The skin covering the human palm and other specialized tactile organs contains a high density of mechanosensory corpuscles tuned to detect transient pressure and vibration. These corpuscles comprise a sensory afferent neuron surrounded by lamellar cells. The neuronal afferent is thought to be the mechanical sensor, whereas the function of lamellar cells is unknown. We show that lamellar cells within Meissner and Pacinian corpuscles detect tactile stimuli. We develop a preparation of bill skin from tactile-specialist ducks that permits electrophysiological recordings from lamellar cells and demonstrate that they contain mechanically gated ion channels. We show that lamellar cells from Meissner corpuscles generate mechanically evoked action potentials using R-type voltage-gated calcium channels. These findings provide the first evidence for R-type channel-dependent action potentials in non-neuronal cells and demonstrate that lamellar cells actively detect touch. We propose that Meissner and Pacinian corpuscles use neuronal and non-neuronal mechanoreception to detect mechanical signals.

Feketa VV, Balasubramanian A, Flores CM, Player MR, Marrelli SP. Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. Am J Physiol Regul Integr Comp Physiol 305: R1040-R1050, 2013. First published September 4, 2013 doi:10.1152/ajpregu.00296.2013.-Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 Ϯ 1.8; compound 5: 23.8 Ϯ 2.0; TRPM8 KO: 19.7 Ϯ 1.9 V·s/min), tachycardia (⌬HR ϭ 124 Ϯ 31; 121 Ϯ 13; 121 Ϯ 31 beats/min) and drop in core temperature (Ϫ3.6 Ϯ 0.1; Ϫ3.4 Ϯ 0.4; Ϫ3.6 Ϯ 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 Ϯ 3.0 vs. DHC: 5.1 Ϯ 2.0 V·s/min), tachycardia (⌬HR ϭ 204 Ϯ 25 vs. 3 Ϯ 35 beats/min) and produced a profound drop in core temperature (Ϫ2.2 Ϯ 0.6 vs. Ϫ8.9 Ϯ 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia. therapeutic hypothermia; pharmacological hypothermia; shivering; transient receptor potential; physical cooling; electromyography; dihydrocapsaicin MILD DECREASE OF CORE TEMPERATURE to 32-34°C has been shown to effectively protect the brain from ischemia and has become a basis for the clinical method of therapeutic hypo-

SUMMARYA major challenge in biology is to link cellular and molecular variations with behavioral phenotypes. Here, we studied somatosensory neurons from a panel of bird species from the family Anatidae, known for their tactile-based foraging behavior. We found that tactile specialists exhibit a proportional expansion of neuronal mechanoreceptors in trigeminal ganglia. The expansion of mechanoreceptors occurs via neurons with intermediately and slowly inactivating mechanocurrent. Such neurons contain the mechanically gated Piezo2 ion channel whose expression positively correlates with the expression of factors responsible for the development and function of mechanoreceptors. Conversely, Piezo2 expression negatively correlates with expression of molecules mediating the detection of temperature and pain, suggesting that the expansion of Piezo2-containing mechanoreceptors with prolonged mechanocurrent occurs at the expense of thermoreceptors and nociceptors. Our study suggests that the trade-off between neuronal subtypes is a general mechanism of tactile specialization at the level of somatosensory system.

Therapeutic hypothermia has emerged as a remarkably effective method of neuroprotection from ischemia and is being increasingly used in clinics. Accordingly, it is also a subject of considerable attention from a basic scientific research perspective. One of the fundamental problems, with which current studies are concerned, is the optimal method of inducing hypothermia. This review seeks to provide a broad theoretical framework for approaching this problem, and to discuss how a novel promising strategy of pharmacological modulation of the thermosensitive ion channels fits into this framework. Various physical, anatomical, physiological and molecular aspects of thermoregulation, which provide the foundation for this text, have been comprehensively reviewed and will not be discussed exhaustively here. Instead, the first part of the current review, which may be helpful for a broader readership outside of thermoregulation research, will build on this existing knowledge to outline possible opportunities and research directions aimed at controlling body temperature. The second part, aimed at a more specialist audience, will highlight the conceptual advantages and practical limitations of novel molecular agents targeting thermosensitive Transient Receptor Potential (TRP) channels in achieving this goal. Two particularly promising members of this channel family, namely TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), will be discussed in greater detail.

Objective Mild decrease in core temperature (therapeutic hypothermia; TH) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing TH trigger a cold-defense response which must be countered by sedatives, muscle paralytics and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential (TRP) channels involved in thermoregulation, TRPV1 and TRPM8. Design Controlled prospective animal study. Subjects Conscious unrestrained young and aged male mice. Setting Research laboratory at academic medical center. Interventions Mice were treated with the TRPV1 agonist dihydrocapsaicin (DHC), a TRPM8 inhibitor (“compound 5”) or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders. Measurements and Main Results TRPV1 agonist DHC produced a dose-dependent (2–4 mg/kg, s.c.) drop in Tcore. A loading dose followed by continuous infusion of DHC produced a rapid and prolonged (>6 hrs) drop of Tcore within the therapeutic range (32–34 °C). The hypothermic effect of DHC was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor “compound 5” (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8 °C). When “compound 5” (30 mg/kg) was combined with DHC (1.25–2.5 mg/kg), the drop in Tcore was amplified and prolonged. Conclusions Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.