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Carlos Belmonte - One of the best experts on this subject based on the ideXlab platform.
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Morphological and functional changes in TRPM8-expressing corneal cold Thermoreceptor neurons during aging and their impact on tearing in mice.
The Journal of comparative neurology, 2018Co-Authors: Ignacio Alcalde, Juana Gallar, Jesús Merayo-lloves, Almudena Íñigo-portugués, Omar González-gonzález, Laura Almaraz, Enol Artime, Cruz Morenilla-palao, Félix Viana, Carlos BelmonteAbstract:Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold Thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8BAC -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold Thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8+ corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8+ corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold Thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.
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functional properties of sensory nerve terminals of the mouse cornea
Investigative Ophthalmology & Visual Science, 2017Co-Authors: Omar Gonzalezgonzalez, Jesus Merayolloves, Juana Gallar, Carlos Belmonte, Federico BechAbstract:Purpose To define the firing properties of sensory nerve terminals innervating the adult mouse cornea in response to external stimuli of differing modality. Methods Extracellular electrical activity of single corneal sensory nerve terminals was recorded in excised eyes of C57BL/6J mice. Eyes were placed in a recording chamber and were continuously superfused with warm saline solution. Nerve terminal impulse (NTI) activity was recorded by means of a glass pipette (tip ∼ 50 μm), applied on the corneal surface. Nerve terminal impulse discharges were stored in a computer for offline analysis. Results Three functionally distinct populations of nerve terminals were identified in the mouse cornea. Pure mechanonociceptor terminals (9.5%) responded phasically and only to mechanical stimuli. Polymodal nociceptor terminals (41.1%) were tonically activated by heat and hyperosmolal solutions (850 mOsm·kg-1), mechanical force, and/or TRPV1 and TRPA1 agonists (capsaicin and allyl isothiocyanate [AITC], respectively). Cold-sensitive terminals (49.4%) responded to cooling. Approximately two-thirds of them fired continuously at 34°C and responded vigorously to small temperature reductions, being classified as high-background activity, low-threshold (HB-LT) cold Thermoreceptor terminals. The remaining one-third exhibited very low ongoing activity at 34°C and responded weakly to intense cooling, being named low-background activity, high-threshold (LB-HT) cold Thermoreceptor terminals. Conclusions The mouse cornea is innervated by trigeminal ganglion (TG) neurons that respond to the same stimulus modalities as corneal receptors of other mammalian species. Mechano- and polymodal endings underlie detection of mechanical and chemical noxious stimuli while HB-LT and LB-HT cold Thermoreceptors appear to be responsible for basal and irritation-evoked tearing and blinking, respectively.
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Effects of TRPM8 and TRPV1 agonists on the neural activity of corneal cold Thermoreceptors in tear-deficient guinea pigs
Acta Ophthalmologica, 2016Co-Authors: Susana Quirce, M C Acosta, Carlos Belmonte, Illes Kovacs, Carolina Luna, Juana GallarAbstract:Purpose To characterize the effects of menthol and capsaicin on the activity of corneal cold Thermoreceptors in tear-deficient guinea pigs Methods The main lachrymal gland was surgically removed in anesthetized animals. Four weeks later, cold-sensitive nerve terminal impulse (NTI) activity was recorded from the superfused cornea. The spontaneous and stimulus-evoked NTI activity was analysed. For thermal stimulation, temperature of perfusion solution was changed from 34°C (basal) down to 20°C (cooling ramp) or up to 50°C (heating ramp). TRP agonists (50–200 μM menthol, 1–10 μM capsaicin) were also added to the perfusion solution. The characteristics of the spontaneous and stimulus-evoked NTI activity recorded in tear-deficient and intact corneas before and during perfusion with TRP channel agonists were compared. Results Removal of the lachrymal gland caused sustained reduction of basal and reflex tearing. NTI activity was significantly higher in cold Thermoreceptors from tear-deficient corneas compared with naive corneas. Response to cooling ramps was also increased. Menthol increased ongoing and stimulus-evoked activity of all cold Thermoreceptors in both intact and tear deficient corneas. Menthol at high concentrations first excited and then inactivated cold Thermoreceptors. Only 10% of Thermoreceptors were activated by capsaicin. Conclusions Chronic tear deficiency alters the activity of corneal sensory nerve fibers, leading to the development of increased spontaneous activity and abnormal responsiveness to natural stimulation. These changes are particularly prominent in cold Thermoreceptor fibers, whose injury-evoked neuropathic firing seems to be due to altered expression of Na+ and K+ channels involved in impulse generation without changes in the activity of TRP channels involved in sensory transduction.
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Cellular/Molecular Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels
2016Co-Authors: Rodolfo Madrid, Elvira De La Peña, Tansy Donovan-rodriguez, Carlos BelmonteAbstract:Molecular determinants of threshold differences among cold Thermoreceptors are unknown. Here we show that such differences corre-late with the relative expression of IKD, a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and ITRPM8, a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (tran-sient receptor potential cation channel, subfamily M, member 8) and low expression of IKD. In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent IKD. Otherwise, both subpopulations have nearly identical membrane and firingproperties, suggesting that theybelong to the sameneuronalpool. Blockadeof IKD shifts the thresholdof cold-sensitiveneurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of IKD blockade were ob-served in TRPA1/mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1does not play amajor role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold Thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain
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what causes eye pain
Current Ophthalmology Reports, 2015Co-Authors: Carlos Belmonte, Jesus Merayolloves, Carmen M Acosta, Juana GallarAbstract:Eye pain is an unpleasant sensory and emotional experience including sensory-discriminative, emotional, cognitive, and behavioral components and supported by distinct, interconnected peripheral and central nervous system elements. Normal or physiological pain results of the stimulation by noxious stimuli of sensory axons of trigeminal ganglion (TG) neurons innervating the eye. These are functionally heterogeneous. Mechano-nociceptors are only excited by noxious mechanical forces. Polymodal nociceptors also respond to heat, exogenous irritants, and endogenous inflammatory mediators, whereas cold Thermoreceptors detect moderate temperature changes. Their distinct sensitivity to stimulating forces is determined by the expression of specific classes of ion channels: Piezo2 for mechanical forces, TRPV1 and TRPA1 for heat and chemical agents, and TRPM8 for cold. Pricking pain is evoked by mechano-nociceptors, while polymodal nociceptors are responsible of burning and stinging eye pain; sensations of dryness appear to be mainly evoked by cold Thermoreceptors. Mediators released by local inflammation, increase the excitability of eye polymodal nociceptors causing their sensitization and the augmented pain sensations. During chronic inflammation, additional, long-lasting changes in the expression and function of stimulus-transducing and voltage-sensitive ion channels develop, thereby altering polymodal terminal’s excitability and evoking chronic inflammatory pain. When trauma, infections, or metabolic processes directly damage eye nerve terminals, these display aberrant impulse firing due to an abnormal expression of transducing and excitability-modulating ion channels. This malfunction evokes ‘neuropathic pain’ which may also result from abnormal function of higher brain structures where ocular TG neurons project. Eye diseases or ocular surface surgery cause different levels of inflammation and/or nerve injury, which in turn activate sensory fibers of the eye in a variable degree. When inflammation dominates (allergic or actinic kerato-conjunctivitis), polymodal nociceptors are primarily stimulated and sensitized, causing pain. In uncomplicated photorefractive surgery and moderate dry eye, cold Thermoreceptors appear to be mainly affected, evoking predominant sensations of unpleasant dryness.
Félix Viana - One of the best experts on this subject based on the ideXlab platform.
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Morphological and functional changes in TRPM8-expressing corneal cold Thermoreceptor neurons during aging and their impact on tearing in mice.
