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Biomedical subjects

Christopher T Simons

Publications and source records attributed to Christopher T Simons.

At least 19 recordsLinked to original sources
PubMed2006

Nicotine suppression of gustatory responses of neurons in the nucleus of the solitary tract.

This study investigated effects of nicotine applied to the tongue surface on responses of gustatory neurons in the nucleus of the solitary tract (NTS) in rats. In pentobarbital-anesthetized rats, single-unit recordings were made from NTS units responsive to one or more tastants (sucrose, NaCl, citric acid, monosodium glutamate, quinine). Application of nicotine (0.87, 8.7, or 600 mM) excited gustatory NTS units and significantly attenuated NTS unit responses to their preferred tastant in a dose-dependent manner. The depressant effect of nicotine was equivalent regardless of which tastant best excited the NTS unit. Nicotinic excitation of NTS units and depression of their tastant-evoked responses were both significantly attenuated by the nicotinic antagonist mecamylamine, which itself did not excite NTS units. In rats with bilateral trigeminal ganglionectomy, nicotine still excited nearly all NTS units but no longer depressed tastant-evoked responses. Nicotine did not elicit plasma extravasation when applied to the tongue. The results indicate that nicotine directly excites NTS units by gustatory nerves and inhibits their tastant-evoked responses by a nicotinic acetylcholine receptor-mediated excitation of trigeminal afferents that inhibit NTS units centrally.

Animals↗
PubMed2005

Nicotinic receptor involvement in antinociception induced by exposure to cigarette smoke.

Direct exposure of rats to tobacco smoke induces antinociception. We presently investigated if this antinociception is mediated via nicotinic and/or mu-opioid receptors. Adult male rats were surgically implanted with Alzet osmotic minipumps that delivered either saline (control), the nicotinic antagonist mecamylamine, or the opiate antagonist naltrexone (3 mg/kg/day i.v. for 21 days). Nocifensive responses were assessed on alternate days using tail-flick reflex latency (TFL) over a 3-week period. During the second week, the rats were exposed to concentrated cigarette smoke in an environmental chamber for 6 h/day for 5 consecutive days; a control group was similarly exposed to filtered cigarette smoke. Rats receiving mecamylamine and naltrexone exhibited a significant weight loss after the first day of infusion. All treatment groups additionally exhibited significant weight loss during exposure to unfiltered or filtered smoke. The saline group exhibited significant antinociception on the first day of smoke exposure with rapid development of tolerance. The mecamylamine and naltrexone groups did not exhibit significant antinociception. Controls exposed to filtered smoke (with approximately 50% lower nicotine concentration) also exhibited significant analgesia on the first exposure day with rapid development of tolerance. Exposure to high levels of cigarette smoke, or to filtered smoke with a lower nicotine concentration in the vapor phase, induces antinociception with rapid development of tolerance. The antinociceptive effect appears to be mediated via nicotinic and mu-opioid receptors.

Analgesics↗
PubMed2004

Antinociception induced by chronic exposure of rats to cigarette smoke.

To investigate if chronic exposure to cigarette smoke induces analgesia, rats were exposed to concentrated cigarette smoke in an environmental chamber over four successive 5-day blocks (6 h/day), with 2 smoke-free days between blocks. A control group was exposed to room air. Tail flick latencies increased significantly (analgesia) during each smoke exposure block, with a relative decline in analgesia across blocks (tolerance) and a return to control levels during the first three smoke-free interludes while remaining higher after the conclusion of the 4-week exposure period. Mechanical (von Frey) withdrawal thresholds declined over time in smoke-exposed and control groups, with the smoke-exposed group showing significantly lower thresholds. Plasma nicotine reached 95.4 +/- 32 (S.D.) ng/ml at the end of weekly smoke exposure and declined to 44.9 +/- 10.6 ng/ml 24 h after withdrawal. Rats lost weight during smoke exposure and quickly regained weight during smoke-free interludes and at the cessation of smoke exposure. Analgesia may contribute to the initiation of smoking, and rapid reversal of the analgesic effect following acute exposure may contribute to the difficulty in quitting smoking.

Analgesia↗
PubMed2004

Spinal c-fos expression associated with spontaneous biting in a mouse model of dry skin pruritus.

