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TRPM8

TRPM8, also known as transient receptor potential cation channel subfamily M member 8, is a non-selective cation channel that primarily functions as a molecular sensor for cool and cold temperatures, as well as cooling agents such as menthol, in mammals.^[1] This Ca²⁺-permeable ion channel belongs to the transient receptor potential melastatin (TRPM) subfamily and is activated by stimuli below approximately 25–28°C, allowing influx of cations like Na⁺ and Ca²⁺ to depolarize sensory neurons and initiate cold sensation.^[2] Discovered in 2002 through independent studies identifying it as a menthol- and cold-activated channel in sensory neurons, TRPM8 plays a critical role in thermosensation and nociception.^[2]^[3] Structurally, TRPM8 forms a tetrameric complex with each subunit featuring six transmembrane segments (S1–S6), a re-entrant pore loop, and intracellular N- and C-terminal domains that include TRP and melastatin motifs.^[4] High-resolution cryo-electron microscopy (cryo-EM) structures, first resolved in 2018, reveal a three-layered architecture with a voltage-sensor-like domain (VSLD) in the S1–S4 region that contributes to polymodal gating by cold, voltage, and ligands.^[4] Key residues in the VSLD cavity, such as tyrosine 745 and arginine 842, are essential for temperature-dependent activation, while the channel's pore domain controls ion selectivity and conductance.^[1] Phosphatidylinositol 4,5-bisphosphate (PIP₂) binding modulates its sensitivity, enhancing responses to both thermal and chemical stimuli. Physiologically, TRPM8 is predominantly expressed in a subset of small-diameter sensory neurons within the dorsal root ganglia (DRG) and trigeminal ganglia, where it mediates the detection of innocuous cold and contributes to cold-induced pain (cold allodynia) under certain conditions.^[1] Beyond thermosensation, it influences thermoregulation, osmosensation, and reflex responses such as tearing and bladder activity, with expression also noted in non-neuronal tissues like the prostate, cornea, and bladder afferents.^[5] In TRPM8 knockout models, mice exhibit deficits in cold avoidance behaviors and reduced nocifensive responses to mild cold, underscoring its role in behavioral thermoregulation.^[2] Clinically, TRPM8 dysregulation is implicated in disorders including migraine, overactive bladder, dry eye disease, and cold hypersensitivity, positioning it as a therapeutic target for analgesics and cooling agents. In May 2025, the U.S. FDA approved acoltremon (TRYPTYR), a TRPM8 agonist, for the treatment of dry eye disease.^[6]^[1] Its overexpression in certain cancers, such as prostate and breast, suggests potential roles in tumor progression, while selective antagonists like AMTB have shown promise in preclinical models for pain relief and cancer treatment.^[7] Ongoing research focuses on structure-based drug design to exploit its polymodal properties for targeted therapies.^[1]

Discovery and Genetics

Historical Discovery

The transient receptor potential melastatin 8 (TRPM8) channel was first identified in 2001 through a screen for genes upregulated in prostate cancer biopsies compared to normal prostate tissue, where it was named trp-p8 due to its homology to transient receptor potential (TRP) cation channels and its prostate-specific expression pattern.^[8] This discovery highlighted trp-p8 as a potential biomarker for prostate malignancies, as it was also overexpressed in other cancers such as colon, lung, and skin, prompting early clinical interest in its diagnostic and prognostic roles.^[8] At the time, its function remained unknown, with no characterized ion channel activity or ligands reported. In 2002, two independent research groups cloned and functionally characterized the channel, establishing its role as a detector of cold temperatures and the cooling agent menthol. David McKemy and colleagues at the University of California, San Francisco, isolated the gene from trigeminal sensory neurons by screening for currents activated by menthol application, using calcium imaging and patch-clamp electrophysiology in HEK293 cells expressing the cloned channel.^[9] Simultaneously, Andrew Peier and colleagues at Genentech used a bioinformatics approach, applying a hidden Markov model based on TRP protein sequences to query genomic databases, followed by RT-PCR cloning from dorsal root ganglion (DRG) RNA, and confirmed function through heterologous expression in CHO cells.^[10] Both studies demonstrated that the channel, previously known as trp-p8, encoded a non-selective cation channel permeable to calcium, expressed in a subset of small-diameter sensory neurons responsible for thermosensation.^[9]^[10] Initial functional assays revealed that the channel activates at cooling temperatures with a threshold of approximately 22–28°C, producing robust inward currents that increase in magnitude as temperatures drop to 10–23°C, and is potently sensitized by menthol concentrations of 10–100 μM, which lowers the activation threshold and enhances responses even at warmer temperatures around 30°C.^[9]^[10] These findings positioned TRPM8 as the primary molecular sensor for environmental cold in mammals, with McKemy et al. initially dubbing it cold and menthol receptor 1 (CMR1).^[9] Shortly thereafter, Peier et al. proposed the standardized nomenclature TRPM8, aligning it with the melastatin subfamily of TRP channels as the eighth member (TRPM8).^[10] The dual expression in sensory neurons and prostate tissue further fueled investigations into its potential contributions to both sensory physiology and cancer progression.^[9]^[10]

Gene Structure and Expression

The TRPM8 gene is located on the long arm of human chromosome 2 at position 2q37.1, spanning approximately 102 kb of genomic DNA. Its canonical transcript, ENST00000324695, comprises 26 exons and encodes a protein consisting of 1,104 amino acids.^[11] Earlier genomic analyses identified 24 exons spanning 95 kb, reflecting updates in annotation over time.^[12] The promoter region of the TRPM8 gene includes putative distal and proximal androgen-responsive elements (AREs), which regulate its transcription in response to androgens and contribute to elevated expression in prostate tissue.^[13] TRPM8 exhibits a distinct expression profile, with high levels in sensory neurons of the trigeminal and dorsal root ganglia, as well as in prostate, bladder, and lung tissues. Lower expression is detected in other tissues, including skin and cornea.^[14] The TRPM8 gene demonstrates strong evolutionary conservation from the origin of amniotes, with molecular signatures of positive selection and local adaptation in human variants linked to enhanced cold sensitivity in populations from colder climates.^[15]

