Nociceptive tuning by stem cell factor/c-Kit signaling.

The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold and reduction in spiking rate of heat-sensitive nociceptors. Acute activation of c-Kit by its ligand, SCF, resulted in a reduced thermal threshold and potentiation of heat-activated currents in isolated small-diameter neurons and thermal hyperalgesia in mice. SCF-induced thermal hyperalgesia required the TRP family cation channel TRPV1. Lack of c-Kit signaling during development resulted in hypersensitivity of discrete mechanoreceptive neuronal subtypes. Thus, c-Kit can now be grouped with a small family of receptor tyrosine kinases, including c-Ret and TrkA, that control the transduction properties of sensory neurons.

Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).

In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.

Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans.

The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRß, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans.

A somatosensory circuit for cooling perception in mice.

The temperature of an object provides important somatosensory information for animals performing tactile tasks. Humans can perceive skin cooling of less than one degree, but the sensory afferents and central circuits that they engage to enable the perception of surface temperature are poorly understood. To address these questions, we examined the perception of glabrous skin cooling in mice. We found that mice were also capable of perceiving small amplitude skin cooling and that primary somatosensory (S1) cortical neurons were required for cooling perception. Moreover, the absence of the menthol-gated transient receptor potential melastatin 8 ion channel in sensory afferent fibers eliminated the ability to perceive cold and the corresponding activation of S1 neurons. Our results identify parts of a neural circuit underlying cold perception in mice and provide a new model system for the analysis of thermal processing and perception and multimodal integration.

Speed and temperature dependences of mechanotransduction in afferent fibers recorded from the mouse saphenous nerve.

Here we have systematically characterized the stimulus response properties of mechanosensitive sensory fibers in the mouse saphenous nerve. We tested mechanoreceptors and nociceptors with defined displacement stimuli of varying amplitude and velocity. For each sensory afferent investigated we measured the mechanical latency, which is the delay between the onset of a ramp displacement and the first evoked spike, corrected for conduction delay. Mechanical latency plotted as a function of stimulus strength was very characteristic for each receptor type and was very short for rapidly adapting mechanoreceptors (<11 ms) but very long in myelinated and unmyelinated nociceptors (49-114 ms). Increasing the stimulus speed decreased mechanical latency in all receptor types with the notable exception of C-fiber nociceptors, in which mean mechanical latency was not reduced less, similar100 ms, even with very fast ramp stimuli (2,945 microm/s). We examined stimulus response functions and mechanical latency at two different temperatures (24 and 32 degrees C) and found that stimulus response properties of almost all mechanoreceptors were not altered in this range. A notable exception to this rule was found for C-fibers in which mechanical latency was substantially increased and stimulus response functions decreased at lower temperatures. We calculated Q(10) values for mechanical latency in C-fibers to be 5.1; in contrast, the Q(10) value for conduction velocity for the same fibers was 1.4. Finally, we examined the effects of short-term inflammation (2-6 h) induced by carrageenan on nociceptor and mechanoreceptor sensitivity. We did not detect robust changes in mechanical latency or stimulus response functions after inflammation that might have reflected mechanical sensitization under the conditions tested.

Stomatin and sensory neuron mechanotransduction.

Somatic sensory neurons of the dorsal root ganglia are necessary for a large part of our mechanosensory experience. However, we only have a good knowledge of the molecules required for mechanotransduction in simple invertebrates such as the nematode Caenorhabiditis elegans. In C. elegans, a number of so-called mec genes have been isolated that are required for the transduction of body touch. One such gene, mec-2 codes for an integral membrane protein of the stomatin family, a large group of genes with a stomatin homology domain. Using stomatin null mutant mice, we have tested the hypothesis that the founding member of this family, stomatin might play a role in the transduction of mechanical stimuli by primary sensory neurons. We used the in vitro mouse skin nerve preparation to record from a large population of low- and high-threshold mechanoreceptors with myelinated A-fiber (n = 553) and unmyelinated C-fiber (n = 157) axons. One subtype of mechanoreceptor, the d-hair receptor, which is a rapidly adapting mechanoreceptor, had reduced sensitivity to mechanical stimulation in the absence of stomatin. Other cutaneous mechanoreceptors, including nociceptive C-fibers were not affected by the absence of a functional stomatin protein. Patch-clamp analysis of presumptive D-hair receptor mechanoreceptive neurons, which were identified by a characteristic rosette morphology in culture, showed no change in membrane excitability in the absence of the stomatin protein. We conclude that stomatin is required for normal mechanotransduction in a subpopulation of vertebrate sensory neurons.