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Irritant and pain-reducing effects of nicotine

Institution: University of California, Davis
Investigator(s): Earl Carstens, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0231 Award: $415,704
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
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.

Final Report
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.
Publications

Oral irritant effects of nicotine: psychophysical evidence for decreased sensation following repeated application and lack of cross-desensitization with capsaicin
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier JM, O'Mahony M, Carstens E ART
Yr: 1997 Vol: 22 Nbr: Abs: Pg: 483-492

No withdrawal from reflexes to assess pain
Periodical: Pain Forum Index Medicus:
Authors: Carstens E ART
Yr: 1997 Vol: 6 Nbr: Abs: Pg: 119-123

Force of limb withdrawals elicited by graded noxious heat compared with other behavioral measures of carrageenen-induced hyperalgesia and allodynia
Periodical: Journal of Neuroscience Methods Index Medicus:
Authors: Tabo E, Eisele JH Jr, Carstens E ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Mecamylamine inhibits nicotine but not capsaicin irritation on the tongue: psychophysical evidence that nicotine and sapsaicin activate separate molecular receptors
Periodical: Neuroscience Letters Index Medicus:
Authors: Dessirier JM, O'Mahoney M, Sieffermann JM, Carstens E ART
Yr: 1998 Vol: 240 Nbr: Abs: Pg: 65-68

Activation of neurons in rat trigenimal subnucleus caudalis by application of different classes of irritant chemicals to the oral or ocular mucosa
Periodical: Journal of Neurophysiology Index Medicus:
Authors: Carstens E, Kuenzler N, Handwerker HO ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Oral irritation by carbonated water is reduced by the carbonic anhydrase inhibitor, acetazolamide
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Dessirier JM, O'Mahony M, Sieffermann JM, Carstens E ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

Activation of spinal nociceptive neurons by intracutaneous microinjection of nicotine
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Jinks SL, Carstens E ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

Modulation of nociceptive thresholds by dopamine in the rostral agranular insular cortex of the rat
Periodical: Journal of Neuroscience Index Medicus:
Authors: Burkey AR, Carstens E, Jasmin L ART
Yr: 1999 Vol: 19 Nbr: Abs: Pg: 4169-4179

Trigeminal mechanisms of oral irritation
Periodical: Achems XXI Index Medicus:
Authors: Carstens E ABS
Yr: 1999 Vol: Nbr: 1999b Abs: Pg: 32

Role of neuronal nicotinic receptors in the activation of neurons in trigeminal subnucleus caudalis by nicotine delivered to the oral mucosa
Periodical: Achems XXI Index Medicus:
Authors: Carstens E, Simons CT, Dessirier J-M, Carstens MI, Jinks SL ABS
Yr: 1999 Vol: Nbr: 1999d Abs: Pg: 22

Oral irritant effects of nicotine
Periodical: Annals of the New York Academy of Sciences Index Medicus:
Authors: Dessirier J-M, O'Mahony M, Carstens E ART
Yr: 1998 Vol: 855 Nbr: Abs: Pg: 828-830

Sensitization, desensitization and stimulus-induced recovery (SIR) of responses of rat trigeminal caudilis (Vc) neurons to repeated oral application of capsaicin
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Dessirier J-M, Simons CT, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999a Abs: Pg:

Oral irritant properties of piperine and nicotine: psychophysical evidence of asymmetrical desensitization effects
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier J-M, Nguyen N, O'Mahony M, Sieffermann J-M, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999b Abs: Pg:

Oral irritation by carbonated water is reduced by the carbonic anhydrase inhibitors, acetazolamide and dorzolamide
Periodical: Achems XXI Index Medicus:
Authors: Dessirier J-M, Simons CT, O'Mahony M, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999c Abs: Pg: 22

Skin cooling attenuates rat dorsal horn neuronal responses to intracutaneous histamine
Periodical: NeuroReport Index Medicus:
Authors: Jinks SL, Carstens E ART
Yr: 1998 Vol: 9 Nbr: Abs: Pg: 4145-4149

Activation of spinal nociceptive neurons by intracutaneous microinjection of nicotine
Periodical: IASP Index Medicus:
Authors: Jinks SL, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999b Abs: Pg:

C-fos expression in trigeminal nucleus caudalis neurons by application of carbonated water to the tongue by blockers of carbonic anhydrase
Periodical: Achems XXI Index Medicus:
Authors: Jinks SL, Simons CT, Dessirier J-M, Carstens MI, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999c Abs: Pg: 22

Oral irritation by carbonated water is reduced by capsaicin desensitization
Periodical: Achems XXI Index Medicus:
Authors: O'Mahony M, Dessirier J-M, Simons CT, Carstens E ABS
Yr: 1999 Vol: Nbr: Abs: Pg: 22

Neurobiological and psychophysical mechanisms underlying the oral sensation produced by carbonated water
Periodical: Journal of Neuroscience Index Medicus:
Authors: Simons CT, Dessirier J-M, Carstens MI, O'Mahony M, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999b Abs: Pg:

Responses of neurons in trigeminal nucleus caudalis to intraoral application of carbonated water are reduced by dorzolamide, a blocker of carbonic anhydrase
Periodical: Achems XXI Index Medicus:
Authors: Simons CT, Dessirier J-M, Carstens E ABS
Yr: 1999 Vol: Nbr: 1999a Abs: Pg: 22

Behavioral manifestations of neuropathic pain and mechanical allodynia, and changes in spinal dorsal horn neurons, following L4-L6 dorsal root contriction
Periodical: Pain Forum Index Medicus:
Authors: Tabo E, Jinks SL, Eisele JH Jr, Carstens E ART
Yr: 1999 Vol: 80 Nbr: Abs: Pg: 503-520

Recognizing pain and distress in laboratory animals
Periodical: Institute of Laboratory Animal Resources Journal Index Medicus:
Authors: Carstens E, Moberg GP ART
Yr: 2000 Vol: 41 Nbr: 2 Abs: Pg: 62-71

Deopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception
Periodical: Journal of Neuroscience Index Medicus:
Authors: Burkey AR, Carstens E, Jasmin L ART
Yr: 1999 Vol: 19 Nbr: N10 Abs: Pg: 4169-4179

Analgesia induced by chronic nicotine infusion in rats: differences by gender and pain test
Periodical: Psychopharmacology Index Medicus:
Authors: Carstens E, Anderson KA, Simons CT, Iodi-Carstens M, Jinks SL ART
Yr: 0 Vol: Nbr: Abs: Pg:

Role of neuronal nicotinic acetylcholine receptors in the activation of neurons in trigeminal subnucleus caudalis by nicotine delivered to the oral mucosa
Periodical: Experimental Brain Research Index Medicus:
Authors: Carstens E, Simond Ct, Dessirier J-M, Iodi-Carstens M, Jinks SL ART
Yr: 2000 Vol: 132 Nbr: Abs: Pg: 375-383

Cross-desensitization of capsaicin-evoked oral irritation by high but not low concentrations of nicotine in human subjects
Periodical: Neuroscience Letters Index Medicus:
Authors: Dessirier J-M, Chang H-K, O'Mahony M, Carstens E ART
Yr: 2000 Vol: 290 Nbr: Abs: Pg: 133-136

Sensory properties of citric acid: Psychophysical evidence for sensitization, self-desensitization, corss-desensitization and corss-stimulus-induced recovery following capsaicin
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier J-M, O'Mahony M, Iodi-Carstens M, Carstens E ART
Yr: 2000 Vol: 25 Nbr: Abs: Pg: 769-780

Oral irritation by sodium chloride: sensitization, self-desensitization and cross-sensitization to capsaicin
Periodical: Physiology & Behavior Index Medicus:
Authors: Dessirier J-M, O'Mahony M, Iodi-Carstens M, Yao E, Carstens E ART
Yr: 2001 Vol: 72 Nbr: Abs: Pg: 317-324

Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and corss-desensitization to nicotine
Periodical: Physiology & Behavior Index Medicus:
Authors: Dessirier J-M, O'Mahony M, Carstens E ART
Yr: 2001 Vol: 73 Nbr: 1-2 Abs: Pg: 25-36

Psychophysical and neurobiological evidence that oral irritation from carbonated water is of chemogenic origin
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier J-M, Simons CT, O'Mahony, Carstens E ART
Yr: 2000 Vol: 25 Nbr: Abs: Pg: 277-284

The oral sensation of carbonated water: cross-desensitization by capsaicin and potentiation by amiloride
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier J-M, Simons CT, O'Mahony M, Carstens E ART
Yr: 0 Vol: Nbr: Abs: Pg:

Sensitization, desensitization and stimulus-induced recovery (SIR) of responses of rat trigeminal caudalis neurons to repeated oral application of capsaicin and nicotine
Periodical: Journal of Neurophysiology Index Medicus:
Authors: Dessirier J-M, Simons CT, Sudo M, Sudo S, Carstens E ART
Yr: 2000 Vol: 84 Nbr: Abs: Pg: 1851-1862

Superficial dorsal horn neurons identified using intracutanious histamine as a search stimulus: chemonociceptive responses and modulation by morphone
Periodical: Journal of Neurophysiology Index Medicus:
Authors: Jinks SL, Carstens E ART
Yr: 2000 Vol: 84 Nbr: Abs: Pg: 616-627

Animal model to assess aversion to intraoral capsaicin: increased threshold in mice lacking substance P
Periodical: Chemical Senses Index Medicus:
Authors: Simons CT, Dessirier J-M, Jinks SL, Carstens E ART
Yr: 2001 Vol: Nbr: Abs: Pg:

Sensitization, desensitization and stimulus-induced recovery (SIR) of responses of rat trigeminal caudalis (Vc) neurons to repeated oral application of capsaicin
Periodical: Chemical Senses Index Medicus:
Authors: Dessirier J-M, Simons CT, Carstens E ABS
Yr: 2000 Vol: 25 Nbr: 5 Abs: 645 Pg:

The role of substance P in signaling the presence of the oral irritant capsaicin
Periodical: Chemical Senses Index Medicus:
Authors: Simons CT, Dessirier J-M, Carstens E ABS
Yr: 2000 Vol: 25 Nbr: 5 Abs: 675 Pg:

Itch-related scratching by intracutaneous serotonin: correlation with prolonged responses of superficial dorsal horn neurons in rats
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Jinks SL, Carstens E ABS
Yr: 2000 Vol: 26 Nbr: Abs: 1139 Pg:

The role of substance P in signaling the presence of the oral irritant capsaicin
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Simons CT, Dessirier J-M, Carstens E ABS
Yr: 2000 Vol: 26 Nbr: Abs: 1698 Pg:

Nicotinic excitation of nociceptive neurons in trigeminal subnucleus caudalis (Vc): desensitization and cross-desensitization of responses to strong acids and salts
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Sudo S, Sudo M, Carstens E ABS
Yr: 2001 Vol: Nbr: Abs: Pg:

Irritant-gustatory interactions: suppression of tastant-evoked responses of neurons in the nucleus of the solitary tract (NTS) by oral capsaicin
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Simons CT, Boucher Y, Carstens E ABS
Yr: 2001 Vol: Nbr: Abs: Pg: