Review
Getting in Touch with Mechanical Pain Mechanisms

https://doi.org/10.1016/j.tins.2020.03.004Get rights and content

Highlights

  • Optogenetics and in vivo physiology combined with new behavioral assays have uncovered functionally and anatomically distinct subtypes of mechanical nociceptors.

  • The mechanosensitive ion channel PIEZO2, once thought to only play a role in innocuous touch, plays a nuanced role in mechanical nociception in mammals.

  • Distinct subtypes of innocuous touch receptors interact with mechanical nociceptors to coordinate pain responses under homeostatic and disease conditions.

  • The somatosensory field is rapidly adopting new and advanced methods to study mechanical pain in rodents.

The peripheral somatosensory system bestows mammals with a diverse repertoire of sensory modalities: gentle touch, mechanical pain, itch, thermosensation, and proprioception. The cells and molecules that transduce many of these stimuli have already been characterized. But how somatosensory neurons transduce acutely painful mechanical forces is largely unknown and remains one of the ‘final frontiers’ of sensory neurobiology. In an effort to fill this gap in knowledge, recent studies have identified subpopulations of mechanical pain neurons and uncovered novel modulators of mechanical pain. These studies have greatly advanced our understanding of how noxious mechanical stimuli are detected in mammals. Here, we discuss recent progress in noxious mechanosensation and highlight new behavioral methods to assess mechanical pain.

Section snippets

Pain Is Essential

The survival of all organisms (plants, animals, fungi, microbes) depends on their ability to detect and respond to a wide variety of external stimuli. Chemicals, temperature, mechanical force, and pH are all cues that can indicate a safe or dangerous environment. While nearly all cells possess some ability to sense and respond to these cues, most multicellular animals have a nervous system that is specialized to detect and transduce signals, perform computation, and generate responses to a wide

Recent Studies Identified Molecularly Defined Subpopulations of Mechanonociceptors

Multiple theories attempt to explain how somatosensory modalities are distinguished peripherally and centrally. Of these, the ‘labeled line’ theory of somatosensation [1., 2., 3., 4.] has gained traction, from the study of mutant mice deficient in ion channels and receptors that transduce specific stimuli and from ablation studies where specific subpopulations of neurons are selectively destroyed using chemical or genetic tools. For example, such approaches have identified a peripheral labeled

Modulators and Transducers of Mechanical Nociception

Molecular transducers of noxious mechanical force have been definitively identified only in invertebrate model organisms, including the nematode C. elegans and the fruit fly Drosophila melanogaster. The transduction molecules that have been identified include the degenerin/Epithelial Sodium Channel (DEG/ENaC) DEG-1/MEC-4 in worms [40] and the Transient Receptor Potential (TRP) channel painless along with the mechanosensitive channel piezo in flies [41., 42., 43., 44., 45.]. It was initially

Drawing the Line: Innocuous versus Noxious Touch

The ability to distinguish between painful and nonpainful mechanical stimuli in animal models is essential for studying mechanonociception. In human studies, asking the subject or providing a standardized pain questionnaire may be sufficient to make the distinction [69., 70., 71., 72.]. By contrast, the gold standard for assessing mechanical pain sensitivity in rats and mice has been and still remains the von Frey filament assay (see details next) [73]. In fact, the major advantage of the von

Concluding Remarks and Future Perspectives

Much progress has been made in demystifying the cells and molecules of mechanical pain. However, several important questions remain to be answered (see Outstanding Questions). First and foremost, the identities of the noxious mechanotransducer(s) in mammalian somatosensory neurons remain poorly understood. Furthermore, the pain field has mostly focused on cutaneous pain, although many diseases of the internal organs including pancreatitis, gastrointestinal disorders, arthritis, and bone cancer

Acknowledgments

We would like to thank S. Mali (UC Berkeley), K. Marshall, and I. Daou (The Scripps Research Institute) for critical comments on the manuscript. D.M.B. is supported by the NIH (AR059385; NS07224 and NS098097) and the Howard Hughes Medical Institute.

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    Present address: Department of Neuroscience, Scripps Research, La Jolla, CA 92037, USA

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