title: Touch Receptor-Derived Sensory Information Alleviates Acute Pain Signaling and Fine-Tunes Nociceptive Reflex Coordination.
abstract: Painful mechanical stimuli activate multiple peripheral sensory afferent subtypes simultaneously, including nociceptors and low-threshold mechanoreceptors (LTMRs). Using an optogenetic approach, we demonstrate that LTMRs do not solely serve as touch receptors but also play an important role in acute pain signaling. We show that selective activation of neuropeptide Y receptor-2-expressing (Npy2r) myelinated A-fiber nociceptors evokes abnormally exacerbated pain, which is alleviated by concurrent activation of LTMRs in a frequency-dependent manner. We further show that spatial summation of single action potentials from multiple NPY2R-positive afferents is sufficient to trigger nocifensive paw withdrawal, but additional simultaneous sensory input from LTMRs is required for normal well-coordinated execution of this reflex. Thus, our results show that combinatorial coding of noxious and tactile sensory input is required for normal acute mechanical pain signaling. Additionally, we established a causal link between precisely defined neural activity in functionally identified sensory neuron subpopulations and nocifensive behavior and pain.
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Arcourt
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Louise
authors.initials: L
authors.lastname: Gorham
authors.affiliation: EMBL Monterotondo, Via Ramarini 32, 00016 Monterotondo, Italy.
authors.forename: Rahul
authors.initials: R
authors.lastname: Dhandapani
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Prato
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Taberner
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Max-Delbrueck-Center (MDC) for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Hagen
authors.initials: H
authors.lastname: Wende
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Vijayan
authors.initials: V
authors.lastname: Gangadharan
authors.affiliation: Max-Delbrueck-Center (MDC) for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.affiliation: EMBL Monterotondo, Via Ramarini 32, 00016 Monterotondo, Italy.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Heppenstall
authors.affiliation: Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address: stefan.lechner@pharma.uni-heidelberg.de.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Lechner
mesh_terms: D000200:Action Potentials; D059787:Acute Pain / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D007150:Immunohistochemistry; D008465:Mechanoreceptors / Q000378:metabolism*; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D059225:Nociception / Q000502:physiology*; D059226:Nociceptive Pain; D009619:Nociceptors / Q000378:metabolism*; D062308:Optogenetics; D010146:Pain; D018408:Patch-Clamp Techniques; D059227:Postsynaptic Potential Summation; D060888:Real-Time Polymerase Chain Reaction; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D012018:Reflex; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014110:Touch / Q000502:physiology
chemical_list: D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor
keywords: A-fiber mechanonociceptors; MafA; Npy2r; acute pain; dorsal root ganglion; gate control theory; nociceptor; optogenetics; pinprick pain; primary afferent