As a model of dry skin pruritus in mice, one hind paw was treated twice daily with a mixture of acetone/diethylether/water (AEW); controls received water only. A protective collar prevented the animals from accessing the treatment area. At 16 days, the collar was removed and AEW-treated mice exhibited marked biting of the treated paw; the number and cumulative duration of bites was significantly greater than in controls. After 3 additional treatment days (collars intact), animals were perfused for c-fos immunohistochemistry. There was significantly more fos-like immunoreactivity in the ipsilateral lumbar spinal cord of AEW-treated animals, with the majority in superficial laminae. It is proposed that biting of the dry skin reflects pruritus, and that neurons predominantly in superficial laminae of the dorsal horn may signal itch sensation.

Acetone↗
PubMed2004

Mustard oil has differential effects on the response of trigeminal caudalis neurons to heat and acidity.

Topical application of mustard oil (allyl isothiocyanate) to the skin or injection into joints induces hyperalgesia, allodynia, and neuroinflammation. However, when applied to the oral or nasal mucosa, mustard oil evokes a desensitizing pattern of irritation. Presently we investigated the responses of neurons in superficial laminae of trigeminal subnucleus caudalis (Vc) to noxious thermal (53 degrees C) and chemical (pentanoic acid; 200 mM) stimuli prior to and following lingual mustard oil application. A low concentration of mustard oil (0.125%) applied by constant flow (0.5 ml/min; 15 min), initially excited Vc neurons followed by partial desensitization. Responses to noxious heat were unchanged following mustard oil. A high concentration of mustard oil (1.25%) initially excited Vc neurons followed quickly (within 20 s) by nearly complete desensitization. The desensitization was transient since reapplication of mustard oil approximately 20 min later elicited a comparable response that also rapidly desensitized. Mustard oil also transiently cross-desensitized Vc responses to pentanoic acid (to 52%), in striking contrast to noxious heat-evoked responses which were significantly sensitized to approximately 160% of pre-mustard oil levels. The data suggest that the effect of mustard oil on subsequent lingual nociceptive responses is concentration dependent, transient, and modality specific.

Action Potentials↗
PubMed2003

Opioid modulation of scratching and spinal c-fos expression evoked by intradermal serotonin.

We investigated a spinal site for opioid modulation of itch-related scratching behavior in rats. Intradermal 5-HT (2%, 10 microl) elicited intermittent bouts of hindlimb scratching directed toward the injection site (nape of neck) beginning within minutes and lasting >1 hr. 5-HT-evoked scratching was significantly reduced by systemic administration of the opiate antagonist naltrexone but was not affected by systemic morphine at a dosage (3 mg/kg) that induces analgesia. Intradermal 5-HT elicited a significant increase in c-fos-like immunoreactivity (FLI) in superficial laminas I-III at the lateral aspect of the cervical C3-C6 dorsal horn compared with controls receiving intradermal saline. Neither systemic morphine nor naltrexone significantly affected counts of 5-HT-evoked FLI. The lack of effect of morphine suggests that intradermal 5-HT activates dorsal horn neurons, signaling itch but not pain. Attenuation of 5-HT-evoked scratching but not spinal FLI by naltrexone suggests a supraspinal site for its antipruritic action. In contrast, morphine significantly attenuated FLI elicited by intradermal capsaicin, a chemical that induces pain but not scratching.

Analgesics, Opioid↗
PubMed2003

Mecamylamine reduces nicotine cross-desensitization of trigeminal caudalis neuronal responses to oral chemical irritation.

We investigated the role of neuronal nicotinic acetylcholine receptors (nAChRs) in nicotine cross-desensitization of chemonociceptive responses of trigeminal subnucleus caudalis (Vc) neurons in rats. Vc responses to lingually applied pentanoic acid were significantly reduced following nicotine, and this was prevented when the nAChR antagonist mecamylamine was applied before or after nicotine. A peripheral site of nicotine cross-desensitization is suggested via a nAChR-mediated reduction in acidic excitation of lingual nociceptors that project to Vc.

Action Potentials↗
PubMed2003

Trigeminal modulation of gustatory neurons in the nucleus of the solitary tract.

