title: Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold.
abstract: Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown whether these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin, and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch-stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception.
authors.affiliation: Department of Cell Biology and Physiology, UNC Neuroscience Center, The University of North Carolina at Chapel Hill, CB #7545, Chapel Hill, NC 27599, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: McCoy
authors.forename: Bonnie
authors.initials: B
authors.lastname: Taylor-Blake
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Street
authors.forename: Alaine L
authors.initials: AL
authors.lastname: Pribisko
authors.forename: Jihong
authors.initials: J
authors.lastname: Zheng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D003080:Cold Temperature; D004167:Diphtheria Toxin / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006632:Histamine / Q000009:adverse effects; D006358:Hot Temperature; D066298:In Vitro Techniques; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016900:Neurofilament Proteins / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced / Q000473:pathology*; D011744:Pyrimidinones / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012684:Sensory Thresholds / Q000502:physiology; D012867:Skin / Q000294:innervation; D013497:Sural Nerve / Q000187:drug effects / Q000502:physiology*; D050053:TRPM Cation Channels / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D004167:Diphtheria Toxin; D037102:Lectins; D016900:Neurofilament Proteins; D011744:Pyrimidinones; D018015:Receptors, Calcitonin Gene-Related Peptide; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C051774:neurofilament protein H; D049452:Green Fluorescent Proteins; D006632:Histamine; C490483:icilin; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin