Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.3, 1 and 3 micrograms/kg intravenously [i.v.]) dose-dependently, reversibly and stereoselectively antagonized the increase of contralateral thalamic activity. This compound, when given i.v. (30 micrograms/kg) or orally (10 mg/kg), also reduced the number of Fos-like immunoreactive cells particularly at the medial and caudal level of the NtV. In contrast, SR48968 did not exert any antagonistic effect either on thalamic activity or on Fos-like immunoreactivity. The data strongly suggest a preferential involvement of NK1 vs NK2 receptors in nociceptive transmission following trigeminal ganglion stimulation. Taken together, our results indicate that SR140333 could provide a potent drug for the relief of pain occurring under excessive activity of sensory trigeminal fibers.