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PubMed1998

Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems.

Isoprenoic compounds play a major part in the global carbon cycle. Biosynthesis and mineralization by aerobic bacteria have been intensively studied. This review describes our knowledge on the anaerobic metabolism of isoprenoids, mainly by denitrifying and fermentative bacteria. Nitrate-reducing beta-Proteobacteria were isolated on monoterpenes as sole carbon source and electron donor. Thauera spp. were obtained on the oxygen-containing monoterpenes linalool, menthol, and eucalyptol. Several strains of Alcaligenes defragrans were isolated on unsaturated monoterpenes as growth substrates. A novel denitrifying beta-Proteobacterium, strain 72Chol, mineralizes cholesterol completely to carbon dioxide. Physiological studies showed the presence of several oxidative pathways in these microorganisms. Investigations by organic geochemists indicate possible contributions of anaerobes to early diagenetic processes. One example, the formation of p-cymene from monoterpenes, could indeed be detected in methanogenic enrichment cultures. In man, cholic acid (CA) and chenodeoxycholic acid (CDCA), are synthesized in the liver from cholesterol. During their enterohepatic circulation, bile acids are biotransformed by the intestinal microflora into a variety of metabolites. Known bacterial biotranformations of conjugated bile acids include: deconjugation, oxidation of hydroxy groups at C-3, C-7 and C-12 with formation of oxo bile acids and reduction of these oxo groups to either alpha- or beta-configuration. Quantitatively, the most important bacterial biotransformation is the 7 alpha-dehydroxylation of CA and CDCA yielding deoxycholic acid and lithocholic acid, respectively. The 7 alpha-dehydroxylation of CA occurs via a novel six-step biochemical pathway. The genes encoding several enzymes that either transport bile acids or catalyze various reactions in the 7 alpha-dehydroxylation pathway of Eubacterium sp. strain VPI 12708 have been cloned, expressed in Escherichia coli, purified, and characterized.

Bacteria, Anaerobic↗
PubMed2005

Permeation-enhancing effects of chitosan formulations on recombinant hirudin-2 by nasal delivery in vitro and in vivo.

AIM: To investigate the enhancing effects of chitosan with or without enhancers on nasal recombinant hirudin-2 (rHV2) delivery in vitro and in vivo, and to evaluate the ciliotoxicity of these formulations. METHODS: The permeation-enhancing effect of various chitosan formulations was estimated by using the permeation coefficient of fluorescein isothiocyanate recombinant hirudin-2 (FITC-rHV2) across the excited rabbit nasal epithelium in vitro. The effect was further evaluated by measuring the blood concentration level after nasal absorption of FITC-rHV2 in rats. The mucosal ciliotoxicity of different formulations was evaluated with an in situ toad palate model. RESULTS: Chitosan at a concentration of 0.5% with or without various enhancers significantly increased the permeability coefficient (P) and relative bioavailability (Fr) of FITC-rHV2 compared with the blank control. The addition of 1% sodium dodecylsulfate, 5% Brij35, 5% Tween 80, 1.5% menthol, 1% glycyrrhizic acid monoammonium salt (GAM) or 4% Azone into the 0.5% chitosan solution resulted in a further increase in absorption (P<0.05) compared with 0.5% chitosan alone. But co-administration of chitosan with 5% hydroxyl-propyl-beta-cyclodextrin (HP-beta-CD), 5% lecithin or 0.1% ethylenediamine tetraacetic acid (EDTA) was not more effective than using the 0.5% chitosan solution alone. Chitosan alone and with 5% HP-beta-CD, 0.1% EDTA, 1% GAM or 5% Tween 80 was relatively less ciliotoxic. CONCLUSION: Chitosan with or without some enhancers was able to effectively promote the nasal absorption of recombinant hirudin, while not resulting in severe mucosal ciliotoxicity. A chitosan formulation system would be a useful approach for the nasal delivery of recombinant hirudin.

Absorption↗
PubMed1996

Effectiveness and mode of action of isopropyl myristate as a permeation enhancer for naproxen through shed snake skin.

