It is well-known that tobacco smoke irritates the eyes, nose and mouth. This irritation is due to nicotine, an active chemical in tobacco. Nicotine also reduces the sensation of pain, and it has been suggested that smokers become addicted to nicotine because of its pain-reducing and calming effects, and that they avoid quitting because of the increased pain and discomfort that occurs during withdrawal. This proposal will study both the irritating and the pain-reducing effects of nicotine, and how these effects might be signaled by the brain. The primary goals of this project are (1) to better understand the biology of nicotine irritation, (2) to better understand biologically how nicotine reduces pain, and (3) to use modern research methods to determine if young smokers have less pain, and if they experience more pain when they quit smoking. A scientific understanding of the irritating effect of nicotine is important in objectively developing policies on exposure to second-hand smoke. It will also clarify the role that the sensory impact or "kick" of cigarette smoke has in nicotine addiction, which might be similar to the preference that many people have for spicy foods. An improved understanding of the pain-reducing effect of nicotine is directly relevant to understanding nicotine addiction, and the role that pain and discomfort play in efforts to quit smoking.
In one experiment, participants will have a weak solution of nicotine placed onto their tongue and will rate how irritating it is. Since we want to know how nicotine irritates the tongue, we will place different chemicals onto the tongue that are known to block nicotine "receptors" (proteins that recognize nicotine in a "lock and key" manner to cause irritation). Nicotine will then be placed onto the same area of the tongue receiving the blocker, and participants rate how irritating it is. We predict that certain blockers will reduce the irritation caused by nicotine. We will also test if menthol, a chemical in mentholated cigarettes that causes a cool sensation, reduces irritation caused by nicotine. In animals, we will record the electrical activity of single nerve cells in the brain that are involved in signaling irritation of the tongue or eye in. We want to determine if individual nerve cells signal irritation by only one chemical such as nicotine, or if they respond indiscriminately to various types of irritating chemicals such as salt, acid, or capsaicin (the chemical in red peppers that causes a burning sensation). The answer to this question is important in understanding how the brain is able to tell the difference between irritating substances, and our results so far indicate that nerve cells are activated by both nicotine and many other chemicals. We also want to study the receptors for nicotine that cause this activation. Similar experiments will also be done to determine if the transmission of pain signals are blocked when nicotine is administered into certain areas of the brain containing nicotine receptors. We are also interested in testing if nicotine has less of a pain-reducing effect in animals that are continually exposed to nicotine for a long period of time (like chronic smokers), and if pain signals increase during withdrawal from nicotine.
Another project will test the hypothesis that young adult chronic smokers are less sensitive to experimental pain than non-smokers because of the pain-reducing effect of nicotine, and that chronic smokers will have increased pain sensitivity during voluntary withdrawal from smoking. This hypothesis will be tested in groups of young smokers and non-smokers matched according to age, gender and ethnicity. The participants will rate the intensity of heat pain on the skin, and whether they can detect small temperature changes. We predict that the smokers will give lower pain ratings and will not be able to detect small temperature changes as well as non smokers because of the pain-reducing effect of nicotine. |
This project continues our studies of the irritant and analgesic (pain-reducing) effects of nicotine, an active constituent of tobacco. We hypothesize that nicotine has two major sensory effects: (1) irritation upon contact with the oral mucosa or skin, which may contribute to the liking of tobacco products (analogous to preference for spicy foods), and (2) analgesia due to activation of pain-inhibitory systems in the brain, which may contribute to dependence. We have made considerable scientific progress toward understanding these effects of nicotine.
Nicotine Irritation: We use electrophysiological methods to study how the activity of neurons in trigeminal subnucleus caudalis (Vc; a relay for pain and other skin senses from the oral cavity and face) in rats correlates with human perception of oral irritation elicited by nicotine and other irritant chemicals. We hypothesize that Vc neurons mediate sensations of oral irritation. Our study of effects of nicotine and capsaicin has now been published. We showed that repeated application of nicotine initially excites Vc neurons followed by a decline, similar to the pattern of declining irritation (desensitization) observed psychophysically. In contrast, capsaicin elicited a progressive rise in Vc firing similar to the sensitization observed psychophysically. Upon reapplication, there was a delay in Vc firing corresponding to desensitization, followed by an eventual rise in firing very similar to "stimulus-induced recovery" of irritation by recurrent capsaicin application in humans. We have continued these studies this year to (a) verify that nicotine excites Vc neurons followed by a decline, (b) show that nicotine cross-desensitizes Vc neuronal responses to other irritants such as pentanoic acid, (c) show that nicotine does not generally depress Vc neuronal excitability to noxious thermal or mechanical stimuli, and (d) show that concentrated salt (NaCI) and acidic (citric and pentanoic acids) stimuli evoke sensitizing responses in Vc neurons that match the sensitization induced by these chemicals in human psychophysical studies (see below). These data therefore support our general hypothesis that irritant chemicals elicit distinct patterns of trigeminal neural activity that are similar to the pattern of oral irritation elicited by the same chemical.
We also use the method of c-fos immunohistochemistry to investigate nicotinic activation of Vc neurons. Our study of the role for neuronal nicotinic acetylcholine receptors (nAChRs) in the activation of Vc neurons by intraoral nicotine has been published. We are continuing to use this approach to study the role of specific nAChR subunits in the activation of Vc neurons by oral nicotine, as well as the activation of Vc neurons by other oral irritant chemicals.
We have also completed several human psychophysical studies of oral irritation. Most importantly, our study of the oral irritant (and cooling) properties of menthol, a common additive to tobacco products, has been published. Mentholinduced irritation declines across repeated trials of application, similar to nicotine. This desensitization occurs even after the cooling effect of menthol has disappeared. Furthermore, menthol cross-desensitizes irritation elicited by nicotine. In addition, our studies of nicotinic cross-desensitization of capsaicin-induced irritation, and citric acid- and NaCl-induced irritation, have been published.
Analgesic Effect of Nicotine: In the past year we have completed two projects that examined the analgesic effects of nicotine. In one, we found that infusion of nicotine (6 mg/kg/day), via an implanted osmotic mini-infusion pump, induced analgesia in both male and female rats as assessed by one pain test (hot plate), while male but not female rats exhibited analgesia in another pain test (tail flick). There was evidence of tolerance to the analgesic effect of nicotine over a two week period. This study will be published soon. In a second study, we found that exposure of male rats to tobacco smoke for 6 hr/day, 5 days/week over a 4-week period, induced significant analgesia as measured by several pain tests. There was also evidence for tolerance to the analgesic effect. These data are currently being prepared for publication. |