pTRG, and the respiratory role of the inspiratory burst-promoting currents described in mammals, i.e. the persistent Na⁺ current (I_NaP) and the Ca²⁺-activated non-specific cation current (I_CAN). Bath application of substance P (SP) as well as of NK1, NK2 and NK3 receptor agonists (0.4-0.8 mM) induced marked increases in both the frequency and amplitude of respiratory bursts. Excitatory effects on respiration were also produced by SP (1 mM) microinjections (0.5-1 nl) into the pTRG, where extra- and intracellular neuronal activity was recorded. Bath application of either riluzole or flufenamic acid (20-50 mM) depressed, but not suppressed respiration. Coapplication of these drugs at 50 mM abolished the respiratory rhythm that was restarted by SP microinjected into the pTRG. The results indicate that endogenous NKs may have a modulatory role through an action on the pTRG. They also provide evidence that I_NaP and I_CAN are expressed in the lamprey and contribute to respiratory rhythm generation.