The effectiveness and mode of action of isopropyl myristate (IPM) as an enhancer for the permeation of naproxen through shed snake skin have been investigated. The highest naproxen permeability was afforded by IPM (36.2 x 10(-4) cm h-1), followed by menthol (25.0 x 10(-4) cm h-1), oleic acid (11.1 x 10(-4) cm h-1), azone (7.3 x 10(-4) cm h-1) and control (1.4 x 10(-4) cm h-1). Whereas the permeability of un-ionized naproxen (47.4 x 10(-5) cm h-1) was much greater than that of ionized naproxen (1.11 x 10(-5) cm h-1), IPM-treatment of the intact skin increased the flux of ionized naproxen significantly more (50-fold) than that of un-ionized naproxen (15-fold). The large effect of pH on the permeation of naproxen through the intact stratum corneum became insignificant after extraction of lipids from the skin. Similar permeation of naproxen through intact and delipidized skin after IPM treatment indicated that the lipid barrier of the skin was largely impaired by IPM. Direct application of IPM to skin yielded a 2.6-fold higher naproxen permeability than the application of IPM as gel. A greater amount of naproxen was absorbed from 1% test gel (pH 5) containing IPM than from 10% commercial gel (pH 7) containing no IPM. These results show that use of IPM can significantly improve the bioavailability of naproxen in topical preparations.

Animals↗
PubMed2005

Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8.

Members of the transient receptor potential (TRP) superfamily of ion channels have now been defined as molecular transducers capable of reproducing the spectrum of temperature sensation exhibited by mammals. Because of their pivotal role in sensory transduction, many of these channels represent good targets for drug discovery. With a view to gaining further insight into the functional and pharmacological properties of these channels, we have used the whole-cell patch-clamp technique to study the human cold-sensitive menthol receptor transient receptor potential melastatin 8 (TRPM8) and compared its behavior with that of its distant relative, the heat-sensitive capsaicin-gated transient receptor potential vanilloid 1 (TRPV1). It is remarkable to find that TRPM8, in addition to its behavior as an outwardly rectifying, nonselective cation channel, shares many functional and pharmacological properties with TRPV1. TRPM8 exhibits prominent time- and voltage-dependent behavior, a property that may underlie the conserved rectification or gating mechanisms exhibited by these channels. We also show that TRPM8 is modulated by ethanol but unlike TRPV1 is insensitive to extracellular acidification. There is also significant overlap in the antagonist pharmacology of these channels with many TRPV1 antagonists such as capsazepine, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (BCTC), (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide (CTPC), and N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}-urea (SB-452533) exhibiting similar activity at TRPM8. Overall, the degree of pharmacological overlap between TRPV1 and TRPM8 has implications for the interpretation of studies conducted with these ligands to date and highlights a clear challenge for the design of selective TRP channel antagonists. Our finding that N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), at least, represents an apparently selective antagonist for TRPV1 suggests that this goal is attainable.

Capsaicin↗
PubMed2005

ATP signaling is crucial for communication from taste buds to gustatory nerves.

Taste receptor cells detect chemicals in the oral cavity and transmit this information to taste nerves, but the neurotransmitter(s) have not been identified. We report that adenosine 5'-triphosphate (ATP) is the key neurotransmitter in this system. Genetic elimination of ionotropic purinergic receptors (P2X2 and P2X3) eliminates taste responses in the taste nerves, although the nerves remain responsive to touch, temperature, and menthol. Similarly, P2X-knockout mice show greatly reduced behavioral responses to sweeteners, glutamate, and bitter substances. Finally, stimulation of taste buds in vitro evokes release of ATP. Thus, ATP fulfils the criteria for a neurotransmitter linking taste buds to the nervous system.

Adenosine Triphosphate↗
PubMed1999

Rhodococcus erythropolis DCL14 contains a novel degradation pathway for limonene.

