This channel is responsible for perceiving harmful heat above 43 °C [19]. A non-selective channel that is permeable to cations, TRPV1 is activated by capsaicin, low pH (<6), temperature increases, and changes in membrane polarity [100]. It thus contrasts to TRPM8, which is activated by cold and menthol [17,104]. TRPV1’s activation range is 43–50 °C. Substances like ethanol also activate endogenous lipids (e.g., endocannabinoids, anandamides, and N-arachidonoyl dopamine), which are products of the lipoxygenase metabolism and topical analgesics. It is also associated with the recognition of harmful stimuli [17].

It is important to point out that diverse inflammatory mediators can reduce the temperature threshold for the activation of this thermoreceptor while increasing the magnitude of the responses of the ionic channel to produce inflammatory pain and heat hyperalgesia. For this reason, studies recommend that TRPV1 be a target for the development of analgesics [46]. In addition to its location in the sensory neurons of the dorsal root ganglia, TRPV1 is present, to a lower degree, in some cerebral structures, smooth muscle cells, adipocytes, the vascular system, and the gastrointestinal tract. Due to these circumstances, it has not yet been possible to precisely elucidate which sites TRPV1 contributes concretely to thermoregulation, for it also performs a function in regulating metabolism [46,105].

The observation that some TRPV1 knockout mice showed slight difficulties in detecting hot temperatures suggests that other mechanisms participate [106]. Reports describe the existence of a variant of the TRPV1 receptor in the sensory neurons of vampire bats that responds to a lower temperature threshold (~30 °C) and has been correlated with a delicate sensitivity that allows detection of warm-blooded prey [46,107].

TRPV2 is considered a receptor present in A-delta heat-sensitive fibers, whose activation is observed at harmful temperatures above 52 °C [19]. It is also associated with the perception of osmotic stress to mechanical stimuli and pharmacological compounds, like cannabidiol and tetrahydrocannabinol [17]. It is found in pulmonary tissue, the spleen, intestines, dorsal root ganglia, sensory ganglia, and the brain. TRPV2 is the principal receptor expressed in cerebral tissues (e.g., cerebellum, forebrain, and hippocampus). It has been suggested that in addition to its thermo-transductor functions, it may participate in the physiological processes in those cerebral structures [108]. Although TRPV2 presents 50% homology with TRPV1, it is not activated by capsaicin and is more permeable to Ca²⁺ than Na⁺ [36]. The role of this thermosensor has been studied in heat-sensitive nociceptors of rats, where administration of drugs like gadolinium—a TRPV2 antagonist—blocked the influx of cations, thus restraining the activation [108]. In contrast, the 2-aminoethoxydiphenyl borate agonist generates action potentials in the receptors in rats and mice, but not in humans [109]. Despite these findings, doubts persist concerning the participation of this receptor in thermoregulation because studies of TRPV2-deficient mice have not reported any aberrant thermosensitivity [110].

TRPV3 is a cation channel activated at warm temperatures around 34 °C [19], and ranging from 32–40 °C [111]. It belongs to the permeable channels group that are non-selective for Ca²⁺. It is expressed in the skin, keratinocytes, and oral and nasal mucosa, where its activation participates in other processes unrelated to thermosensitivity—such as hair growth, wound healing, itching, and pain perception [112]. Its presence in dermal tissues and the process of hair growth in mammals has led to studies of its participation in the processes of alopecia in hairless rodents. In those animals, mutations generate the absence of hairy structures due to an ionic alteration in the skin and observations of non-responsiveness to thermal stimuli and harmful chemicals [113]. Similarly, experimental results from Ferreira et al. [17] and Moqrich et al. [101] report that mice with genetic deficiencies of this receptor show altered responses to both harmless and harmful thermal stimuli. In contrast, Huang et al. [114] and Miyamoto et al. [115] mention that the TRPV3 and TRPV4 channels in mice do not play a fundamental role in heat perception or processes of heat hyperalgesia since animals deficient in this ionic channel did not manifest a deficit in their responses to heat stimuli. Variability in these results suggest that these phenotypes depend significantly on the genetic background of the mice tested [46].

This is a non-selective polymodal receptor similar to TRPV1 that is activated by moderately warm temperatures in the range of 27–34 °C [19]. In mammals, exposure to this temperature range, and the subsequent activation of TRPV4, generate the influx of Ca²⁺ and an action potential that helps them maintain thermal homeostasis concerning their environment or external stimuli [116]. Other functions of TRPV4 consist of acting as a sensor of hypotonicity [111] and as a mediator of such pathological processes as heat hyperalgesia and mechanical hyperalgesia. In both cases, excessive excitation due to direct damage, like spinal cord compression, leads to nitric oxide generation and a cascade that triggers sensitization processes like hyperalgesia and allodynia [117].

Other examples have been observed in species like mice when the TRPV4 gene is experimentally removed. This procedure revealed a deficit in perception of mechanical and chemical stimuli (tail pressure and the acetic acid test, respectively). However, those same subjects’ thermal responses to harmful heat (50 °C) were not altered, suggesting that one of TRPV4’s main roles is to perceive nociceptive mechanical stimuli rather than participating in thermal sensibility [118]. Like TRPV3, the fact that TRPV4 is heat-activated suggests that it participates in maintaining body temperature; however, no clear evidence exists to support this hypothesis [46].

Since these three receptors require modulation by intermediaries (e.g., ADP-ribose, intracellular Ca²⁺, oxidative stress), and because they are mainly located in the brain, pancreas (TRPM2 specifically in β cells), and immune system cells, they tend to be excluded from the list of primary thermosensitive receptors [17,119]. Nonetheless, some studies have demonstrated their importance as thermal sensors involved in events like fever, where they intervene to prevent hyperthermia and its organic consequences, and their participation in hypothermia development since TRPM2 activation and inhibition modulate body temperature [120]. However, no thermosensory phenotype has been described in mice whose TRPM2 or TRPM4 receptor is inactivated. TRPM5 has been associated with the modulation of taste perception [121], but it remains unknown whether this characteristic acquires an important role in other homeostatic contexts [46].

This receptor responds to a thermal threshold of 17 °C, which is considered harmful cold [19]. Increased intracellular Ca²⁺ concentrations mediate its activation due to the cold more than any direct action. Significantly, depolarization of TRPA1 is considered a fundamental element for inducing the cutaneous vasoconstriction responses that occur when individuals are exposed to low temperatures [122]. Some studies have found differences between species in which cold temperatures have activated TRPA1, like in rats and mice but not in humans or Rhesus monkeys [123]. Moreover, contrasting results have been reported within the same species (mice) since some authors indicate that this receptor contributes to the sensation of cold [124,125], but others rule out any such participation in detecting cold in vivo [126,127] or in mediating cold defense responses [128,129].

This receptor’s responses to harmful thermal (heat) and chemical stimuli have been studied in frogs and lizards, like the green anole (Anolis carolinensis). Saito et al. [130], for example, found that TRPA1 is activated under exposure to both conditions. A finding related to an evolutionary effect in which those species have preserved the TRPA1 channel for the detection of temperatures that significantly alter their homeostasis and, in this way, increase their probability of survival. Similarly, TRPA1 is associated with the transduction of nociceptive stimuli, like those linked to pro-inflammatory transmitters, such as the bradykinins [131].

This ion channel was the first one to be described as a thermoreceptor that specialized in the thermal sensation of cold. Activation of TRPM8 occurs under exposure to temperatures below 25 °C [19]. However, some authors mention that its activation begins at around 33 °C in the sensory neurons and that its signaling velocity increases proportionally to the temperature decrease [17,104,120]. This receptor is present in a subset of afferent neurons in the dorsal root ganglia that innervate the skin and sensory neurons of the trigeminal ganglion that innervate the head, eyes, and cornea [46]. There are also reports that TRPM8 is expressed in adipocytes, as mentioned with regards to TRPV1 [132,133].

Scientific evidence indicates that diverse, selective TRPM8 antagonists produce dose-dependent hypothermia in rats and mice. The topical application of menthol, a TRPM8 agonist, triggers hyperthermia and shivering-like muscle activity, vasoconstriction at the level of the skin of the tail, and heat-seeking behavior [134]. These findings concluded that there is a hypothermic effect dependent on this receptor’s activity [46].

TRPC5 is considered a cold-sensitive receptor that is activated at temperatures of 37–25 °C. It is present in the neurons of the dorsal ganglia and the dorsal lamina of the spinal cord [17]. Despite reports that describe the cold-induced gating of this receptor, studies of mice after ablation of the TRPC5 gene have concluded that those subjects do not present detectable defects related to cold sensitivity. Those findings call the role of this ion channel into question [46].