Molecular Structure

Protein Topology and Domains

TRPM8 is a member of the transient receptor potential melastatin (TRPM) subfamily of ion channels, characterized by a monomeric topology consisting of a large intracellular N-terminal domain, a transmembrane region, and a C-terminal cytoplasmic extension.^[16] The channel assembles as a tetramer to form the functional pore.^[17] The transmembrane domain comprises six alpha-helical segments (S1–S6), with S1–S4 forming a voltage-sensor-like domain and S5–S6 contributing to the central ion conduction pore; a re-entrant pore loop connects S5 and S6, while the TRP domain—a conserved ~25-amino-acid motif—lies in the intracellular linker immediately following S6, influencing channel gating and lipid interactions.^[18] The N-terminus features four melastatin homology regions (MHR1–4), spanning approximately 700 amino acids, which are implicated in tetrameric assembly and trafficking to the plasma membrane.^[16] Specifically, MHR1–3 form a structurally conserved pocket that stabilizes the channel complex.^[19] The C-terminus includes a proximal TRP domain extension and distal helical elements that mediate interactions with regulatory lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2).^[18] Post-translational modifications further tune TRPM8 function: N-linked glycosylation at asparagine residues, such as Asn-934, in the extracellular loop between S5 and S6 affects channel trafficking and cold sensitivity, with two distinct glycoforms observed depending on cellular context.^[20] Phosphorylation, including serine sites in the C-terminus and tyrosine residues modulated by kinases like LCK, serves as a negative regulator of channel activity and surface expression.^[21]

Tetrameric Assembly and Cryo-EM Insights

TRPM8 assembles as a homotetramer, consisting of four identical subunits that collectively form the functional ion channel, with each subunit contributing the S5 and S6 transmembrane helices and the intervening re-entrant pore loop to the central ion conduction pore. This quaternary structure measures approximately 140 × 110 × 110 Å and integrates N-terminal melastatin homology regions (MHR1-4), a transmembrane domain (TMD) with six helices (S1-S6), and a C-terminal domain (CTD).^[22]^[23] Subunit interactions are mediated by key interfaces that ensure stable tetramerization. The S1-S4 helices form voltage-sensing-like domains (VSLD) that pack hydrophobically against adjacent pore domains via S4-S5 linkers, facilitating inter-subunit contacts. Additionally, the C-terminal coiled-coil domains in the CTD promote assembly by forming a tetrameric bundle that stabilizes the overall architecture.^[22]^[23] Cryo-EM has delivered atomic-level insights into TRPM8's structure since 2018, with resolutions improving to ~3 Å or better in subsequent studies. Landmark structures include the ligand-free apo-state of mouse TRPM8 at 3.0 Å and 2.5 Å (in nanodiscs), capturing a closed conformation, as well as human TRPM8 at 2.7 Å. These reveal menthol-bound models and PIP₂-associated states, highlighting ligand-induced conformational shifts in the TMD and CTD without fully opening the pore in the resolved snapshots. More recent 2025 cryo-EM structures have captured cold- and menthol-induced activation states, revealing conformational changes in the gating mechanism.^[22]^[23]^[24] Lipid interactions play a crucial role in TRPM8 tetramer stability and function, particularly through phosphatidylinositol 4,5-bisphosphate (PIP₂) binding to sites in the inner leaflet, such as the pre-S1 region, S1 helix, S4-S5 junction, and TRP helix. PIP₂ is essential for maintaining basal channel activity and modulates conformational dynamics observed in cryo-EM structures. Densities for other lipids like cholesteryl hemisuccinate (CHS) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) further delineate the annular lipid environment around the TMD.^[22]^[23]

Biophysical Properties

Ion Selectivity and Permeation

TRPM8 functions as a non-selective cation channel permeable to monovalent ions such as Na⁺, K⁺, and Cs⁺, as well as divalent cations including Ca²⁺. The relative permeability of Ca²⁺ to Na⁺ (P_Ca/P_Na) is approximately 0.97 under typical experimental conditions, though reported values range from 0.97 to 3.2 depending on expression system and ionic conditions.^[25]^[26] This near-equivalent permeability enables substantial Ca²⁺ influx upon channel opening, which contributes to membrane depolarization in sensory neurons and intracellular Ca²⁺ signaling.^[25]^[22] The single-channel conductance of TRPM8 is approximately 80 pS when measured at positive membrane potentials, with single-channel currents displaying near-linear current-voltage relationships.^[27] Whole-cell currents through TRPM8 exhibit strong outward rectification, characterized by larger outward currents at depolarized potentials compared to inward currents at hyperpolarized potentials; this behavior arises primarily from the voltage dependence of channel gating rather than asymmetric permeation or voltage-dependent block.^[27]^[28] The ion permeation pathway in TRPM8 is lined by a selectivity filter located at the extracellular entrance of the pore, formed by the backbone carbonyl oxygen atoms of conserved residues in the pore helix (such as Phe912 and Gly913 in the mouse ortholog) and influenced by the adjacent outer pore loop (often referred to as the turret region).^[22]^[18] This structural arrangement, revealed through cryo-electron microscopy structures, accommodates hydrated cations with a short but wide filter that permits passage of both monovalent and divalent ions without high selectivity for Ca²⁺ over Na⁺.^[22]^[29] At physiological concentrations, intracellular Mg²⁺ and polyamines can modulate TRPM8 activity, though direct pore blockade is less pronounced compared to other TRP channels; instead, these cations often influence gating indirectly through interactions with regulatory lipids like PIP₂.^[30]^[31]

Voltage and Temperature Gating

TRPM8 exhibits voltage-dependent activation, characterized by a half-activation voltage (V_{1/2}) that typically resides at highly depolarized potentials in the absence of stimuli, around +100 to +200 mV, rendering the channel closed under physiological conditions. Upon stimulation by cold temperatures or agonists like menthol, the voltage-activation curve shifts negatively, with V_{1/2} moving to more physiological ranges, such as +15 mV for cold alone or -100 mV when combined with menthol, thereby facilitating channel opening at resting membrane potentials.^[32] This shift reflects a lowering of the energy barrier for gating, integrating voltage sensitivity with thermal and chemical cues to enable polymodal responsiveness.^[33] The temperature sensitivity of TRPM8 is exceptionally high, with a Q_{10} value ranging from approximately 20 to 40, indicating a profound increase in channel activity upon cooling. The activation threshold lies between 25°C and 28°C, below which the probability of opening rises steeply, allowing detection of innocuous cold.^[34]^[35] This polymodal gating mechanism couples temperature changes to voltage dependence, where cooling not only directly enhances open probability but also synergizes with chemical activators to amplify responses through parallel shifts in the activation curve.^[32] Gating kinetics of TRPM8 involve rapid activation upon stimulation, with time constants (τ) for activation on the order of 5-10 ms at depolarizing voltages, followed by slower inactivation processes that vary with stimulus intensity and duration. The cooperative nature of tetrameric gating is evidenced by a Hill coefficient of approximately 1.3, suggesting subunit interactions contribute to the steepness of the activation curve and overall sensitivity.^[36]^[37] TRPM8 activity is also modulated by extracellular pH, where acidification below 6.5 significantly reduces channel responses to cold and certain agonists. This pH-dependent inhibition, with half-maximal effect around pH 6.3, provides a mechanism for fine-tuning sensitivity in acidic microenvironments without affecting permeation in open states.^[38]

Physiological Roles

Cold Sensation in the Nervous System

TRPM8 is predominantly expressed in a subset of small-diameter sensory neurons within the trigeminal ganglia (TG) and dorsal root ganglia (DRG), specifically in Aδ and C-fiber nociceptors that mediate noxious cold detection.00652-9)^[39] These neurons co-express voltage-gated sodium channels such as Nav1.8, which are essential for the initiation and propagation of action potentials following TRPM8 activation. This selective expression pattern positions TRPM8 as a key molecular transducer for cold stimuli in the peripheral nervous system. Upon exposure to cooling temperatures (typically below 28°C), TRPM8 channels open, permitting influx of monovalent cations (primarily Na⁺) and divalent cations (Ca²⁺) into the neuron.00652-9) This cation entry depolarizes the plasma membrane, activating voltage-gated sodium channels like Nav1.8 to generate action potentials that propagate along the axon to central synapses in the spinal cord dorsal horn. At these synapses, the action potentials trigger Ca²⁺-dependent exocytosis of neurotransmitters, including glutamate, facilitating signal transmission to second-order neurons in the pain pathway.^[40] In models of neuropathic pain, such as chronic constriction injury, TRPM8 contributes significantly to cold allodynia, where innocuous cold evokes painful sensations.^[40] Genetic knockout of TRPM8 in mice abolishes cold hypersensitivity in these models and markedly reduces behavioral responses to noxious cold, including withdrawal reflexes and avoidance behaviors in thermal preference assays.^[41] These findings underscore TRPM8's essential role in pathological cold pain signaling. TRPM8 integrates with other transient receptor potential (TRP) channels, notably TRPA1, to encode a broader range of cold temperatures in the peripheral nervous system.^[42] While TRPM8 primarily detects moderate cooling (8–28°C), TRPA1 activation at harsher cold (<17°C) synergizes with TRPM8 to enhance nociceptor excitability and amplify behavioral avoidance of extreme cold stimuli.^[43] This cooperative mechanism ensures robust detection of environmentally relevant cold threats.

Non-Neuronal Functions

TRPM8 channels are expressed in adipocytes of brown adipose tissue (BAT), where cold-induced activation triggers calcium influx that promotes thermogenesis through upregulation of uncoupling protein 1 (UCP1).^[44] This process enhances mitochondrial activity and heat production, contributing to non-shivering thermogenesis independent of neuronal inputs in mature adipocytes.^[45] Studies in TRPM8 knockout mice demonstrate reduced UCP1-dependent thermogenesis in BAT upon cold exposure, underscoring the channel's direct role in energy expenditure for body temperature maintenance.^[46] In the ocular system, TRPM8 is present in corneal afferent neurons and epithelial cells, where it senses evaporative cooling to regulate basal tear production and maintain ocular surface wetness. Activation of these channels by mild cold stimuli increases tear secretion from the lacrimal glands, preventing dryness without eliciting nociceptive responses.^[47] Additionally, TRPM8 mediates reflex blinking in response to corneal cooling, which helps distribute tears evenly across the ocular surface and protects against environmental stressors.^[48] TRPM8 channels are expressed in vascular smooth muscle cells, where their activation by cooling modulates vasoconstriction to facilitate peripheral temperature control.^[49] In response to mild hypothermia, TRPM8 promotes calcium-dependent constriction of cutaneous arteries, reducing blood flow to the skin and conserving core body heat during environmental cold exposure.^[50] This mechanism is evident in isolated vessel preparations, where cold or menthol application induces sustained vasoconstriction, highlighting TRPM8's role in autonomic thermoregulation beyond sensory detection.^[51] In the lower urinary tract, TRPM8 contributes to detrusor muscle contraction in the bladder through calcium signaling in epithelial and smooth muscle cells, facilitating voiding reflexes triggered by cooling.^[52] Channel activation enhances bladder contractility, as shown by increased micturition pressure in response to menthol in animal models of outlet obstruction.^[53] In the prostate, TRPM8 is localized to secretory epithelial cells, where it regulates calcium-dependent exocytosis and fluid secretion, supporting glandular function in androgen-responsive tissues.^[54] This expression pattern suggests TRPM8's involvement in maintaining secretory homeostasis in prostatic acini.^[55] TRPM8 is also expressed in various tissues of the digestive system, including the esophagus, stomach, small intestine, colon, liver, and pancreas, where it plays roles in sensory transduction via vagal afferents, regulation of gastrointestinal motility, and anti-inflammatory effects. For instance, in the colon, TRPM8 activation reduces inflammation by modulating cytokines such as IL-10 and TNF-α, while in the stomach and liver, it contributes to protection against ulcers and fibrosis, respectively. These functions highlight TRPM8's broader involvement in visceral sensory and protective mechanisms in the gastrointestinal tract.^[56]

Pharmacological Ligands

Agonists and Activators

TRPM8, a transient receptor potential melastatin 8 channel, is activated by various chemical agonists that mimic or enhance cold-induced gating, primarily through binding to specific sites within its voltage-sensor-like domain (VSLD). These ligands include natural compounds derived from plants and synthetic molecules designed to potentiate channel opening, thereby eliciting cooling sensations or therapeutic effects. Agonist activation typically shifts the channel's voltage-dependence toward more negative potentials, facilitating cation influx at physiological temperatures.^[57] Menthol, a monoterpene alcohol found in peppermint, serves as a prototypical natural agonist of TRPM8 with an EC50 of approximately 30 μM. It binds to a hydrophobic pocket in the S2-S3 linker of the VSLD, stabilizing an open conformation and allosterically enhancing the channel's sensitivity to cold stimuli below 28°C. This binding induces conformational changes that propagate from the VSLD to the pore domain, promoting ion permeation. Icilin, a synthetic imidazole derivative, acts as a potent super-cooling agonist with an EC50 of about 0.2 μM, engaging a distinct binding site involving residues in the transmembrane helices and intracellular loops, distinct from menthol's location. Unlike menthol, icilin activation is less dependent on voltage modulation but strongly potentiates cold responses through type II agonism.^[38]^[57]^[58]^[59] Other plant-derived cooling mimics, such as eucalyptol (from eucalyptus oil) and geraniol (from rose oil), also activate TRPM8, eliciting sensations akin to mild cooling by interacting with the menthol-binding pocket or adjacent sites in the VSLD. These monoterpenoids provide milder activation compared to menthol, with eucalyptol showing an EC50 of approximately 150 μM for human TRPM8 and geraniol an EC50 of about 6 mM in mouse TRPM8.^[60]^[61]^[62]^[63]^[64] In 2025, a novel series of adamantane-based compounds emerged as high-potency TRPM8 agonists, featuring scaffolds like 2-((3S,5S,7S)-adamantan-1-ylamino)-2-oxoethyl derivatives, which exhibit sub-micromolar EC50 values and improved selectivity over related TRP channels. These ligands bind within the VSLD cavity, offering enhanced pharmacological profiles for potential analgesic applications due to their increased potency and reduced off-target effects.^[64] A significant clinical advancement occurred in 2025 with the FDA approval of acoltremon (marketed as Tryptyr 0.003% ophthalmic solution by Alcon), the first selective TRPM8 agonist for treating signs and symptoms of dry eye disease. This compound stimulates basal tear secretion by activating corneal TRPM8 channels on sensory nerve endings, thereby enhancing reflex tearing without systemic cooling effects, with demonstrated efficacy in phase 3 trials showing improved ocular surface staining and symptom relief. Cryo-EM structures of TRPM8, resolved at resolutions up to 2.7 Å, have elucidated the menthol-binding pocket as a solvent-accessible cavity in the VSLD, lined by residues from S2, S3, and S4 helices, where agonists like menthol and WS-12 (a menthol analog) induce allosteric rearrangements that lower the energetic barrier for cold gating. This mechanism underscores the therapeutic potential of targeted agonists in modulating TRPM8 for sensory and secretory functions.^[65]^[6]^[23]^[16]

Antagonists and Inhibitors

TRPM8 antagonists and inhibitors are pharmacological agents that block the channel's activation by cold temperatures, menthol, or icilin, thereby reducing calcium influx and downstream signaling. These compounds are primarily small molecules that target the voltage-sensor-like domain (VSLD) or the TRP domain, stabilizing the channel in a closed conformation as revealed by cryo-EM structures.^[66] Early antagonists like AMTB (N-(3-methoxyphenyl)-4-chlorocinnamide), with an IC50 of 25 nM against menthol-evoked currents, were among the first potent blockers identified and have served as tool compounds for studying TRPM8 function in cold sensation and pain.^[66] Synthetic small-molecule antagonists dominate the pharmacological landscape, with several classes developed for therapeutic applications. Tetrahydroisoquinoline-derived ureas, such as AMG333, exhibit high potency (IC50 = 13 nM) and selectivity over other TRP channels, blocking all modes of TRPM8 activation including voltage, temperature, and ligand gating. AMG333 advanced to phase I clinical trials for migraine treatment but was discontinued due to modest efficacy; it remains a benchmark for orally bioavailable inhibitors.^[67] Similarly, pyrazole-based compounds like PF-05105679 (IC50 ≈ 10 nM) progressed to phase II trials for cold-induced pain hypersensitivity, demonstrating reduced cold pain in human subjects without significant off-target effects on other TRP channels. Naphthyl derivatives, identified through virtual screening, offer excellent selectivity (inactive against TRPA1, TRPV1, and TRPV4) with pIC50 values around 7 (IC50 ≈ 50-100 nM); they bind via hydrophobic interactions with residues like Tyr745 and Asp802 in the VSLD cavity.^[68] Natural products and derivatives also provide TRPM8 inhibition, often with moderate potency but favorable safety profiles. Sesamin, a lignan from sesame, inhibits TRPM8 with an IC50 of 9.79 µM by forming hydrogen bonds with Arg832 and Arg998, locking the channel closed and showing potential in prostate cancer models where TRPM8 overexpression promotes proliferation.^[66] Oroxylin A, a flavonoid from Scutellaria baicalensis, blocks cold- and menthol-induced activation (IC50 = 1.7 µM) through interactions in the binding pocket, with preclinical evidence for anti-inflammatory effects in cold hypersensitivity.^[66] Tryptophan-derived antagonists, such as compound 38, achieve sub-nanomolar potency (IC50 = 0.2 nM) and reduce cold allodynia in rodent models, highlighting their analgesic potential.^[67] Recent developments emphasize peripherally acting inhibitors to minimize central side effects like core body temperature changes. The biphenyl carboxamide VBJ103 (IC50 = 64 nM) administered subcutaneously reverses oxaliplatin-induced cold hypersensitivity in mice at doses of 3-30 mg/kg while attenuating hypothermia, suggesting utility in chemotherapy-induced peripheral neuropathy with targeted delivery.^[69] β-Lactam derivatives from phenylalanine scaffolds exhibit potent, selective antagonism (IC50 in low nanomolar range) and improved pharmacokinetic properties, with ongoing optimization for overactive bladder disorders.^[70] Cannabidivarin, a phytocannabinoid (IC50 ≈ 0.8 μM), was tested in a 2020 clinical trial for HIV-associated neuropathic pain but did not demonstrate significant efficacy in reducing pain intensity.^[67]^[71] Mechanistically, most antagonists compete for or allosterically modulate sites in the VSLD-TRP domain interface, preventing conformational changes necessary for pore opening; for instance, cryo-EM structures of TRPM8 bound to AMTB (PDB: 6O6R) or TC-I 2014 (PDB: 6O72) illustrate how these ligands narrow the ion conduction pathway via lipid interactions.^[66] Selectivity is enhanced by targeting species-specific residues, as human TRPM8 structures guide the design of compounds avoiding off-target binding to TRPV1 or TRPA1. Despite progress, challenges remain in achieving brain penetration for central pain indications without thermoregulatory disruption, driving research toward topical or peripheral formulations.^[68]

Clinical and Pathophysiological Significance

Role in Pain and Sensory Disorders

TRPM8 channels play a pivotal role in the sensitization of cold perception following peripheral nerve injury, contributing to cold hyperalgesia and allodynia in neuropathic pain states. In rodent models of chronic constriction injury (CCI), TRPM8 expression is significantly upregulated in ipsilateral dorsal root ganglia (DRG) neurons, particularly in small-diameter C-fibers and medium-diameter Aδ-fibers, leading to heightened responsiveness to innocuous cold stimuli.^[72] This upregulation enhances cold-evoked currents and behavioral hypersensitivity, as demonstrated by increased paw withdrawal latencies to acetone application or cold plates post-injury.^[40] Genetic ablation of TRPM8 attenuates these pain phenotypes, underscoring its mechanistic involvement. In TRPM8-null mice subjected to CCI, cold allodynia is markedly reduced, with no significant increase in acetone-evoked responses over 28 days, compared to wild-type mice exhibiting sustained hypersensitivity.^[41] Similarly, mechanical allodynia is diminished in knockout models, indicating TRPM8's broader contribution to injury-induced sensory dysfunction beyond thermal modalities.^[40] Recent genetic studies have linked TRPM8 variants to migraine susceptibility and associated affective disorders. Non-coding polymorphisms such as rs10166942 in the TRPM8 gene are associated with reduced risk of polygenic migraine, with carriers showing lower mRNA expression in DRG and attenuated cold pain thresholds.^[73] A 2025 study further revealed that Trpm8 knockout in mice exacerbates migraine-like behaviors, including mechanical hypersensitivity and impulsive/depressive phenotypes in nitroglycerin models, suggesting protective effects of certain variants against migraine and its emotional comorbidities like anxiety and depression.^[74] TRPM8 undergoes adaptive desensitization during sustained cold exposure, limiting prolonged nociceptive signaling. Tachyphylaxis, a slower phase of downregulation, is mediated by Ca²⁺-dependent activation of protein kinase C (PKC) and subsequent phosphatase involvement, which reduces channel sensitivity through altered PIP₂ affinity and dephosphorylation events.^[75] This mechanism, distinct from rapid Ca²⁺-calmodulin-mediated acute desensitization, helps mitigate excessive cold-evoked pain but can be dysregulated in chronic conditions. Pharmacological blockade of TRPM8 holds therapeutic promise for cold-induced pain in sensory disorders. Selective antagonists alleviate cold allodynia in chemotherapy-induced peripheral neuropathy models, such as oxaliplatin-treated rodents, where TRPM8 inhibition restores normal cold thresholds without affecting heat pain.^[76] In fibromyalgia, where cold hyperalgesia is prevalent due to potential TRPM8 dysregulation, antagonists may similarly target amplified cold nociception, offering a modality-specific approach to symptom relief.^[77]

Involvement in Cancer

TRPM8 is overexpressed in early-stage, androgen-dependent prostate cancer, where its expression is regulated by androgen receptor activity, distinguishing it from normal prostate epithelial cells. This upregulation facilitates calcium influx that promotes tumor cell proliferation by activating downstream pathways such as MAPK and increasing expression of cyclin D1 and CDK2/6.^[78]^[79] In advanced metastatic castration-resistant prostate cancer, TRPM8 expression is downregulated, with the channel relocating to the endoplasmic reticulum, potentially contributing to apoptosis resistance and disease progression.^[78] In other cancers, TRPM8 plays context-dependent roles in tumor progression. In bladder cancer, TRPM8 is upregulated in tumor tissues and drives invasion and metastasis by enhancing cell migration, proliferation, and epithelial-mesenchymal transition through activation of MAPK and AKT/GSK3β pathways, while also modulating reactive oxygen species metabolism.^[80] In breast cancer, TRPM8 overexpression stimulates cell migration and proliferation by elevating basal autophagy via calcium-dependent activation of the AMPK-ULK1 pathway, with knockdown reducing these aggressive phenotypes.^[81] In lung cancer, TRPM8 expression supports tumor cell survival and contributes to resistance against apoptosis, alongside promoting migration and invasion, though its effects on proliferation can vary by cell line.^[82] Recent 2025 research indicates that high TRPM8 protein levels in prostate tumors predict increased vulnerability to agonist-induced cell death, particularly when combined with sub-lethal chemotherapy such as docetaxel or 5-FU/oxaliplatin. In experimental models, including patient-derived organoids, TRPM8 agonists like D-3263 triggered over 70% apoptosis in high-TRPM8-expressing cells, an effect abolished by TRPM8 knockdown, highlighting its potential for precision oncology targeting.^[83] TRPM8 holds diagnostic potential as a biomarker for prostate cancer, with elevated TRPM8 mRNA detectable in patient plasma, aiding in the identification of metastatic disease. Therapeutically, TRPM8 antagonists, such as compounds with IC50 values in the nanomolar range (e.g., 0.2 nM for compound 6), inhibit androgen-dependent prostate cancer growth by blocking calcium influx, reducing proliferation, migration, and invasion in AR-positive cell lines like LNCaP without affecting AR-negative cells.^[84]^[85]

Applications in Ocular and Metabolic Diseases

TRPM8 modulation has emerged as a promising therapeutic strategy in ocular diseases, particularly dry eye disease (DED). In May 2025, the U.S. Food and Drug Administration approved acoltremon (TRYPTYR) 0.003% ophthalmic solution, the first TRPM8 agonist indicated for the treatment of DED signs and symptoms.^[6]^[86] As a selective topical agonist, acoltremon activates TRPM8 channels on corneal afferent nerves, stimulating natural tear production and reflex lacrimation without the irritative effects seen in earlier non-selective agents like menthol.^[87] Phase 3 pivotal trials (COMET-2 and COMET-3) demonstrated statistically significant increases in tear production, as measured by Schirmer's test, along with reductions in ocular discomfort and conjunctival staining scores, providing clinically meaningful symptom relief in patients with moderate to severe DED.^[88]^[89] TRYPTYR was launched in the United States in July 2025. As of November 2025, long-term data from extension studies confirm sustained improvements in tear production and symptom relief over 12 weeks.^[90] In metabolic diseases, TRPM8 plays a role in renal and adipose tissue pathophysiology, with genetic and pharmacological studies highlighting its therapeutic potential. A 2025 study in murine models of chronic kidney disease (CKD) showed that TRPM8 deletion significantly reduced vascular endothelial dysfunction, inflammation, and perivascular fibrosis, thereby mitigating CKD progression and preserving microvascular integrity.^[91] This suggests that TRPM8 antagonists could attenuate fibrotic and inflammatory pathways in CKD, potentially offering renoprotective benefits. Additionally, TRPM8 activation in adipose tissue enhances uncoupling protein 1 (UCP1)-dependent thermogenesis, promoting energy expenditure and preventing diet-induced obesity, as evidenced by preclinical data where agonists like menthol induced browning of white adipose tissue and improved metabolic profiles.^[46]^[92] These findings position TRPM8 agonists as candidates for obesity management by boosting non-shivering thermogenesis in brown and beige adipocytes. Beyond ocular and metabolic contexts, TRPM8-targeted therapies show promise in other conditions. A 2025 study showed that repeated administration of a TRPM8 agonist (rapamycin) alleviates mechanical hypersensitivity and pain-like behaviors in mouse models of chronic migraine, without affecting depressive phenotypes, suggesting TRPM8 activation as a potential therapeutic strategy for migraine-associated pain.^[74] For bladder overactivity, selective TRPM8 antagonists like KPR-5714 have demonstrated efficacy in preclinical models by suppressing afferent nerve hyperactivity, decreasing micturition frequency, and alleviating hypersensitive symptoms in overactive bladder disorders.^[93]^[94] Despite these advances, challenges in TRPM8 modulation arise from its broad tissue expression, including sensory neurons, prostate, bladder, and vasculature, which raises concerns about off-target effects such as unintended thermoregulatory disruptions or urogenital impacts with systemic agents.^[95] Topical formulations, like acoltremon, mitigate these risks by limiting exposure, but further research is needed to optimize selectivity for multi-indication use.

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[10]
Evidence for specific TRPM8 expression in human prostate ...
TRPM8 mRNA has also been shown to be overexpressed in prostate cancer and is considered to play an important role in prostate physiology. This study was ...Introduction · DHT is essential and sufficient... · TRPM8 expression involves...
[11]
Tissue expression of TRPM8 - Summary - The Human Protein Atlas
The IHC image panel to the right display selected tissues that give a visual summary of the protein expression profile. To the left, the two human bodies ...Missing: cornea | Show results with:cornea
[12]
Human local adaptation of the TRPM8 cold receptor along a ...
We show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate ...Missing: conservation | Show results with:conservation
[13]
Structure of the cold- and menthol-sensing ion channel TRPM8 - PMC
Dec 7, 2017 · We determined the cryo-electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 Å.
[14]
Trafficking and assembly of the cold-sensitive TRPM8 channel
... ankyrin-like repeats, and hydrophobicity predictions that may allow for more tha … ... Here we have shown that TRPM8 channels assemble as multimers using ...
[15]
Structure of the cold- and menthol-sensing ion channel TRPM8
Dec 7, 2017 · The three-layered architecture of the TRPM8 channel provides the framework for understanding the mechanisms of cold and menthol sensing.
[16]
The acquisition of cold sensitivity during TRPM8 ion channel evolution
Our study shows the formation of the functional MHR1-3 domain in transient receptor potential melastatin 8 (TRPM8) bestowed the channel with cold sensitivity.
[17]
N-Glycosylation of TRPM8 Ion Channels Modulates Temperature ...
TRPM8 channel is N-glycosylated, a post-translational modification affecting trafficking and gating properties of other TRP channels.
[18]
Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel ...
Oct 13, 2021 · The main finding of this study is the demonstration that serine-phosphorylation acts as a key negative modulator of mammalian TRPM8 channel function.
[19]
Structures of a mammalian TRPM8 in closed state - Nature
Jun 3, 2022 · Each MmTRPM8 subunit contains multiple domains, including the N-terminal four TRPM homology repeats (MHR1 to MHR4), S1–S6 six transmembrane ...
[20]
Structure of human TRPM8 channel | Communications Biology
Oct 19, 2023 · TRPM8 is a non-selective cation channel permeable to both monovalent and divalent cations that is activated by multiple factors, ...
[21]
https://www.jneurosci.org/content/41/41/8475
[22]
TRPM8 Channels and SOCE: Modulatory Crosstalk between Na+ ...
TRPM8 channels are non-selective ion-permeable channels exhibiting multi-gating mechanisms, being activated by innocuous cool to cold temperatures. The opening ...
[23]
TRPM8: The Cold and Menthol Receptor - TRP Ion Channel ... - NCBI
The first TRP channel shown to be responsive to temperatures in the cold range (<30°C), TRPM8, a member of the melastatin TRP channel subfamily.
[24]
Voltage- and cold-dependent gating of single TRPM8 ion channels
Jan 31, 2011 · Conductance was found to increase with increasing temperature (95 ± 3 pS at 30°C, n = 15 cells; not depicted). The increase in channel activity ...Missing: original | Show results with:original
[25]
Structural insights into TRPM8 inhibition and desensitization - PMC
Sep 5, 2019 · The pore of TRPM8 is formed by S5 and S6, as well as the intervening pore helix and outer pore loop (Fig. ... Residues lining the selectivity ...
[26]
Electrostatic Interaction of Internal Mg2+ with Membrane PIP2 Seen ...
We give evidence that Mg2+ and polyamines weaken the KCNQ channel–phospholipid interaction. Lowering internal Mg2+ augmented inward and outward KCNQ currents ...
[27]
On the modulation of TRPM channels: Current perspectives and ...
TRPM8 is a Ca2+-permeant but non-selective cation channel (Cs+, K+, Na+, Ba2+, Ca2+, and Mg2+) identified as the physiological sensor of environmental cold (98, ...
[28]
Bidirectional shifts of TRPM8 channel gating by temperature and ...
TRPM8 is a non-selective calcium-permeable TRP channel that is activated by cold and menthol, and is postulated to play a critical role in the transduction ...
[29]
The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels - Nature
### Summary of TRPM8 Voltage and Temperature Gating
[30]
Clues to understanding cold sensation: thermodynamics ... - PubMed
TRPM8 is a channel activated by cold temperatures, voltage, and menthol. In ... The Q10 calculated in the same temperature range is 24. This ...
[31]
TRPM8 Activation by Menthol, Icilin, and Cold Is Differentially ...
Jun 9, 2004 · TRPM8 is a nonselective cation channel activated by cold and the cooling compounds menthol and icilin (Peier et al., 2002).
[32]
(PDF) Ethanol inhibits cold-menthol receptor TRPM8 by modulating ...
Aug 5, 2025 · ... (Hill coefficient 1.30 ± 0.04; n ¼ 11) and 1.5 ± 0.3% (Hill coefficient 1.2 ± 0.2; n ¼ 4), respectively. …
[33]
(PDF) Voltage- and cold-dependent gating of single TRPM8 ion ...
Aug 7, 2025 · Closed-time constants (and normalized areas) are 0.21 ms (0.39), 1.4 ms (0.28), 5.8 ms (0.27), 23 ms (0.066), and 2,256 ms (0.00064) at 40 mV ...
[34]
TRPM8 Activation by Menthol, Icilin, and Cold Is Differentially ...
When cells were exposed to solutions in the range of pH 8.1-6.5, the temperature threshold for activation was elevated at higher pH and depressed at lower pH.
[35]
Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat ...
Dec 26, 2005 · Both A-fiber and C-fiber neurons expressed TRPM8, whereas TRPV1 was almost exclusively seen in C-fiber neurons. All TRPM8-expressing neurons ...
[36]
TRPM8 Mechanism of Cold Allodynia after Chronic Nerve Injury
Dec 12, 2007 · Recent studies using TRPM8 knock-out mice have suggested the involvement of TRPM8 in cold avoidance behavior and cold allodynia in mice ( ...
[37]
Attenuated Cold Sensitivity in TRPM8 Null Mice - ScienceDirect.com
May 3, 2007 · TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury- ...
[38]
Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8 ...
We compared the frequency and characteristics of the cold responses of TRPM8-expressing and TRPM8-negative C-fiber nociceptors in C57BL/6J mice with nociceptors ...
[39]
How cold is it? TRPM8 and TRPA1 in the molecular logic of cold ...
Apr 22, 2005 · ... cold sensation, TRPM8 and TRPA1, have only recently been described. The former channel is a receptor for menthol, and links the sensations ...
[40]
Activation of the cold-sensing TRPM8 channel triggers UCP1 ...
Brown adipose tissue (BAT) is an energy-expending organ that produces heat ... Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis ...
[41]
Human white adipocytes express the cold receptor TRPM8 which ...
Mar 5, 2014 · Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production.
[42]
Activation of the cold-sensing TRPM8 channel triggers UCP1 ...
TRPM8, uncoupling protein 1, menthol, thermogenesis, brown adipose tissue, obesity ... (C) UCP1 protein expression in the brown fat of WT and TRPM8 ...
[43]
A novel TRPM8 agonist relieves dry eye discomfort - PMC
Jun 26, 2017 · TRPM8 may be associated with the detection of “dryness” on the eye surface because it is activated by evaporative cooling and by hyperosmolar ...
[44]
TRPV1 activity and substance P release are required for corneal ...
Dec 12, 2019 · In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia.
[45]
Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone | American Journal of Physiology-Heart and Circulatory Physiology | American Physiological Society
### Summary of TRPM8 Role in Vascular Smooth Muscle and Effects on Vasoconstriction/Vasodilation
[46]
Dysfunctional TRPM8 signalling in the vascular response to ... - eLife
Nov 2, 2021 · We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein ...
[47]
Activation of Cold-Sensing Transient Receptor Potential Melastatin ...
Mar 17, 2014 · Our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling–mediated RhoA/Rho kinase ...
[48]
Function of the Cold Receptor (TRPM8) Associated with Voiding ...
Detrusor contraction by the bladder cooling reflex is mediated by C-fiber ... Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical ...
[49]
Essential Role of Transient Receptor Potential M8 (TRPM8) in a ...
These data suggest that although various sensory stimuli can evoke an acute bladder response, cold stimuli acting via TRPM8 are by far the most provocative.Missing: prostate secretory
[50]
Evidence for specific TRPM8 expression in human prostate ...
This study was designed to determine the androgen-regulation mechanisms for TRPM8 mRNA expression and to identify the phenotype of TRPM8-expressing cells in the ...
[51]
Prostate cell differentiation status determines transient receptor ... - JCI
Jun 1, 2007 · Figure 6A shows the alignment of known TRPM8 mRNAs and the putative genomic structure of the trpm8 gene. Although trpm8 is composed of 27 exons ...<|control11|><|separator|>
[52]
Molecular mechanisms underlying menthol binding and activation of ...
Jul 29, 2020 · TRPM8 channel is a polymodal receptor activated by a plethora of stimuli such as cold, membrane depolarization, and chemical ligands. It is also ...
[53]
Activation mechanism of the mouse cold-sensing TRPM8 channel ...
Oct 14, 2022 · It is required for sensing cold temperatures as TRPM8-knockout mice show severe behavioral deficiency in response to cold stimuli (3–5). Recent ...
[54]
Article The Super-Cooling Agent Icilin Reveals a Mechanism of ...
When exposed to menthol or cold, TRPM8 behaves like many ligand-gated channels, exhibiting rapid activation followed by moderate Ca2+-dependent adaptation. In ...Missing: Ca2+ neurotransmitter
[55]
Modulation of Thermoreceptor TRPM8 by Cooling Compounds - PMC
In addition to menthol, a number of other cooling agents, including icilin, eucalyptol, and WS-3 activate TRPM8 in vitro. The former of these compounds ...
[56]
Characterization of the mouse cold-menthol receptor TRPM8 and ...
Aug 7, 2025 · Cooling sensations can be mediated by menthol, geraniol and eucalyptol interacting with TRPM8 (Behrendt et al., 2004) . However, several ...
[57]
An adamantane‐based ligand as a novel chemical ... - FEBS Press
Mar 23, 2025 · Here, we report a family of adamantane-based TRPM8 agonists and antagonists that increase the channel pharmacopeia. Among all ligands tested ...
[58]
FDA approves first-in-class TRPM8 ion channel agonist for dry eye ...
Jun 10, 2025 · The FDA has approved Alcon's acoltremon (Tryptyr) for signs and symptoms of dry eye disease. This is the first approval for an agonist of TRPM8.
[59]
Alcon Announces FDA Approval of TRYPTYR (acoltremon ...
May 28, 2025 · Alcon Announces FDA Approval of TRYPTYR (acoltremon ophthalmic solution) 0.003% for the Treatment of the Signs and Symptoms of Dry Eye Disease.
[60]
TRPM8 Channels: Advances in Structural Studies and ...
Sensory neurons expressing TRPV1, TRPA1 and TRPM8 have been found in the mouse and monkey cornea, constituting accessible tissue sources to further explore the ...
[61]
Recent Progress in TRPM8 Modulation: An Update - MDPI
These channels are highly expressed in peripheral sensory neurons (Aδand C fiber afferents), and also on deep visceral afferents in prostate, bronchopulmonary ...
[62]
Novel selective, potent naphthyl TRPM8 antagonists identified ...
Sep 8, 2017 · However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we ...
[63]
Subcutaneous administration of a novel TRPM8 antagonist reverses ...
May 24, 2024 · We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a ...
[64]
β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol ...
We have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity.
[65]
https://www.nature.com/articles/d41573-025-00106-x
[66]
Reduced TRPM8 expression underpins reduced migraine risk and ...
Dec 23, 2019 · Based on AEI analysis, we present haplotype data suggesting that decreased expression of TRPM8 is associated with a reduced risk for migraine.
[67]
Cold receptor TRPM8 as a target for migraine-associated pain and ...
Jun 23, 2025 · Genetic variations in the Trpm8 gene that encodes the cold receptor TRPM8 have been linked to protection against polygenic migraine, ...Missing: risk | Show results with:risk<|separator|>
[68]
TRPM8 acute desensitization is mediated by calmodulin and ...
The Ca2+-dependent functional downregulation of TRPM8 is manifested with two distinctive phases, acute desensitization and tachyphylaxis. Here we show in rat ...Missing: Ca2+ | Show results with:Ca2+
[69]
Development of TRPM8 Antagonists to Treat Chronic Pain and ...
Mar 30, 2017 · Much data also suggests that TRPM8 plays a role in amplifying pain sensation after injury, especially in models of neuropathic pain.
[70]
Evaluation of cold pain tolerance in patients with fibromyalgia and ...
Mar 31, 2022 · ... (TRPM8), and alterations to this receptor may account for cold hyperalgesia in a variety of chronic pain conditions, including fibromyalgia.
[71]
The potential of TRP channels as new prognostic and therapeutic ...
Roles of TRPM8 in prostate cancer. According to Tsavaler's hypothesis, TRPM8 may be considered a prostate oncogene and its overexpression/overactivity ...
[72]
TRPM8 in prostate cancer cells: a potential diagnostic and ... - PubMed
TRPM8 is a potential tissue marker in differential diagnosis and a potential prognostic marker for androgen-unresponsive and metastatic prostate cancer.Missing: identification screening
[73]
TRPM8 Inhibition Regulates the Proliferation, Migration and ROS ...
Sep 4, 2020 · TRPM8 might play an essential for BCa tumor progression and metastasis by interfering with BCa cell proliferation, motility, ROS metabolism and ...
[74]
https://pmc.ncbi.nlm.nih.gov/articles/PMC12183901/
[75]
Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and ...
Oct 23, 2015 · Experimental data implicate that TRPM8 channels play important roles in cancer cells proliferation, survival, migration, invasion, and neurosecretion.
[76]
FEBS Press
### Summary of 2025 Findings on TRPM8 Levels Predicting Vulnerability to Agonist-Induced Cell Death in Prostate Tumors
[77]
a potential mRNA marker for metastatic prostate cancer detection in ...
Semi-quantitative RT-PCR analysis revealed that TRPM8 levels were higher in tumor than in non-tumor tissue from 31 of 40 (>75%) patients examined.Missing: serum | Show results with:serum
[78]
Therapeutic potential of TRPM8 antagonists in prostate cancer
Dec 1, 2021 · TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness.
[79]
[PDF] 217370Orig1s000 - accessdata.fda.gov
May 28, 2025 · TRYPTYR is indicated for the treatment of the signs and symptoms of dry eye disease. 2. DOSAGE AND ADMINISTRATION. 2.1 Recommended Dosage.
[80]
FDA Approves New Treatment for Dry Eye Disease - WebMD
May 30, 2025 · The FDA has approved Tryptyr (acoltremon) as the first TRPM8-targeting eye drop for dry eye disease, stimulating natural tear production as ...<|separator|>
[81]
Acoltremon Ophthalmic Solution 0.003% for Signs and Symptoms of ...
Sep 30, 2025 · In the phase 3 pivotal COMET-2 and COMET-3 studies, the primary endpoint (increased tear production) was met following use of acoltremon 0.003%, ...
[82]
Acoltremon Ophthalmic Solution 0.003% for Signs and Symptoms of ...
Sep 30, 2025 · In both phase 3 studies, ACO compared with VEH led to consistent, clinically meaningful tear production as well as reductions in other DED signs ...
[83]
Genetic Deletion of TRPM8 Channels Restores Microvascular ...
Oct 8, 2025 · Our findings revealed that TRPM8 channel deletion significantly alleviated endothelial dysfunction, inflammation, and fibrosis in mice with CKD.
[84]
https://pubmed.ncbi.nlm.nih.gov/20043080/
[85]
Mechanisms of sensory adaptation and inhibition of the cold and ...
Aug 2, 2024 · Antagonism against TRPM8 has thus emerged as a promising strategy for treating cold-associated pain disorders, bladder sensory disorders, and ...
[86]
KPR-5714, a Novel Transient Receptor Potential Melastatin 8 ...
KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, ...
[87]
(PDF) The TRPM8 channel as a potential therapeutic target for ...
Aug 5, 2025 · Aims: Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders.
[88]
TRPM8 Channels: Advances in Structural Studies and ... - MDPI
TRPM8 channels are activated by a wide range of stimuli, including innocuous to noxious cold temperature (8–26 °C) and cooling agents [4,5,6,33], such as ...