Strain DCL14, which is able to grow on limonene as a sole source of carbon and energy, was isolated from a freshwater sediment sample. This organism was identified as a strain of Rhodococcus erythropolis by chemotaxonomic and genetic studies. R. erythropolis DCL14 also assimilated the terpenes limonene-1,2-epoxide, limonene-1,2-diol, carveol, carvone, and (-)-menthol, while perillyl alcohol was not utilized as a carbon and energy source. Induction tests with cells grown on limonene revealed that the oxygen consumption rates with limonene-1,2-epoxide, limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and carveol were high. Limonene-induced cells of R. erythropolis DCL14 contained the following four novel enzymatic activities involved in the limonene degradation pathway of this microorganism: a flavin adenine dinucleotide- and NADH-dependent limonene 1, 2-monooxygenase activity, a cofactor-independent limonene-1, 2-epoxide hydrolase activity, a dichlorophenolindophenol-dependent limonene-1,2-diol dehydrogenase activity, and an NADPH-dependent 1-hydroxy-2-oxolimonene 1,2-monooxygenase activity. Product accumulation studies showed that (1S,2S,4R)-limonene-1,2-diol, (1S, 4R)-1-hydroxy-2-oxolimonene, and (3R)-3-isopropenyl-6-oxoheptanoate were intermediates in the (4R)-limonene degradation pathway. The opposite enantiomers [(1R,2R,4S)-limonene-1,2-diol, (1R, 4S)-1-hydroxy-2-oxolimonene, and (3S)-3-isopropenyl-6-oxoheptanoate] were found in the (4S)-limonene degradation pathway, while accumulation of (1R,2S,4S)-limonene-1,2-diol from (4S)-limonene was also observed. These results show that R. erythropolis DCL14 metabolizes both enantiomers of limonene via a novel degradation pathway that starts with epoxidation at the 1,2 double bond forming limonene-1,2-epoxide. This epoxide is subsequently converted to limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and 7-hydroxy-4-isopropenyl-7-methyl-2-oxo-oxepanone. This lactone spontaneously rearranges to form 3-isopropenyl-6-oxoheptanoate. In the presence of coenzyme A and ATP this acid is converted further, and this finding, together with the high levels of isocitrate lyase activity in extracts of limonene-grown cells, suggests that further degradation takes place via the beta-oxidation pathway.

Alcohol Oxidoreductases↗
PubMed2001

Genetic and biochemical characterization of a novel monoterpene epsilon-lactone hydrolase from Rhodococcus erythropolis DCL14.

A monoterpene epsilon-lactone hydrolase (MLH) from Rhodococcus erythropolis DCL14, catalyzing the ring opening of lactones which are formed during degradation of several monocyclic monoterpenes, including carvone and menthol, was purified to apparent homogeneity. It is a monomeric enzyme of 31 kDa that is active with (4R)-4-isopropenyl-7-methyl-2-oxo-oxepanone and (6R)-6-isopropenyl-3-methyl-2-oxo-oxepanone, lactones derived from (4R)-dihydrocarvone, and 7-isopropyl-4-methyl-2-oxo-oxepanone, the lactone derived from menthone. Both enantiomers of 4-, 5-, 6-, and 7-methyl-2-oxo-oxepanone were converted at equal rates, suggesting that the enzyme is not stereoselective. Maximal enzyme activity was measured at pH 9.5 and 30 degrees C. Determination of the N-terminal amino acid sequence of purified MLH enabled cloning of the corresponding gene by a combination of PCR and colony screening. The gene, designated mlhB (monoterpene lactone hydrolysis), showed up to 43% similarity to members of the GDXG family of lipolytic enzymes. Sequencing of the adjacent regions revealed two other open reading frames, one encoding a protein with similarity to the short-chain dehydrogenase reductase family and the second encoding a protein with similarity to acyl coenzyme A dehydrogenases. Both enzymes are possibly also involved in the monoterpene degradation pathways of this microorganism.

Amino Acid Sequence↗
PubMed2002

The phenolic hydroxyl group of carvacrol is essential for action against the food-borne pathogen Bacillus cereus.

The natural antimicrobial compound carvacrol shows a high preference for hydrophobic phases. The partition coefficients of carvacrol in both octanol-water and liposome-buffer phases were determined (3.64 and 3.26, respectively). Addition of carvacrol to a liposomal suspension resulted in an expansion of the liposomal membrane. Maximum expansion was observed after the addition of 0.50 micromol of carvacrol/mg of L-alpha-phosphatidylethanolamine. Cymene, a biological precursor of carvacrol which lacks a hydroxyl group, was found to have a higher preference for liposomal membranes, thereby causing more expansion. The effect of cymene on the membrane potential was less pronounced than the effect of carvacrol. The pH gradient and ATP pools were not affected by cymene. Measurement of the antimicrobial activities of compounds similar to carvacrol (e.g., thymol, cymene, menthol, and carvacrol methyl ester) showed that the hydroxyl group of this compound and the presence of a system of delocalized electrons are important for the antimicrobial activity of carvacrol. Based on this study, we hypothesize that carvacrol destabilizes the cytoplasmic membrane and, in addition, acts as a proton exchanger, thereby reducing the pH gradient across the cytoplasmic membrane. The resulting collapse of the proton motive force and depletion of the ATP pool eventually lead to cell death.

Adenosine Triphosphate↗
PubMed1969

Microbial transformation of terpenoids. I. Identification of metabolites produced by a pseudomonad from citronellal and citral.

A bacterium capable of utilizing citronellal or citral as the sole source of carbon and energy has been isolated from soil by the enrichment culture technique. It metabolizes citronellal to citronellic acid (65%), citronellol (0.6%), dihydrocitronellol (0.6%), menthol (0.75%), and 3,7-dimethyl-1,7-octane diol (1.7%). The metabolites of citral were geranic acid (62%), 6-methyl-5-heptanoic acid (0.5%), 3-methyl-2-butenoic acid (1%), and 1-hydroxy-3, 7-dimethyl-6-octen-2-one (0.75%).

Bacteria↗
PubMed2002

The dark side of marketing seemingly "Light" cigarettes: successful images and failed fact.

OBJECTIVE: To understand the development, intent, and consequences of US tobacco industry advertising for low machine yield cigarettes. METHODS: Analysis of trade sources and internal US tobacco company documents now available on various web sites created by corporations, litigation, or public health bodies. RESULTS: When introducing low yield products, cigarette manufacturers were concerned about maintaining products with acceptable taste/flavour and feared consumers might become weaned from smoking. Several tactics were employed by cigarette manufacturers, leading consumers to perceive filtered and low machine yield brands as safer relative to other brands. Tactics include using cosmetic (that is, ineffective) filters, loosening filters over time, using medicinal menthol, using high tech imagery, using virtuous brand names and descriptors, adding a virtuous variant to a brand's product line, and generating misleading data on tar and nicotine yields. CONCLUSIONS: Advertisements of filtered and low tar cigarettes were intended to reassure smokers concerned about the health risks of smoking, and to present the respective products as an alternative to quitting. Promotional efforts were successful in getting smokers to adopt filtered and low yield cigarette brands. Corporate documents demonstrate that cigarette manufacturers recognised the inherent deceptiveness of cigarette brands described as "Light"or "Ultra-Light" because of low machine measured yields.

Advertising↗
PubMed2002

Tobacco availability and point of sale marketing in demographically contrasting districts of Massachusetts.

OBJECTIVE: To assess the prevalence and characteristics of tobacco sales and point-of-sale promotions and advertising in predominantly Latino business districts, and in comparison districts; and the economic importance of tobacco sales and marketing to Latino owned small businesses. DESIGN: Observational surveys of retail establishments and interviews with store managers. SETTING: Demographically contrasting business districts of eastern Massachusetts. MAIN OUTCOME MEASURES: Percentage of businesses selling tobacco, numbers and characteristics of exterior and interior tobacco advertisements per store, merchant reports of promotional allowances received from tobacco distributors. RESULTS: The proportion of businesses selling tobacco, and hence having storefront tobacco advertising, is strongly negatively correlated with per capita income in the census tracts where businesses are located (Spearman's rho = -0.794, p = 0.006). Mentholated brands are marketed disproportionately in low income, urban communities. Latino merchants are highly dependent on tobacco sales, but would require relatively modest compensation to forego tobacco promotional allowances. CONCLUSIONS: Storefront tobacco advertising is far more prevalent in predominantly minority, low income communities than in non-minority, higher income communities, principally because of the differing mix of kinds of businesses in the two types of communities, and the greater prevalence of tobacco vendors in lower income neighbourhoods. Tobacco companies obtain this advertising at little cost.

