Molecular and Cellular Mechanisms of Trigeminal Chemosensation

Gerhold, Kristin A.; Bautista, Diana M.

doi:10.1111/j.1749-6632.2009.03895.x

Cited by 73 publications

(63 citation statements)

References 39 publications

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“…Sensory neurons expressing TRPM8s project to superficial laminae of the spinal cord dorsal horn [48,49], which contain cold-sensitive neurons projecting supraspinally via the spino-thalamic tract [50]. Responses of nociceptive neurons in superficial laminae of the trigeminal subnucleus caudalis (Vc) to lingual cooling are enhanced by menthol [51,52].…”

Section: Introductionmentioning

confidence: 99%

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Tsagareli¹

2011

Neurophysiology

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It was recently found that transient receptor potential (TRP) channels play an important role in the transduction of thermal, mechanical, and chemical stimuli underlying the somatic sensation. Several types of TRP channels exhibit sensitivity to increases or decreases in temperature, as well as to the action of chemical ligands that elicit similar thermal or painful sensations. These agents include menthol, mustard oil, cinnamaldehyde (CA), gingerol, capsaicin, camphor, eugenol, and others. Cinnamaldehyde is a pungent chemical obtained from cinnamon, which acts as an agonist of the TRPA1 channels; these channels were originally reported to be activated by cold temperatures (below 18°C). TRPA1 is also implicated in cold nociception. However, its role in the formation of cold pain is more controversial, with discrepant reports that TRPA1s do or do not respond to intense cooling. Menthol derived from plants of the mint family enhances the feeling of coldness by interacting with the cold-sensitive TRPM8 channels, but its effect on pain is less well understood. Using behavioral methods, we showed that unilateral intraplantar injection of CA (5 to 20%) induced a significant concentration-dependent decrease in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. Cinnamaldehyde also significantly reduced mechanical withdrawal thresholds for the injected paw, i.e., evoked mechanical allodynia. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). In contrast to CA, menthol in a dose-dependent manner increased the latency for noxious heat-evoked withdrawal, i.e., exerted an antinociceptive effect. Menthol did not affect mechanosensation except for a weak allodynic effect when applied in the highest concentration used (40 %), indicating that it did not exert a local anesthetic effect. Menthol had a biphasic effect on cold avoidance. High concentrations of menthol reduced cold avoidance, i.e., induced cold hypoalgesia, while low menthol concentrations significantly intensified cold avoidance. The highest menthol concentration provided cold hypoalgesia (cold plate test), while lower concentrations had no effect. Taken together, our data support the idea that TRPA1 and TRPM8 channels represent promising peripheral targets for pain modulation.

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Section: Introductionmentioning

confidence: 99%

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Tsagareli¹

2011

Neurophysiology

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“…These organs are located at specific sites within the nasal cavity ( Fig. 1) and have been studied in much detail in recent years (for reviews, see Gerhold and Bautista 2009;Ma 2007Ma , 2010Munger et al 2009). As has become apparent, every subsystem serves distinct functions in analyzing the incoming air and each subsystem conveys its sensory signal to distinct sites in the brain (Fuss et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Expression patterns of anoctamin 1 and anoctamin 2 chloride channels in the mammalian nose

et al. 2012

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Calcium-activated chloride channels are expressed in chemosensory neurons of the nose and contribute to secretory processes and sensory signal transduction. These channels are thought to be members of the family of anoctamins (alternative name: TMEM16 proteins), which are opened by micromolar concentrations of intracellular Ca(2+). Two family members,ANO 1 (TMEM16A) and ANO 2 (TMEM16B), are expressed in the various sensory and respiratory tissues of the nose.We have examined the tissue specificity and sub-cellular localization of these channels in the nasal respiratory epithelium and in the five chemosensory organs of the nose: the main olfactory epithelium, the septal organ of Masera, the vomeronasal organ, the Grueneberg ganglion and the trigeminal system. We have found that the two channels show mutually exclusive expression patterns. ANO 1 is present in the apical membranes of various secretory epithelia in which it is co-localized with the water channel aquaporin 5. It has also been detected in acinar cells and duct cells of subepithelial glands and in the supporting cells of sensory epithelia. In contrast, ANO 2 expression is restricted to chemosensory neurons in which it has been detected in microvillar and ciliary surface structures. The different expression patterns of ANO 1 and ANO 2 have been observed in the olfactory, vomeronasal and respiratory epithelia. No expression has been detected in the Grueneberg ganglion or trigeminal sensory fibers. On the basis of this differential expression, we derive the main functional features of ANO 1 and ANO 2 chloride channels in the nose and suggest their significance for nasal physiology.

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“…TRPM8 is expressed in the trigeminal ganglia (Nealen et al, 2003;Abe et al, 2005) and oral mucosa (Abe et al, 2005), and therefore this effect could be due to the pharmacology of the molecule; however, it cannot be the only factor involved. One possible explanation is that blocking TRPM8-mediated cold sensation unmasks constitutive activity of other temperature-sensing TRP channels expressed in the mouth, such as TRPV1 and TRPA1 (Zanotto et al, 2007;Gerhold and Bautista, 2009;Morgan et al, 2009). Furthermore, clinical and preclinical studies using agonists for the different channels have clearly demonstrated an interplay between them and an ability to modulate cold and heat sensitivity (Zanotto et al, 2007;Albin et al, 2008).…”

Section: Trpm8 Antagonism Reduces Experimental Cold Pain In Humansmentioning

confidence: 99%

Inhibition of TRPM8 Channels Reduces Pain in the Cold Pressor Test in Humans

Winchester

Gore

Glatt

et al. 2014

J Pharmacol Exp Ther

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The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC 50 5 103 nM), selective TRPM8 antagonist, PF-05105679It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC 50 of 200 nM and reduced core body temperature in the rat (at concentrations .1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC 50 were achieved with 600-and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600-and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.

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Molecular and Cellular Mechanisms of Trigeminal Chemosensation

Cited by 73 publications

References 39 publications

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Expression patterns of anoctamin 1 and anoctamin 2 chloride channels in the mammalian nose

Inhibition of TRPM8 Channels Reduces Pain in the Cold Pressor Test in Humans

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