Brainstem neurons expressing c-Fos immunoreactivity following irritant chemical stimulation of the rat's tongue.

Many chemicals including nicotine, capsaicin and piperine (pungent chemicals in red and black peppers, respectively) evoke oral pain and irritation via largely unknown neural mechanisms. As a first step in defining the central pathway for oral chemical irritation, we have used an immunohistochemical method to map locations of brainstem neurons expressing the nuclear protein, c-Fos (a putative nociceptive marker), following application of various irritants to the tongue. In barbiturate-anesthetized rats, one of the following was applied to the dorsal surface of the tongue: nicotine (0.5%), capsaicin (0.1%), histamine (2 or 20%), piperine (0.2%), acetylcholine (10%) or vehicle control (0.9% saline, dH2O, 70% ethanol). After 2 h the rat was perfused with fixative and the brainstem removed, sectioned, and processed immunohistochemically. Following application of each irritant, fos-immunoreactive nuclei were consistently observed in the superficial dorsal horn of dorsomedial trigeminal nucleus caudalis (-3 to +0.5 mm relative to obex), interstitial (paratrigeminal) nucleus, and area postrema. Approximately equal numbers were observed bilaterally even with unilateral application to the tongue. Fos-immunoreactive nuclei were observed in dorsomedial trigeminal caudalis bilaterally when a restricted area on the tip of the tongue was stimulated with capsaicin, but were located predominantly ipsilaterally following stimulation of the lateral tongue. Few or no Fos-immunoreactive nuclei were seen in these areas in control rats. Numbers of Fos-immunoreactive nuclei were significantly increased following nicotine and capsaicin in ventrolateral trigeminal nucleus caudalis and nucleus of the solitary tract. Fos-immunoreactivity was also seen consistently in the ventrolateral medulla dorsal to the lateral reticular nucleus, and vestibular and cochlear nuclei, and less consistently in nucleus raphe pallidus and inferior olive, in both irritant and in control groups, indicating that it was not stimulus-evoked. These results have identified a population of neurons in the dorsomedial trigeminal nucleus caudalis likely to be involved in signaling chemical irritation of the tongue. Increases in Fos-immunoreactivity observed in the nucleus of the solitary tract, area postrema, and ventrolateral trigeminal caudalis also suggest roles for these areas in autonomic responses consequent to oral irritation.