Advertising↗
PubMed2004

A "clean cigarette" for a clean nation: a case study of Salem Pianissimo in Japan.

OBJECTIVE: To illustrate, through internal industry documents, how RJ Reynolds exploited the concerns of the Japanese society about cleanliness to market the concept of cleaner, implicitly healthier cigarettes in Japan. DESIGN: Systematic keyword and opportunistic website searches of formerly private internal industry documents. RESULTS: Industry documents show that RJ Reynolds developed marketing plans based upon their cultural assumptions of Japanese people as fastidious about hygiene and manners, and with relatively high penchants to try new products. RJ Reynolds found there was also a growing concern for health, the environment, and smokers were conscious about annoying others. Deodorised consumer products were one of Japan's biggest trends. These characteristics presented RJ Reynolds with a profitable formula for marketing Salem Pianissimo, a clean cigarette with less smell and smoke. Salem Pianissimo, a 100 mm cigarette claiming to contain 1 mg tar and 0.1 mg nicotine, targeted women since menthol cigarettes were popular among 18-24 year old female smokers, although Japan's law prohibited those below 20 years to smoke and the tobacco industry had a voluntary code disallowing advertising to women and youth. CONCLUSION: RJ Reynolds successfully launched its clean cigarette, Salem Pianissimo, in Japan aiming to exploit perceived cultural characteristics such as a penchant for cleanliness, an eagerness to try new products, and social harmony.

Adolescent↗
PubMed2006

Adolescent smoking behaviour and cigarette brand preference in Japan.

OBJECTIVES: As part of efforts to develop a smoking control strategy for Japanese adolescents, the results of two nationwide surveys on adolescent smoking behaviour were compared. DESIGN: Descriptive study on smoking behaviour among high school students was conducted. Self-reporting anonymous questionnaires were administered to 115,814 students in 1996 and 106,297 in 2000 through randomly sampled junior and senior high schools throughout Japan. MAIN OUTCOME MEASURES: Smoking prevalence, proportion of smokers by usual sources of cigarettes, national estimated cigarettes consumed by minors, share of cigarette brands smoked by high school students. RESULTS: The experiment rate among junior high school boys decreased in 2000 compared with that in 1996, whereas current and daily smoking rates did not. Although prevalence among Japanese girls was much lower than that among boys, prevalence among girls increased in 2000. The main source of cigarettes among high school smokers was vending machines. The proportion of smokers who usually purchased cigarettes from vending machines increased in 2000, in spite of the 1998 introduction of restrictions on night-time operations. Japanese adolescents were more likely than adults to smoke American cigarette brands, and the adolescent market share of American brands has increased rapidly, especially for menthol brands. CONCLUSIONS: This survey revealed the seriousness of the problem of smoking behaviour among Japanese high school students, and suggested that this behaviour may be influenced by social environmental factors, including the marketing strategies of the tobacco industry. Action should be taken to reduce the prevalence and impact of pro-tobacco marketing messages and to abolish cigarette vending machines.

Adolescent↗
PubMed2006

Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle.

Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca(2+) transients ([Ca(2+)](i)) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 muM) and the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (1 muM) evoked significant increases in [Ca(2+)](i) in PASMCs and ASMCs. These Ca(2+) responses were abolished in the absence of extracellular Ca(2+) or the presence of 300 muM Ni(2+) but were unaffected by 1 muM nifedipine, suggesting Ca(2+) influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca(2+) entry pathways may play important roles in the regulation of pulmonary and systemic circulation.

Animals↗
PubMed1992

Quantitative analysis on odor intensity and quality of optical isomers in turtle olfactory system.

No systematic electrophysiological study on differences in odor intensity and quality between optical isomers has been carried out. In the present study, we measured the turtle olfactory bulbar responses to six pairs of highly pure optical isomers and compared the differences in odor intensity and quality between the optical isomers. The results obtained indicated that with all odorants tested, there was no difference in odor threshold and intensity in the whole concentration range examined between optical isomers. The difference in odor quality of optical isomers was evaluated by a quantitative cross-adaptation method in which odorant concentration was varied. The degree of cross adaptation between optical isomers greatly varied with species of odorants. The rank order of the magnitude of the differences in odor quality between optical isomers was carvone greater than beta-citronellol greater than menthol greater than hydroxycitronellal greater than citronellal greater than limonene.

