Jean Marc Dessirier

It hurts so good: oral irritation by spices and carbonated drinks and the underlying neural mechanisms

Abstract This paper reviews neurophysiological and psychological studies of oral irritation elicited by chemicals in spicy foods and carbonated drinks. Oral irritant, thermal and textural sensations are conveyed to the brain by the trigeminal pathway, which is separate from the gustatory and olfactory systems. In humans, repetitive application of capsaicin, citric acid, or concentrated NaCl elicits oral irritation that grows in intensity across trials (“sensitization”). After a rest period, reapplication elicits less irritation (“self-desensitization”), but if given recurrently will eventually evoke a progressive rise in irritation (“stimulus-induced recovery”=SIR). In neurophysiological recordings from neurons in the trigeminal subnucleus caudalis (Vc), the first relay in the pathway for oral somatosensation, these irritants elicit a similar pattern of progressively increasing firing, followed after a rest by self-desensitization and SIR. In contrast, nicotine, menthol or mustard oil elicit irritation that decreases across trials (“desensitization”), a pattern also observed in Vc neuronal responses to these irritants. Carbonated water elicits an oral tingling sensation and excites Vc neurons largely through its conversion to carbonic acid. The good correspondence in temporal profiles for perception and neuronal activity supports a role for Vc neurons in the mediation of oral irritation. Finally, the development of preference for foods containing aversive chemicals is addressed. This may involve mere exposure, social reinforcement, the “thrill” of the strong sensation, or physiological reinforcement associated with satiety or release of endorphins by the painful stimulus.

Mecamylamine inhibits nicotine but not capsaicin irritation on the tongue: psychophysical evidence that nicotine and capsaicin activate separate molecular receptors

Using a two-alternative forced-choice (2-AFC) discrimination test coupled with category intensity ratings, we investigated the effect of mecamylamine, an antagonist of neuronal nicotinic acetylcholine receptors (nAchRs), on oral irritation elicited by nicotine or capsaicin. Mecamylamine (0.075%) was first delivered to one side of the tongue with distilled H2O delivered to the other side. After 10 min either capsaicin (1 ppm) or nicotine (0.12%) was applied bilaterally to the tongue, and subjects were asked to choose which side yielded a stronger sensation (2-AFC) as well as to provide a rating of the irritation intensity difference between the two sides of the tongue. When nicotine was given after mecamylamine, a significant proportion of subjects chose the mecamylamine-untreated side as yielding stronger irritation. When capsaicin was given after mecamylamine, both sides of the tongue were chosen in equal numbers. These data indicate that mecamylamine reduced irritation elicited by nicotine but not capsaicin, and provide further evidence that nicotine oral irritation is mediated via a neuronal nAchR while capsaicin activates trigeminal fibers via a separate molecular receptor.

Sensitization of trigeminal caudalis neuronal responses to intraoral acid and salt stimuli and desensitization by nicotine.

&NA; In human studies, repeated intraoral application of strong acidic or salt stimuli induces irritation that progressively increases across trials (sensitization), whereas irritation elicited by nicotine progressively decreases (desensitization). We investigated whether nociceptive neurons in trigeminal subnucleus caudalis (Vc) exhibit increasing or decreasing patterns of firing to the intraoral application of these irritants. In rats anesthetized with halothane and thiopental, single‐unit recordings were made from nociceptive neurons in superficial layers of dorsomedial Vc that responded to mechanical and noxious thermal and chemical stimulation of the tongue. NaCl (5 M), citric acid (300 mM), pentanoic acid (300 mM) or nicotine (600 mM) were separately delivered to the tongue by constant flow (0.32 ml/min) for 15 or 25 min. NaCl, citric acid and pentanoic acid each elicited a progressive, significant increase in Vc neuronal firing over the initial 10 min to a plateau level that was maintained for the stimulus duration. Nicotine induced a significant increase in firing rate of Vc neurons within 6 min, followed by a decline back to the baseline level over the ensuing 10 min. Following a rest period, reapplication of nicotine no longer activated Vc neurons, indicative of self‐desensitization. We additionally tested for nicotine cross‐desensitization to acid. After recording the responses of Vc neurons to pentanoic acid and noxious heat, nicotine was then applied for 15 min. Post‐nicotine responses to pentanoic acid were markedly reduced (to 13% of control), indicative of cross‐desensitization; responses to noxious heat were also reduced to a lesser degree (to 71% of control). The progressive increase in Vc neuronal firing elicited by NaCl and acid, and the decline in firing after initial nicotinic excitation, resemble psychophysical patterns of sensitization and desensitization, respectively, and support the involvement of Vc neurons in the signaling of oral irritant sensations.

Activation of neurons in trigeminal caudalis by noxious oral acidic or salt stimuli is not reduced by amiloride.

We investigated the possible role of amiloride-sensitive ion channels of the ENaC/DEGenerin superfamily in the activation of trigeminal nociceptive neurons elicited by noxious chemical stimulation of the oral mucosa using two methodologies, single-unit recording and c-fos immunohistochemistry. In pentobarbital-anesthetized rats, single-unit recordings were made from neurons in superficial laminae of dorsomedial trigeminal subnucleus caudalis (Vc) that responded to noxious thermal and chemical stimuli applied to the dorsal tongue. Successive application of each of three chemicals (250 mM pentanoic acid, n=6 units; 250 mM citric acid, n=8; 5 M NaCl, n=6) evoked responses that were not affected following topical application of amiloride (1 mM). In separate experiments, pentobarbital-anesthetized rats received one of the following stimuli delivered to the dorsal tongue: 250 mM pentanoic acid (n=6); 1 mM amiloride followed by 250 mM pentanoic (N=6); 5 M NaCl (n=5); or 1 mM amiloride followed by 5 M NaCl (n=5). Two hours later they were perfused with 4% paraformaldehyde and the brain stems processed for c-fos immunoreactivity. Both pentanoic acid and 5 M NaCl evoked similar numbers and patterns of fos-like immunoreactivity (FLI) in dorsomedial Vc and other brain stem regions, with no significant difference in counts of FLI in animals pretreated with amiloride. These results suggest that amiloride-sensitive Na(+) channels are not essential in mediating the activation of intraoral trigeminal nociceptors.