This study was carried out to determine whether activation of dopamine D₂-like receptors inhibits the hyperresponsiveness of pulmonary C fibers induced by inflammatory mediators such as prostaglandin E₂ (PGE₂). In anesthetized, open-chest rats, constant infusion of PGE₂ (1.5-4.5 µg/kg/min, 2 min) significantly enhanced the C-fiber response to capsaicin injection. At 20 minutes after pretreatment with quinpirole (3 mg/kg, IV), a D₂-like receptor agonist, the hyperresponsiveness to capsaicin of the same C fibers induced by PGE₂ infusion was markedly attenuated, and this inhibitory effect lasted for >90 minutes. The effect of quinpirole was dose-dependent and was antagonized by pretreatment with domperidone (5 mg/kg, IV), a D₂-like receptor antagonist, administrated 10 minutes before the quinpirole injection. In a separate series of experiments, C-fiber responses to injections of phenyl biguanide and lactic acid and to constant-pressure lung inflation were augmented by PGE₂; these potentiating responses were also significantly reduced by quinpirole. Furthermore, the effect of quinpirole was equally effective in inhibiting the increase in excitability of pulmonary C fibers induced by alveolar hypercapnia or constant infusion of adenosine. In conclusion, these results clearly show that activation of the dopamine D₂-like receptors attenuates the hyperresponsiveness of pulmonary C fibers to both chemical stimuli and lung inflation.