The Journal of comparative neurology, 2018Co-Authors: Ignacio Alcalde, Juana Gallar, Jesús Merayo-lloves, Almudena Íñigo-portugués, Omar González-gonzález, Laura Almaraz, Enol Artime, Cruz Morenilla-palao, Félix Viana, Carlos BelmonteAbstract:Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold Thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8BAC -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold Thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8+ corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8+ corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold Thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.
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Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018Co-Authors: Alfonso Reimúndez, Félix Viana, Carlos Fernández-peña, Guillermo García, Rubén Fernández, Purificación Ordás, Rosalía Gallego, Jose L. Pardo-vazquez, Víctor M. Arce, Rosa SeñarísAbstract:The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold Thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (
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Role of Ih in the firing pattern of mammalian cold Thermoreceptor endings
Journal of neurophysiology, 2012Co-Authors: Patricio Orio, Carlos Belmonte, Andres Parra, Rodolfo Madrid, Omar Gonzalez Gonzalez, Félix VianaAbstract:Mammalian peripheral cold Thermoreceptors respond to cooling of their sensory endings with an increase in firing rate and modification of their discharge pattern. We recently showed that cultured t...
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N-glycosylation of TRPM8 ion channels modulates temperature sensitivity of cold Thermoreceptor neurons.
The Journal of biological chemistry, 2012Co-Authors: María Pertusa, Carlos Belmonte, Cruz Morenilla-palao, Rodolfo Madrid, Félix VianaAbstract:TRPM8 is a member of the transient receptor potential ion channel superfamily, which is expressed in sensory neurons and is activated by cold and cooling compounds, such as menthol. Activation of TRPM8 by agonists takes place through shifts in its voltage activation curve, allowing channel opening at physiological membrane potentials. Here, we studied the role of the N-glycosylation occurring at the pore loop of TRPM8 on the function of the channel. Using heterologous expression of recombinant channels in HEK293 cells we found that the unglycosylated TRPM8 mutant (N934Q) displays marked functional differences compared with the wild type channel. These differences include a shift in the threshold of temperature activation and a reduced response to menthol and cold stimuli. Biophysical analysis indicated that these modifications are due to a shift in the voltage dependence of TRPM8 activation toward more positive potentials. By using tunicamycin, a drug that prevents N-glycosylation of proteins, we also evaluated the effect of the N-glycosylation on the responses of trigeminal sensory neurons expressing TRPM8. These experiments showed that the lack of N-glycosylation affects the function of native TRPM8 ion channels in a similar way to heterologously expressed ones, causing an important shift of the temperature threshold of cold-sensitive Thermoreceptor neurons. Altogether, these results indicate that post-translational modification of TRPM8 is an important mechanism modulating cold Thermoreceptor function, explaining the marked differences in temperature sensitivity observed between recombinant and native TRPM8 ion channels.
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variable threshold of trigeminal cold thermosensitive neurons is determined by a balance between trpm8 and kv1 potassium channels
The Journal of Neuroscience, 2009Co-Authors: Rodolfo Madrid, Carlos Belmonte, Tansy Donovanrodriguez, Elvira De La Pena, Félix VianaAbstract:Molecular determinants of threshold differences among cold Thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I KD , a current dependent on Shaker -like Kv1 channels that acts as an excitability brake, and I TRPM8 , a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of I KD . In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent I KD . Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of I KD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of I KD blockade were observed in TRPA1 −/− mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold Thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.
Juana Gallar - One of the best experts on this subject based on the ideXlab platform.
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Morphological and functional changes in TRPM8-expressing corneal cold Thermoreceptor neurons during aging and their impact on tearing in mice.
The Journal of comparative neurology, 2018Co-Authors: Ignacio Alcalde, Juana Gallar, Jesús Merayo-lloves, Almudena Íñigo-portugués, Omar González-gonzález, Laura Almaraz, Enol Artime, Cruz Morenilla-palao, Félix Viana, Carlos BelmonteAbstract:Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold Thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8BAC -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold Thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8+ corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8+ corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold Thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.