Adaptation, Physiological↗
PubMed1999

Enantioselectivity of odor perception in squirrel monkeys and humans.

With use of a conditioning paradigm, the ability of six squirrel monkeys to distinguish between 10 pairs of enantiomers, i.e., odorants that are identical except for chirality, was investigated. As a group, the animals were only able to discriminate between the optical isomers of alpha-pinene, carvone, limonene, and fenchone, whereas they failed to distinguish between the (+) and (-) forms of beta-citronellol, menthol, rose oxide, 2-butanol, alpha-terpineol, and camphor. With use of a triple forced-choice procedure, 10 human subjects were tested for their ability to discriminate between the same enantiomeric odor pairs in parallel and, with the exception of fenchone, showed a very similar pattern of performance compared with the squirrel monkeys. These findings support the assumption that human and nonhuman primates may share common principles of odor quality perception. Furthermore, the results suggest that, in both species, enantioselective molecular odor receptors may only exist for some, but not all volatile enantiomers and thus that chiral recognition of odorants is not a general phenomenon, but may be restricted to some substances.

Adult↗
PubMed2003

Differential thermosensitivity of sensory neurons in the guinea pig trigeminal ganglion.

Intracellular recordings were employed to study the effects of temperature on membrane properties and excitability in sensory neurons of the intact guinea pig trigeminal ganglion (TG) maintained in vitro. Neurons were classified according to the shape and duration of the action potential into F (short-duration, fast spike) and S (long duration, slow spike with a "hump") types. Most type F (33/34) neurons had axons with conduction velocities >1.5 m/s, while only 30% (6/23) of type S neurons reached these conduction speeds suggesting differences in myelination. Cooling reduced axonal conduction velocity and prolonged spike duration in both neuronal types. In F-type neurons with strong inward rectification. cooling also increased the excitability, augmenting the input resistance and reducing the current firing threshold. These effects were not observed in S-type neurons lacking inward rectification. In striking contrast to results obtained in cultured TG neurons, cooling or menthol did not induce firing in recordings from the acutely isolated ganglion. However, after application of submillimolar concentrations (100 microM) of the potassium channel blocker 4-aminopyridine (4-AP), 29% previously unresponsive neurons developed cold sensitivity. An additional 31% developed ongoing activity that was sensitive to temperature. Only neurons with strong inward rectification (mostly F-type) became thermosensitive. Cooling- and 4-AP-evoked firing were insensitive to intracellular application of 4-AP or somatic membrane hyperpolarization, suggesting that their action was most prominent at the level of the axon. The lack of excitatory actions of low temperature in the excised intact ganglion contrasts with the impulse discharges induced by cooling in trigeminal nerve terminals of the same species, suggesting a critical difference between cold-transduction mechanisms at the level of the nerve terminals and the soma.

Action Potentials↗
PubMed2003

TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat.

Recent electrophysiological studies of cultured dorsal root and trigeminal ganglion neurons have suggested that multiple ionic mechanisms underlie the peripheral detection of cold temperatures. Several candidate "cold receptors," all of them ion channel proteins, have been implicated in this process. One of the most promising candidates is TRPM8, a nonselective cationic channel expressed in a subpopulation of sensory neurons that is activated both by decreases in temperature and the cooling compound menthol. However, evidence for the expression of TRPM8 in functionally defined cold-sensitive neurons has been lacking. Here, we combine fluorometric calcium imaging of cultured rat trigeminal neurons with single-cell RT-PCR to demonstrate that there are distinct subpopulations of cold responsive neurons and that TRPM8 likely contributes to cold transduction in one of them. TRPM8 is preferentially expressed within a subset of rapidly responsive, low-threshold (approximately 30 degrees C), cold-sensitive neurons. A distinct class of slowly responsive cold-sensitive neurons that is activated at lower temperatures (approximately 20 degrees C) generally lacks detectable TRPM8 mRNA. Together with previous findings, our data support the notion that cold responsive neurons are functionally heterogeneous.

Animals↗