Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions.

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair1, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP+ neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.

Analgesic effect of Photobiomodulation Therapy: An in vitro and in vivo study.

Laser therapy, also known as Photobiomodulation (PBM) is indicated to reduce pain associated with different pathologies and applied using protocols that vary in wavelength, irradiance and fluence. Its mechanisms of action are still unclear and possibly able to directly impact on pain transmission, reducing nociceptor response. In our study, we examined the effect of two specific laser wavelengths, 800 and 970 nm, extensively applied in the clinical context and known to exert important analgesic effects. Our results point to mitochondria as the primary target of laser light in isolated dorsal root ganglion (DRG) neurons, reducing adenosine triphosphate content and increasing reactive oxygen species levels. Specifically, the 800 nm laser wavelength induced mitochondrial dysregulation, that is, increased superoxide generation and mitochondrial membrane potential. When DRG neurons were firstly illuminated by the different laser protocols and then stimulated with the natural transient receptor potential cation channel subfamily V member 1 (TRPV1) ligand capsaicin, only the 970 nm wavelength reduced the calcium response, in both amplitude and frequency. Consistent results were obtained in vivo in mice, by subcutaneous injection of capsaicin. Our findings demonstrate that the effect of PBM depends on the wavelength used, with 800 nm light mainly acting on mitochondrial metabolism and 970 nm light on nociceptive signal transmission.

Src kinase controls signaling pathways in sensory neuron triggered by low-power infrared radiation.

Low-power (non-thermal) infrared (IR) radiation with the wavelength of 10.6 µm activates the Na,K-ATPase transducer function in sensory neurons, which is manifested in decrease of NaV1.8 channel voltage sensitivity at the cellular membrane level and in inhibition of growth of chick embryo dorsal root ganglia neurites at the tissue level. It is shown that the effect of low-power IR radiation is totally blocked by a specific Src kinase inhibitor, PP2. Upon irradiation on the background of PP2, the effective charge of NaV1.8 channel activation gating system does not differ from its control value in patch-clamp experiments, and the area index of sensory ganglia neurites growth remains unchanged as compared with the control in organotypic tissue culture. The data obtained demonstrate that Src kinase is involved in intracellular signaling pathways triggered by CO2 laser low-power IR radiation by the transducer-activated mechanism. This is the first indication that in primary sensory neuron the signals of low-power IR radiation are sensed, amplified, and transduced by the Na,K-ATPase/Src complex and not by G proteins.

Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons.

Mechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury in mice. Mice in which TrkB-Cre-expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB-positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.

The impact of infrared radiation in flight control in the Australian "firebeetle" Merimna atrata.

Infrared (IR) receptors are rare in insects and have only been found in the small group of so-called pyrophilous insects, which approach forest fires. In previous work the morphology of the IR receptors and the physiology of the inherent sensory cells have been investigated. It was shown that receptors are located on the thorax and the abdomen respectively and show an astounding diversity with respect to structure and the presumed transduction mechanism. What is completely missing, however, is any behavioral evidence for the function of the IR receptors in pyrophilous insects. Here we describe the responses of the Australian "firebeetle", Merimna atrata to IR radiation. Beetles in a restrained flight were laterally stimulated with IR radiation of an intensity 20% above a previously determined electrophysiological threshold of the IR organs (40 mW/cm2). After exposure, beetles always showed an avoidance response away from the IR source. Reversible ablation experiments showed that the abdominal IR receptors are essential for the observed behavior. Tests with weaker IR radiation (11.4 mW/cm2) also induced avoidance reactions in some beetles pointing to a lower threshold. In contrast, beetles were never attracted by the IR source. Our results suggest that the IR receptors in Merimna atrata serve as an early warning system preventing an accidental landing on a hot surface. We also tested if another fire specific stimulus, the view of a large smoke plume, influenced the flight. However, due to an unexpected insensitivity of the flying beetles to most visual stimuli results were ambiguous.

Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of paclitaxel and other chemotherapeutic agents. Paclitaxel binds and stabilizes microtubules, but the cellular mechanisms that underlie paclitaxel's neurotoxic effects are not well understood. We therefore used primary cultures of adult murine dorsal root ganglion neurons, the cell type affected in patients, to examine leading hypotheses to explain paclitaxel neurotoxicity. We address the role of microtubule hyperstabilization and its downstream effects. Paclitaxel administered at 10-50nM for 1-3days induced retraction bulbs at the tips of axons and arrested axon growth without triggering axon fragmentation or cell death. By correlating the toxic effects and microtubule stabilizing activity of structurally different microtubule stabilizing compounds, we confirmed that microtubule hyperstabilization, rather than an off-target effect, is the likely primary cause of paclitaxel neurotoxicity. We examined potential downstream consequences of microtubule hyperstabilization and found that changes in levels of tubulin posttranslational modifications, although present after paclitaxel exposure, are not implicated in the paclitaxel neurotoxicity we observed in the cultures. Additionally, defects in axonal transport were not implicated as an early, causative mechanism of paclitaxel's toxic effects on dorsal root ganglion neurons. By using microfluidic chambers to selectively treat different parts of the axon with paclitaxel, we found that the distal axon was primarily vulnerable to paclitaxel, indicating that paclitaxel acts directly on the distal axon to induce degenerative effects. Together, our findings point to local effects of microtubule hyperstabilization on the distal-most portion of the axon as an early mediator of paclitaxel neurotoxicity. Because sensory neurons have a unique and ongoing requirement for distal growth in order to reinnervate the epidermis as it turns over, we propose that the ability of paclitaxel to arrest their growth accounts for the selective vulnerability of sensory neurons to paclitaxel neurotoxicity.

Heat pulse excitability of vestibular hair cells and afferent neurons.

In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in <3 ms and decaying with a time constant of ∼24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68 mV and in 67% of hair cells at -60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability.

Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart.

PURPOSE: Radiation-induced heart disease (RIHD) is a chronic severe side effect of radiation therapy of intrathoracic and chest wall tumors. The heart contains a dense network of sensory neurons that not only are involved in monitoring of cardiac events such as ischemia and reperfusion but also play a role in cardiac tissue homeostasis, preconditioning, and repair. The purpose of this study was to examine the role of sensory nerves in RIHD. METHODS AND MATERIALS: Male Sprague-Dawley rats were administered capsaicin to permanently ablate sensory nerves, 2 weeks before local image-guided heart x-ray irradiation with a single dose of 21 Gy. During the 6 months of follow-up, heart function was assessed with high-resolution echocardiography. At 6 months after irradiation, cardiac structural and molecular changes were examined with histology, immunohistochemistry, and Western blot analysis. RESULTS: Capsaicin pretreatment blunted the effects of radiation on myocardial fibrosis and mast cell infiltration and activity. By contrast, capsaicin pretreatment caused a small but significant reduction in cardiac output 6 months after irradiation. Capsaicin did not alter the effects of radiation on cardiac macrophage number or indicators of autophagy and apoptosis. CONCLUSIONS: These results suggest that sensory nerves, although they play a predominantly protective role in radiation-induced cardiac function changes, may eventually enhance radiation-induced myocardial fibrosis and mast cell activity.

A method for selective ablation of neurons in C. elegans using the phototoxic fluorescent protein, KillerRed.

Specific neuron ablation with laser microbeam has been used in behavioral analysis of Caenorhabditis elegans. However, this method is hard to acquire many ablated worms, and is unable to compare behavioral changes just before and after ablation. Here, we developed an ablation method by using genetically encoded photosensitizer protein, KillerRed, which produces reactive oxygen species by green light irradiation. Ablation of AWA sensory neurons abolished the chemotaxis to AWA specific sensitive attractant, diacetyl, and no functional effect on the other sensory neuron, AWC, which senses benzaldehyde. This ablation method can be useful for analyzing neural in situ.

Photochemical activation of TRPA1 channels in neurons and animals.

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans.

Effect of ionizing radiation in sensory ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.

Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0-G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.

The repair function of the multifunctional DNA repair/redox protein APE1 is neuroprotective after ionizing radiation.

Although exposure to ionizing radiation (IR) can produce significant neurotoxicity, the mechanisms mediating this toxicity remain to be determined. Previous studies using neurons isolated from the central nervous system show that IR produces reactive oxygen species and oxidative DNA damage in those cells. Because the base excision DNA repair pathway repairs single-base modifications caused by ROS, we asked whether manipulating this pathway by altering APE1 expression would affect radiation-induced neurotoxicity. In cultures of adult hippocampal and sensory neurons, IR produces DNA damage as measured by phosphorylation of histone H2A.X and results in dose-dependent cell death. In isolated sensory neurons, we demonstrate for the first time that radiation decreases the capsaicin-evoked release of the neuropeptide CGRP. Reducing APE1 expression in cultured cells augments IR-induced neurotoxicity, whereas overexpressing APE1 is neuroprotective. Using lentiviral constructs with a neuronal specific promoter that selectively expresses APE1s different functions in neurons, we show that selective expression of the DNA repair competent (redox inactive) APE1 constructs in sensory neurons resurrects cell survival and neuronal function, whereas use of DNA-repair deficient (redox active) constructs is not protective. Use of an APE1 redox-specific inhibitor, APX3330, also facilitates neuronal protection against IR-induced toxicity. These results demonstrate for the first time that the repair function of APE1 is required to protect both hippocampal and DRG neuronal cultures--specifically neuronal cells--from IR-induced damage, while the redox activity of APE1 does not appear to be involved.

Cutaneous sensory nerves: mediators of phototherapeutic effects?

Exposures to ultraviolet radiation (UVR) during accidental or voluntary sun exposure or treatment with phototherapy or photochemotherapy have a significant impact on the skin. Many skin diseases such as psoriasis, atopic dermatitis, or cutaneous T-cell lymphoma significantly improve by photo(chemo)therapy, though the mechanisms behind the therapeutic effects of photo(chemo)therapy are still far from understood. Various pathways and means through which the energy of UVR from natural or artificial sources is ultimately transformed into biologic effects within the skin have been suggested and cutaneous sensory nerves, neuropeptides, neurotrophins, and certain nerve-related receptors have been among them. In fact a three-dimensional network of sensory nerve fibers derived from dorsal root ganglia intersperses all layers of the skin including the epidermis. In this forefront of defense against environmental impacts (including UVR) on the skin, sensory nerve fibers become targets by itself and closely contact resident and infiltrating cutaneous cells. Thus, terminals of cutaneous sensory nerve fibers, and neuropeptides within these fibers, are in a central position to participate in mediating therapeutic effects of photo(chemo)therapy.

Sensory neuron sodium current requires nongenomic actions of thyroid hormone during development.

Development of the embryonic nervous system requires thyroid hormone. However, the underlying mechanisms and targets of thyroid hormone action are not well defined. To identify embryonic roles for thyroid hormone we tested for effects on a key neuronal trait, voltage-gated sodium current (I(Na)), in the zebrafish model system. We recorded from Rohon-Beard sensory neurons (RBs) using whole cell voltage-clamp methods. Here, we provide in vivo evidence for thyroid hormone regulation of I(Na). Chronic thyroid hormone application increased RB peak I(Na) density 1.4-fold. However, I(Na) density showed a similar increase within 5 min of an acute hormone application, a time course not expected for a genomic mechanism. Tetraiodothyroacetic acid (tetrac), a thyroid hormone blocker, blocked both chronic and acute effects. Further, the thyroid hormone precursor thyroxine (T4) affected I(Na), yet the traditionally active form triiodothyronine did not. Consequently, we tested for a nonconventional T4 receptor. LM609, a selective antagonist of integrin alphaVbeta3, occluded the rapid effect of T4, implicating a specific integrin dimer as a T4 receptor. Chronic application of either tetrac or LM609 significantly reduced sodium conductance, demonstrating an in vivo requirement for T4-integrin regulation of I(Na). Further, removing endogenous T4 levels via yolkectomy reduced sodium conductance, an effect that was partially rescued by T4 supplementation following surgery. Because RBs mediate the embryonic touch response, we tested for behavioral effects. Tetrac and LM609 significantly reduced the percentage of touch trials eliciting a normal touch response. T4's rapid effect on RB I(Na) highlights the importance of embryonic T4 availability and nongenomic T4 signaling.

Mechanism of signal amplification in the olfactory sensory cilia.

Molecular mechanisms underlying olfactory signal amplification were investigated by monitoring cAMP dynamics in the intact sensory cilia. We saw that [cAMP]i increased superlinearly with time during odorant stimuli for >1 s. This time course was remarkably different from that obtained with the rapid quench method previously applied to the in vitro preparation, in which [cAMP]i change has been reported to be transient. The superlinear increase of [cAMP]i was attributable to a gradual increase of cAMP production rate that was consistent with the thermodynamical interaction model between elemental molecules, as has been revealed on the rod photoreceptor cell. It thus seems likely that the fundamental mechanism for molecular interactions between olfactory transduction elements is similar to that of the rod. In olfaction, however, cAMP production was extremely small (approximately 200,000 molecules/s/cell at the maximum), in contrast to the cGMP hydrolysis in the rod (250,000 molecules/photon). The observed numbers indicate that the olfactory receptor cell has lower amplification at the enzymatic cascade. Seemingly, such low amplification is a disadvantage for the signal transduction, but this unique mechanism would be essential to reduce the loss of ATP that is broadly used for the activities of cells. Apparently, transduction by a smaller number of second-messenger formations would be achieved by the fine ciliary structure that has a high surface-volume ratio. In addition, it is speculated that this low amplification at their enzymatic processes may be the reason why the olfactory receptor cell has acquired high amplification at the final stage of transduction channels, using Ca2+ as a third messenger.

Augmented mechanical response of muscle thin-fiber sensory receptors recorded from rat muscle-nerve preparations in vitro after eccentric contraction.

Unaccustomed strenuous exercise, especially that from eccentric muscular work, often causes muscle tenderness, which is a kind of mechanical hyperalgesia. We developed an animal model of delayed-onset muscle soreness (DOMS) from eccentric muscular contraction (ECC) in rats and demonstrated the existence of muscle tenderness by means of behavioral pain tests and c-Fos protein expression in the spinal dorsal horn. The purpose of the present study was to examine whether the sensitivities of muscle thin-fiber sensory receptors to mechanical, chemical, and thermal stimuli were altered after repetitive ECC in a rat model of DOMS. ECC was caused in the animals by electrical stimulation of the common peroneal nerve innervating the extensor digitorum longus muscle (EDL) while the muscle was being stretched. Activities of single thin-fiber receptors (sensitive to pressure but insensitive to stretch, with conduction velocity slower than 2.0 m/s) were recorded from muscle (EDL)-nerve preparations in vitro 2 days after ECC when mechanical hyperalgesia was at its peak. The mechanical threshold of thin-fiber receptors was found to be very much lower in the ECC preparations than in the nontreated control (CTR) [median 65.4 mN (interquartile range [IQR]; 46.6-122.0 mN) in the CTR preparation vs. 38.2 mN (IQR; 26.8-55.8 mN) in the ECC, P < 0.001]. In addition, the total number of evoked discharges during a ramp mechanical stimulus, taken as an index of the magnitude of the mechanical response, nearly doubled in the ECC preparations compared with the CTR [24.7 spikes (IQR; 14.2-37.1 spikes) in the CTR preparation vs. 54.2 spikes (IQR; 24.3-89.0 spikes) in the ECC, P < 0.001]. In contrast, the numbers of discharges induced by chemical (pH 5.5, lactic acid, adenosine triphosphate, and bradykinin) and thermal (cold and heat) stimuli were not different between the two preparations. These results suggest that augmentation of the mechanical response in muscle thin-fiber sensory receptors might be related to the muscle tenderness in DOMS after ECC.

Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine.

The mechanisms for the induction of primary mechanical hyperalgesia are unclear. We analyzed the neurogenic axon reflex erythema (flare) following phasic mechanical stimulation in normal and in UV-B irradiated skin. In a cross-over double blind design (n = 10), low dose of systemic lidocaine suppressed mechanical hyperalgesia in sunburned skin and in the mechanically induced flare. Phasic mechanical stimulation, even at painful intensities, did not evoke a flare reaction in normal skin. However, stimulation within the UV-B burn dose-dependently provoked an immediate flare reaction. Systemic lidocaine suppressed the mechanically induced flare as well as the mechanical hyperalgesia in sunburned skin, while leaving the impact-induced ratings in normal skin unchanged. Systemic lidocaine reduced these effects of sensitization, but did not reduce ratings in normal skin. As mechanically insensitive ("sleeping") nociceptors have been shown to mediate the axon-reflex in human skin, sensitization of this class of nociceptors might contribute also to the UV-B-induced primary mechanical hyperalgesia.

[Mechanisms of primary reception of electromagnetic waves of optical range]. / Mekhanizmy pervynnoï retseptsiï elektromahnitnykh khvyl' optychnoho diapazonu.

An existence of separate functional system of regulation of electromagnetic balance of organism has been substantiated and a working conception of light therapy has been formulated. As a basis, there is a possibility to use the acupuncture points for input of biologically necessary electromagnetic waves into the system of their conductors in a body that might be considered as a transport facility for energy of the polarized electromagnetic waves. Zones-recipients are organs having an electromagnetic disbalance due to excess of biologically inadequate radiation and being the targets for peroxide oxidation. Foremost, a body has the neurohormonal and immune regulatory systems. Electromagnetic stimulation or modification of functions of the zones-recipients determines the achievement of therapeutic and useful effects, and their combination with local reparative processes allows to attain a clinical goal. We represent own and literary experimental data about the development of physiological responses (analgesia) to BIOPTRON-light exposure on the acupuncture points or biologically active zones. We show the experimental facts in support of a hypothesis that a living organism can perceive an action of the electromagnetic fields of optical range not only via the visual system, but also through the off-nerve receptors (specific energy-sensitive proteins detecting critical changes of energy in cells and functioning as the "sensory" cell systems), as well as via the acupuncture points. It confirms an important role of the electromagnetic waves of optical range in providing normal vital functions of living organisms. A current approach to BIOPTRON light therapy (by polarized polychromatic coherent low energy light) consists in combined (local and system) exposure of the electromagnetic waves within the biologically necessary range.

Reception of low-intensity millimeter-wave electromagnetic radiation by the electroreceptors in skates.

Low intensity millimeter-wave electromagnetic radiation of less than 10 mW cm-2 power intensity has a nonthermal effect on the body and it is widely used in medical practice for treatment of various diseases. Nevertheless, the effect of EMR on biological tissues is not understood. The skin and its sensory receptors are considered to be responsible for EMR reception, but this has yet to be confirmed. The present experiments were designed to study the effect of millimeter-wave electromagnetic radiation on the ampullae of Lorenzini in skates, which are very sensitive to weak electrical stimuli at low frequency. Reception of low-intensity millimeter-wave electromagnetic radiation at 37-55 GHz by the electroreceptors (ampullae of Lorenzini) in the skate has been shown. At a power intensity of 1-5 mW cm-2 irradiating the duct opening at 1-20 mm distance caused a transient increase in the firing rate of a single afferent unit. When the power intensity was increased inhibitory responses were also observed. Some receptors responded with a prolonged excitatory activity lasting up to 30 min to the irradiation of the duct opening. Direct irradiation of the sensory cells produced only an inhibition, probably due to a rise in temperature. It is proposed that millimeter-wave electromagnetic radiation generates a d.c. potential at the vicinity of duct opening which can be detected by the electroreceptors.