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activity in eye surface sensory neurons is disturbed by inflammation and vice versa
Acta Ophthalmologica, 2017Co-Authors: Juana Gallar, M C AcostaAbstract:Summary Ocular pain results from noxious stimulation of peripheral axons of functionally heterogeneous (Mechanonociceptors, polymodal nociceptors, and cold Thermoreceptors) trigeminal ganglion neurons whose sensitivity to different stimulating agents depends on the expression of specific classes of membrane channels, evoking also different pain sensations. Inflammatory mediators increase the excitability (sensitization) of ocular polymodal nociceptors, enhancing pain sensations. In turn, excited polymodal nociceptors release locally neuropeptides, contributing to local inflammatory reaction (neurogenic inflammation). However, inflammatory mediators reduce the excitability of cold Thermoreceptors. Regenerating nerve terminals damaged by ocular surgery, trauma, infections or systemic metabolic diseases, develop spontaneous activity and abnormal responses to natural stimulation, inducing changes in the experienced sensations (dysesthesia, neuropathic pain), and disturbances in tearing, blinking and ocular surface trophism. Besides, ocular tissues provide molecular signals that increase nerve regeneration. (Supported by ARREST-BLINDNESS, GA No. 667400-2, Horizon 2020-EC, and in part by SAF2014-54518-C3-1-R, MINECO, Spain and FEDER-EC)
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functional properties of sensory nerve terminals of the mouse cornea
Investigative Ophthalmology & Visual Science, 2017Co-Authors: Omar Gonzalezgonzalez, Jesus Merayolloves, Juana Gallar, Carlos Belmonte, Federico BechAbstract:Purpose To define the firing properties of sensory nerve terminals innervating the adult mouse cornea in response to external stimuli of differing modality. Methods Extracellular electrical activity of single corneal sensory nerve terminals was recorded in excised eyes of C57BL/6J mice. Eyes were placed in a recording chamber and were continuously superfused with warm saline solution. Nerve terminal impulse (NTI) activity was recorded by means of a glass pipette (tip ∼ 50 μm), applied on the corneal surface. Nerve terminal impulse discharges were stored in a computer for offline analysis. Results Three functionally distinct populations of nerve terminals were identified in the mouse cornea. Pure mechanonociceptor terminals (9.5%) responded phasically and only to mechanical stimuli. Polymodal nociceptor terminals (41.1%) were tonically activated by heat and hyperosmolal solutions (850 mOsm·kg-1), mechanical force, and/or TRPV1 and TRPA1 agonists (capsaicin and allyl isothiocyanate [AITC], respectively). Cold-sensitive terminals (49.4%) responded to cooling. Approximately two-thirds of them fired continuously at 34°C and responded vigorously to small temperature reductions, being classified as high-background activity, low-threshold (HB-LT) cold Thermoreceptor terminals. The remaining one-third exhibited very low ongoing activity at 34°C and responded weakly to intense cooling, being named low-background activity, high-threshold (LB-HT) cold Thermoreceptor terminals. Conclusions The mouse cornea is innervated by trigeminal ganglion (TG) neurons that respond to the same stimulus modalities as corneal receptors of other mammalian species. Mechano- and polymodal endings underlie detection of mechanical and chemical noxious stimuli while HB-LT and LB-HT cold Thermoreceptors appear to be responsible for basal and irritation-evoked tearing and blinking, respectively.
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Effects of TRPM8 and TRPV1 agonists on the neural activity of corneal cold Thermoreceptors in tear-deficient guinea pigs
Acta Ophthalmologica, 2016Co-Authors: Susana Quirce, M C Acosta, Carlos Belmonte, Illes Kovacs, Carolina Luna, Juana GallarAbstract:Purpose To characterize the effects of menthol and capsaicin on the activity of corneal cold Thermoreceptors in tear-deficient guinea pigs Methods The main lachrymal gland was surgically removed in anesthetized animals. Four weeks later, cold-sensitive nerve terminal impulse (NTI) activity was recorded from the superfused cornea. The spontaneous and stimulus-evoked NTI activity was analysed. For thermal stimulation, temperature of perfusion solution was changed from 34°C (basal) down to 20°C (cooling ramp) or up to 50°C (heating ramp). TRP agonists (50–200 μM menthol, 1–10 μM capsaicin) were also added to the perfusion solution. The characteristics of the spontaneous and stimulus-evoked NTI activity recorded in tear-deficient and intact corneas before and during perfusion with TRP channel agonists were compared. Results Removal of the lachrymal gland caused sustained reduction of basal and reflex tearing. NTI activity was significantly higher in cold Thermoreceptors from tear-deficient corneas compared with naive corneas. Response to cooling ramps was also increased. Menthol increased ongoing and stimulus-evoked activity of all cold Thermoreceptors in both intact and tear deficient corneas. Menthol at high concentrations first excited and then inactivated cold Thermoreceptors. Only 10% of Thermoreceptors were activated by capsaicin. Conclusions Chronic tear deficiency alters the activity of corneal sensory nerve fibers, leading to the development of increased spontaneous activity and abnormal responsiveness to natural stimulation. These changes are particularly prominent in cold Thermoreceptor fibers, whose injury-evoked neuropathic firing seems to be due to altered expression of Na+ and K+ channels involved in impulse generation without changes in the activity of TRP channels involved in sensory transduction.
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what causes eye pain
Current Ophthalmology Reports, 2015Co-Authors: Carlos Belmonte, Jesus Merayolloves, Carmen M Acosta, Juana GallarAbstract:Eye pain is an unpleasant sensory and emotional experience including sensory-discriminative, emotional, cognitive, and behavioral components and supported by distinct, interconnected peripheral and central nervous system elements. Normal or physiological pain results of the stimulation by noxious stimuli of sensory axons of trigeminal ganglion (TG) neurons innervating the eye. These are functionally heterogeneous. Mechano-nociceptors are only excited by noxious mechanical forces. Polymodal nociceptors also respond to heat, exogenous irritants, and endogenous inflammatory mediators, whereas cold Thermoreceptors detect moderate temperature changes. Their distinct sensitivity to stimulating forces is determined by the expression of specific classes of ion channels: Piezo2 for mechanical forces, TRPV1 and TRPA1 for heat and chemical agents, and TRPM8 for cold. Pricking pain is evoked by mechano-nociceptors, while polymodal nociceptors are responsible of burning and stinging eye pain; sensations of dryness appear to be mainly evoked by cold Thermoreceptors. Mediators released by local inflammation, increase the excitability of eye polymodal nociceptors causing their sensitization and the augmented pain sensations. During chronic inflammation, additional, long-lasting changes in the expression and function of stimulus-transducing and voltage-sensitive ion channels develop, thereby altering polymodal terminal’s excitability and evoking chronic inflammatory pain. When trauma, infections, or metabolic processes directly damage eye nerve terminals, these display aberrant impulse firing due to an abnormal expression of transducing and excitability-modulating ion channels. This malfunction evokes ‘neuropathic pain’ which may also result from abnormal function of higher brain structures where ocular TG neurons project. Eye diseases or ocular surface surgery cause different levels of inflammation and/or nerve injury, which in turn activate sensory fibers of the eye in a variable degree. When inflammation dominates (allergic or actinic kerato-conjunctivitis), polymodal nociceptors are primarily stimulated and sensitized, causing pain. In uncomplicated photorefractive surgery and moderate dry eye, cold Thermoreceptors appear to be mainly affected, evoking predominant sensations of unpleasant dryness.