Electrophysiological methods were used to investigate the effects of trigeminal nerve stimulation or transection on responses of single gustatory neurons in the nucleus of the solitary tract (NTS) to tastants (NaCl, sucrose, citric acid, monosodium glutamate) in pentobarbital-anesthetized rats. Unilateral transection of the lingual nerve, or the mandibular branch of the trigeminal nerve, resulted in significant reductions (by 21 and 29%, respectively; P<0.01) in tastant-evoked responses, with no further effect following bilateral transection. Electrical stimulation of the central cut end of the mandibular nerve directly excited nine of 14 gustatory NTS units. For these units, central mandibular stimulation facilitated the tastant-evoked responses in six, depressed responses in three, and had no effect in five. Facilitation of tastant-evoked responses peaked 4 min after mandibular stimulation and recovered within 8 min. Electrical stimulation of the peripheral cut end of the mandibular nerve significantly reduced tastant-evoked responses in nine other NTS units, with a maximal reduction at 4 min post-stimulation followed by recovery. Stimulation of the superior cervical sympathetic ganglion did not affect NTS tastant-evoked responses. These results suggest the presence of complex central modulation of NTS neurons by trigeminal afferents, as well as a peripheral depressant effect on gustatory processing possibly mediated via neuropeptide release from trigeminal nerve endings in the tongue.

Action Potentials↗
PubMed2003

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments.

The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many "side effects" not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by approximately 2 degrees C) and long-lasting (>3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1beta (500 ng/kg iv) was tested. The sham-operated rats developed typical monophasic fevers ( approximately 0.5 degrees C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39-40 degrees C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain.

Animals↗
PubMed2003

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.

Amiloride↗
PubMed2003

Deletion of the preprotachykinin A gene in mice does not reduce scratching behavior elicited by intradermal serotonin.

Itch is thought to be signaled by a sub-population of pruritogen-selective C-fiber primary afferents. To assess a possible role of the neuropeptide, substance P (SP), in the central neurotransmission of itch, we investigated itch-related scratching behavior elicited by intradermal injection of serotonin (5-HT; 0.03-0.3%) in normal mice (wildtype, WT) and knockout mice (KO) with deletion of the preprotachykinin A gene. Both KO and WT groups showed dose-related increases in the number of 5-HT-evoked scratching bouts over the 44 min observation period. There were no significant differences in the numbers or durations of scratching bouts between WT and KO groups, although KO mice exhibited numerically more spontaneous and 5-HT-evoked scratching. It is concluded that either SP is not involved in the central neurotransmission of itch-related scratching behavior in this strain of mouse, or that compensatory developmental changes in the KO mice allow itch-related signaling.

Animals↗
PubMed2003

Suppression of central taste transmission by oral capsaicin.

Because intraoral capsaicin is reported to reduce the perceived intensity of certain taste qualities, we investigated whether it affects the central processing of gustatory information. The responses of gustatory neurons in the nucleus tractus solitarius (NTS) to tastant stimuli were recorded before and after lingual application of capsaicin in anesthetized rats. Thirty-four NTS units were characterized as responding best to sucrose (0.3 m), NaCl (0.1 m), citric acid (0.03 m), monosodium glutamate (0.2 m), or quinine (0.001 m). During lingual application of 330 microm capsaicin for 7 min, the firing rate increased for five units and decreased for four units; the remainder were unaffected. Immediately after capsaicin, responses to each tastant were in nearly all cases depressed (mean, 61.5% of control), followed by recovery in most cases. NTS tastant-evoked unit responses were unaffected by lingual application of vehicle (5% ethanol). Capsaicin elicited an equivalent reduction (to 64.5%) in tastant-evoked responses of nine additional NTS units recorded in rats with bilateral trigeminal ganglionectomy, arguing against a trigeminally mediated central effect. Furthermore, capsaicin elicited a puncate pattern of plasma extravasation in the tongue that matched the distribution of fungiform papillae. These results support a peripheral site of capsaicin suppression of taste possibly via direct or indirect effects on taste transduction or taste receptor cell excitability. The depressant effect of capsaicin on gustatory transmission might underlie its ability to reduce the perceived intensity of some taste qualities.

Administration, Oral↗
PubMed2003

Lack of quinine-evoked activity in rat trigeminal subnucleus caudalis.

