Molecular taxonomy of nociceptors and pruriceptors

Abstract

1. Introduction The ability to feel the warmth of the sun or the coolness of a breeze on a summer's day; a pleasant caress of skin; to explore the texture, size, and shape of an object; and to feel pain as a mechanism to protect us from what is dangerous around us has fascinated mankind for centuries. Perhaps this fascination is rooted in the fact that the somatic senses of temperature, pain, touch, itch, and proprioception endow us with the ability to continuously stay in contact with the world within and around us. Attempting to explain how we react to heat, the 17th century philosopher René Descartes depicted a thread connecting the skin with the brain and particles of fire pulling on the thread.20 In the 1880s, distinct sensory spots on the skin were recognized and shown to respond to specific stimuli, such as touch, heat, or cold. This finding was taken as evidence for different sensations relying on the existence of distinct nerves tuned to specific types of stimuli.83,94 In the beginning of the 20th century, the discovery of different nerve fiber types with distinct conduction velocities, activation thresholds, and refractory periods made it possible to link specific fiber types to unique qualities of sensation, such as proprioception and different kinds of touch. Unlike innocuous touch and pressure, which are communicated through nerve fibers responding only to mechanical stimuli, noxious stimuli were found to activate a class of polymodal nociceptive nerve fibers responding to several kinds of unpleasant stimuli, including high-threshold mechanical force and intense heat.7,12 This work led to the general idea that the capacity to discriminate perceptual qualities arises from unique functions of a variety of sensory neurons involved in somatic sensation. This is possible because different neuron types are tuned to respond and transduce certain, but not all, kinds of stimuli, such as warm and cool temperatures, noxious heat, noxious cold, light punctate sensation, painful pressure, sharp objects, hair pull, chemical irritants, inflammatory substances, chemical and mechanical itch, and various kinds of touch and vibration.29,38 Apart from providing sensory awareness about our body and its surroundings, the somatosensory system is also essential for other functions we perform effortlessly and without much thought. For example, a continuous flow of information in a sensory–motor feedback loop involving several dozen muscles is necessary to coordinate movements when taking a sip from a glass of water or for the seemingly simple task of walking. Somatosensory neurons are also organized in discreet pathways with autonomic sympathetic and parasympathetic motor neurons driving reflexes involved in physiological homeostasis, such as thermoregulation through reflex control of sweat glands and selective vasoconstrictor systems in muscle and skin active when standing up and during hypothermia, respectively.16,49,74 Furthermore, pleasant and painful sensations involve not only discriminative perception and coordination of efferent reflex functions but also emotional and motivational components important for behavior. For example, social touch such as hugging and caressing induce sensations of pleasantness to facilitate emotional bonding, affiliative behavior, and well-being,82,88 while noxious stimuli not only convey sensory discriminative and protective reflexes but also include an affective-motivational dimension of unpleasantness contributing to long-term behavior avoiding harm.112,125 The existence of molecularly unique neuron types coding for each quality and dimension of somatosensation is unlikely. Instead, summation of activity and inactivity from different types of nerve fibers is likely to contribute to the sensory qualities and dimensions involved. Several recent studies support this conjecture, eg. the discovery of warmth sensation relying on the simultaneous activation of warmth-sensing and inhibition of cold-sensing nerves97; the requirement of different sensory neurons for protective reflexes and affective coping behavior elicited by the same stimuli45; the suppression of noxious cold (−10 to 10°C) by Calca+ neurons18,81; the modulation of touch-evoked itch by Merkel cells and Slc17a8-lineage (low-threshold mechanoreceptor [LTMR]) sensory neurons32,33,108; and alleviation of Npy2r+ neuron-dependent acute pain behavior by the simultaneous activity of the A-LTMR touch neurons.3 With a thorough molecular categorization of sensory neuron types, experiments can be designed with even greater precision, opening possibilities for gaining new, deeper insights into the cellular basis for nociception and pruriception. 2. Categorizing sensory neurons Sensory neurons have historically been classified based on physiological properties, morphology, target innervation, spinal termination, developmental hierarchy, and functional and neurochemical properties (reviewed by Emery and Ernfors, 202029). This work has been instrumental for deciphering how the peripheral sensory nervous system is organized. However, these strategies have measured a dozen or so quantitative features, such as response to cold, heat, and mechanical stimuli; conduction velocity; neuron size; or a handful of marker genes, which might not be sufficient for reliable identification of functional units. By contrast, single-cell RNA sequencing (scRNA-seq) can measure thousands of features, is quantitative, and allows for an unbiased classification of cell types. 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