Michael A. Henry - One of the best experts on this subject based on the ideXlab platform.
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trpm8 axonal expression is decreased in painful human teeth with irreversible pulpitis and cold hyperalgesia
Journal of Endodontics, 2007Co-Authors: Lisa T Alvarado, Griffin M. Perry, Kenneth M Hargreaves, Michael A. HenryAbstract:Pulpitis pain may be triggered by a cold stimulus, yet the cellular mechanisms responsible for this phenomenon are largely unknown. One possible mechanism involves the direct activation of cold-responsive Thermoreceptors. The purpose of this study was to evaluate the possible role of the TRPM8 Thermoreceptor in cold-mediated noxious pulpal pain mechanisms by comparing expression patterns in pulpal nerves from healthy control molars to cold-sensitive painful molars with irreversible pulpitis. Samples were identically processed with the indirect immunofluorescence method and images obtained with confocal microscopy. The immunofluorescence intensity and area occupied by TRPM8 within N52/PGP9.5 identified nerve fibers were quantified. Results showed that relative to normal samples, TRPM8 nerve area expression was significantly less in the cold-sensitive painful samples (34.9% vs. 8%, p<0.03), but with no significant difference in immunofluorescence intensity between the two groups. These results suggest that TRPM8 is most likely not involved in cold-mediated noxious pulpal pain mechanisms.
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TRPM8 axonal expression is decreased in painful human teeth with irreversible pulpitis and cold hyperalgesia
Journal of Endodontics, 2007Co-Authors: Lisa T Alvarado, Griffin M. Perry, Kenneth M Hargreaves, Michael A. HenryAbstract:Pulpitis pain may be triggered by a cold stimulus, yet the cellular mechanisms responsible for this phenomenon are largely unknown. One possible mechanism involves the direct activation of cold-responsive Thermoreceptors. The purpose of this study was to evaluate the possible role of the TRPM8 Thermoreceptor in cold-mediated noxious pulpal pain mechanisms by comparing expression patterns in pulpal nerves from healthy control molars to cold-sensitive painful molars with irreversible pulpitis. Samples were identically processed with the indirect immunofluorescence method and images obtained with confocal microscopy. The immunofluorescence intensity and area occupied by TRPM8 within N52/PGP9.5 identified nerve fibers were quantified. Results showed that relative to normal samples, TRPM8 nerve area expression was significantly less in the cold-sensitive painful samples (34.9% vs. 8%, p
Rodolfo Madrid - One of the best experts on this subject based on the ideXlab platform.
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Cellular/Molecular Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels
2016Co-Authors: Rodolfo Madrid, Elvira De La Peña, Tansy Donovan-rodriguez, Carlos BelmonteAbstract:Molecular determinants of threshold differences among cold Thermoreceptors are unknown. Here we show that such differences corre-late with the relative expression of IKD, a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and ITRPM8, a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (tran-sient receptor potential cation channel, subfamily M, member 8) and low expression of IKD. In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent IKD. Otherwise, both subpopulations have nearly identical membrane and firingproperties, suggesting that theybelong to the sameneuronalpool. Blockadeof IKD shifts the thresholdof cold-sensitiveneurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of IKD blockade were ob-served in TRPA1/mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1does not play amajor role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold Thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain
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Role of Ih in the firing pattern of mammalian cold Thermoreceptor endings
Journal of neurophysiology, 2012Co-Authors: Patricio Orio, Carlos Belmonte, Andres Parra, Rodolfo Madrid, Omar Gonzalez Gonzalez, Félix VianaAbstract:Mammalian peripheral cold Thermoreceptors respond to cooling of their sensory endings with an increase in firing rate and modification of their discharge pattern. We recently showed that cultured t...
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N-glycosylation of TRPM8 ion channels modulates temperature sensitivity of cold Thermoreceptor neurons.
