The sites of origin of brain stem enkephalin and cholecystokinin projections to the rodent spinal trigeminal nucleus were studied utilizing the combined retrograde transport-peroxidase antiperoxidase immunohistochemical technique. Several brain stem areas were found to contain enkephalin- like immunoreactive double-labeled neurons following injection of wheat germ agglutinin-horseradish peroxidase or horseradish peroxidase into the spinal trigeminal nucleus. The largest numbers of enkephalin doubled-labeled neurons were identified in the nucleus pontis oralis, nucleus raphe obscurus, nucleus raphe medianis, medial vestibular nucleus and the midbrain periaqueductal gray. Enkephalin projections to the spinal trigeminal nucleus were also found to originate from the nucleus solitarius, nucleus raphe pallidus, nucleus raphe magnus, nucleus raphe dorsalis, nucleus reticularis paragigantocellularis, nucleus reticularis gigantocellularis pars alpha and the deep mesencephalic nucleus. In contrast to the numerous sources of enkephalin input to the spinal trigeminal nucleus, cholecystokinin projections to this region were limited to four brain stem nuclei. These included the nucleus solitarius, raphe obscurus, nucleus paragigantocellularis and the ventral reticular nucleus of the medulla. The finding that only a small number of brain stem cholecystokinin-like immunoreactive neurons project to the spinal trigeminal nucleus supports the hypothesis that most of the cholecystokinin input to the spinal trigeminal nucleus arises from primary afferent trigeminal fibers. The spinal trigeminal nucleus is known to play a role in processing sensory information and in the transmission of orofacial nociception. The present study identifies several brain stem sites which provide enkephalin and/or cholecystokinin input to the spinal trigeminal nucleus. Several of these nuclei have been implicated as components of the endogenous pain control system and the present results raise the possibility that they may modulate incoming orofacial nociception by releasing the endogenous opioid, enkephalin. Cholecystokinin, on the other hand, has been demonstrated in other studies to attenuate the action of opiates and thus may play an opposing role in the spinal trigeminal nucleus.