Conflicting reports exist regarding the ability of quinine to activate neurons in the trigeminal system. We used the complementary approaches of single-unit electrophysiology and c-fos immunohistochemistry to investigate whether quinine (100 mM) activates chemonociceptive cells in the brainstem trigeminal subnucleus caudalis (Vc). In electrophysiological experiments, 38 units responded to noxious mechanical, thermal and chemical (200 mM pentanoic acid) stimuli applied to the tongue with an increase in firing rate; none responded to lingual quinine whether the quinine was presented before or after application of pentanoic acid. In the c-fos immunohistochemical experiment, both quinine and water elicited equivalent levels of fos-like immunoreactivity (FLI) in dorsomedial Vc that were significantly lower than the level of FLI evoked by pentanoic acid. These data collectively indicate that quinine does not elicit activity in chemonociceptive Vc neurons.

Animals↗
PubMed2003

Oral irritation by mustard oil: self-desensitization and cross-desensitization with capsaicin.

We investigated the temporal pattern of oral irritation elicited by sequential application of mustard oil (allyl-isothiocyanate), and whether it exhibits self-desensitization and cross-desensitization with capsaicin. Mustard oil (0.125%, 40 micro l) was sequentially applied to one side of the tongue at 1 min intervals, and subjects rated the intensity of the irritant sensation elicited by each stimulus. Ratings successively declined across trials, indicating desensitization. In contrast, sequential application of capsaicin (10 ppm) elicited irritation that increased in intensity across trials (sensitization). To test for self-desensitization by mustard oil, a 10 min hiatus was imposed following the series of unilateral mustard oil stimuli, after which mustard oil was applied to both sides of the tongue. In a two-alternative forced-choice paradigm, subjects chose which side had stronger irritation and also independently rated the irritant intensity on each side. A significant majority of subjects chose the side not previously receiving mustard oil as more intense, and assigned significantly higher intensity ratings to that side, indicating self-desensitization. In two additional sessions, the same paradigm was used to show mustard oil cross-desensitization of irritation elicited by capsaicin, and capsaicin cross-desensitization of irritation from mustard oil. In a final session, sequential application of mustard oil at faster (20 s) intervals initially evoked a sensitizing pattern followed by desensitization. The temporal patterns of oral irritation exhibited by mustard oil, and its reciprocal cross-desensitization with capsaicin, are similar to those of menthol and nicotine.

Administration, Oral↗
PubMed2002

Reduced aversion to oral capsaicin following neurotoxic destruction of superficial medullary neurons expressing NK-1 receptors.

Aversion to capsaicin (0.1-10 ppm) was assessed using a two-bottle paired preference paradigm, before and after intracisternal injection of substance P conjugated to saporin (SP-SAP) to ablate neurons in superficial medullary and cervical dorsal horn that express NK-1 receptors. Before SP-SAP, there was a concentration-dependent decrease in consumption of capsaicin with a threshold of 0.1-0.3 ppm. Following SP-SAP, significantly more capsaicin solution was consumed at 1- and 10-ppm concentrations. These results support a role for substance P in the mediation of high, but not low, levels of capsaicin-induced oral irritation.

Administration, Oral↗
PubMed2002

C-fos induction in rat superficial dorsal horn following cutaneous application of noxious chemical or mechanical stimuli.

The method of c-fos immunodetection was used to map the distributions of neurons in the lumbar spinal dorsal horn that were activated following intracutaneous (i.c.) microinjection, or iontophoretic application, of different irritant chemicals to the lateral hindpaw of rats. Microinjections (1 microl) of histamine, serotonin (5-HT), nicotine, capsaicin, or formalin each elicited similar distributions of Fos-like immunoreactivity (FLI) in laminae I-II of the ipsilateral superficial dorsal horn, with little or no FLI in deeper laminae or contralaterally. In laminae I and II, FLI cell counts were significantly higher following i.c. histamine, 5-HT, capsaicin, formalin, and noxious pinch, compared to i.c. saline controls. Capsaicin-evoked FLI was dose-dependent. Multivariate analysis of variance revealed no significant difference in spatial distributions of FLI induced by any of the chemical or pinch stimuli. Iontophoretic application of histamine, 5-HT, or nicotine also elicited similar distributions of FLI in the superficial dorsal horn, and cell counts of FLI were significantly higher compared to controls receiving iontophoretic vehicle (methyl cellulose). These results indicate either that individual laminae I-II neurons are activated by each of the irritant chemicals, or that neurons selectively responsive to a given irritant are comingled without any apparent laminar segregation.

Administration, Cutaneous↗
PubMed2002

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

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 (5M), 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.

Action Potentials↗