The Journal of biological chemistry, 2012Co-Authors: María Pertusa, Carlos Belmonte, Cruz Morenilla-palao, Rodolfo Madrid, Félix VianaAbstract:TRPM8 is a member of the transient receptor potential ion channel superfamily, which is expressed in sensory neurons and is activated by cold and cooling compounds, such as menthol. Activation of TRPM8 by agonists takes place through shifts in its voltage activation curve, allowing channel opening at physiological membrane potentials. Here, we studied the role of the N-glycosylation occurring at the pore loop of TRPM8 on the function of the channel. Using heterologous expression of recombinant channels in HEK293 cells we found that the unglycosylated TRPM8 mutant (N934Q) displays marked functional differences compared with the wild type channel. These differences include a shift in the threshold of temperature activation and a reduced response to menthol and cold stimuli. Biophysical analysis indicated that these modifications are due to a shift in the voltage dependence of TRPM8 activation toward more positive potentials. By using tunicamycin, a drug that prevents N-glycosylation of proteins, we also evaluated the effect of the N-glycosylation on the responses of trigeminal sensory neurons expressing TRPM8. These experiments showed that the lack of N-glycosylation affects the function of native TRPM8 ion channels in a similar way to heterologously expressed ones, causing an important shift of the temperature threshold of cold-sensitive Thermoreceptor neurons. Altogether, these results indicate that post-translational modification of TRPM8 is an important mechanism modulating cold Thermoreceptor function, explaining the marked differences in temperature sensitivity observed between recombinant and native TRPM8 ion channels.
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variable threshold of trigeminal cold thermosensitive neurons is determined by a balance between trpm8 and kv1 potassium channels
The Journal of Neuroscience, 2009Co-Authors: Rodolfo Madrid, Carlos Belmonte, Tansy Donovanrodriguez, Elvira De La Pena, Félix VianaAbstract:Molecular determinants of threshold differences among cold Thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I KD , a current dependent on Shaker -like Kv1 channels that acts as an excitability brake, and I TRPM8 , a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of I KD . In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent I KD . Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of I KD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of I KD blockade were observed in TRPA1 −/− mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold Thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.
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Characteristics and physiological role of hyperpolarization activated currents in mouse cold Thermoreceptors.
The Journal of physiology, 2009Co-Authors: Patricio Orio, Carlos Belmonte, Victor Meseguer, Andres Parra, Rodolfo Madrid, Elvira De La Pena, Douglas A Bayliss, Félix VianaAbstract:Hyperpolarization-activated currents (I(h)) are mediated by the expression of combinations of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel subunits (HCN1-4). These cation currents are key regulators of cellular excitability in the heart and many neurons in the nervous system. Subunit composition determines the gating properties and cAMP sensitivity of native I(h) currents. We investigated the functional properties of I(h) in adult mouse cold Thermoreceptor neurons from the trigeminal ganglion, identified by their high sensitivity to moderate cooling and responsiveness to menthol. All cultured cold-sensitive (CS) neurons expressed a fast activating I(h), which was fully blocked by extracellular Cs(+) or ZD7288 and had biophysical properties consistent with those of heteromeric HCN1-HCN2 channels. In CS neurons from HCN1(-/-) animals, I(h) was greatly reduced but not abolished. We find that I(h) activity is not essential for the transduction of cold stimuli in CS neurons. Nevertheless, I(h) has the potential to shape the excitability of CS neurons. First, I(h) blockade caused a membrane hyperpolarization in CS neurons of about 5 mV. Furthermore, impedance power analysis showed that all CS neurons had a prominent subthreshold membrane resonance in the 5-7 Hz range, completely abolished upon blockade of I(h) and absent in HCN1 null mice. This frequency range matches the spontaneous firing frequency of cold Thermoreceptor terminals in vivo. Behavioural responses to cooling were reduced in HCN1 null mice and after peripheral pharmacological blockade of I(h) with ZD7288, suggesting that I(h) plays an important role in peripheral sensitivity to cold.
