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.

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 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.An accurate sense of surface temperature helps animals to perceive object structure and identity. Psychophysical experiments have shown that humans are able to perceive tiny changes in skin cooling with a range between 0.4 and 1.8 ˚C 1,2 . It has, however, proved challenging to assess the perceptual ability of rodents to discriminate small temperature steps at threshold levels.Classical paw withdrawal tests cannot differentiate between reflexive avoidance behavior and sensory perception 3 . Two-plate thermal preference arenas have shown that mice avoid cooler floor temperatures [4][5][6] , but this test has limited spatial and temporal control of the stimulus and lacks fine-grained resolution for near threshold perception. We therefore developed a shortlatency, goal-directed thermal perception task using the glabrous skin of the mouse forepaw.A general dogma is that all somatosensory input, including thermal, is integrated by the primary somatosensory cortex (S1) to form a coherent sensory percept. S1 is necessary for tactile somatosensory perception in rodents [7][8][9][10][11][12][13] . The role of S1 in thermal perception, however, is under debate, 3 with three studies concluding that rodent S1 is not involved [14][15][16] and another concluding that it is 17 . This may be because these studies used large cortical lesions with long recovery and retraining periods in freely moving rats that used facial regions to detect temperature [14][15][16][17] .Likewise, very little is known about the underlying cortical neural processing of non-noxious thermal stimuli in rodents. To the best of our knowledge, only one study, conducted in anesthetized rats stimulating scrotal skin, has shown extracellular responses of cortical neurons to thermal stimulation 18 . At the sensory periphery, a range of primary afferents including myelinated Aβ mechanoreceptors 2,19 , thinly myelinated Aδ-fibers and unmyelinated polymodal C fibers, fire during skin cooling 4,20,21 . Although it is thought that thickly myelinated Aδ fibers are responsible for cooling perception, C fibers ...

Milenkovic N, Wetzel C, Moshourab R, Lewin GR. Speed and temperature dependences of mechanotransduction in afferent fibers recorded from the mouse saphenous nerve. J Neurophysiol 100: 2771-2783, 2008. First published September 24, 2008 doi:10.1152/jn.90799.2008. 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 (Ͻ11 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 Շ100 ms, even with very fast ramp stimuli (2,945 m/s). We examined stimulus response functions and mechanical latency at two different temperatures (24 and 32°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.

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.