title: Genotype-selective phenotypic switch in primary afferent neurons contributes to neuropathic pain.
abstract: Pain is normally mediated by nociceptive Aδ and C fibers, while Aβ fibers signal touch. However, after nerve injury, Aβ fibers may signal pain. Using a genetic model, we tested the hypothesis that phenotypic switching in neurotransmitters expressed by Aβ afferents might account for heritable differences in neuropathic pain behavior. The study examined selection-line rats in which one line, high autotomy (HA), shows higher levels of spontaneous pain in the neuroma neuropathy model, and of tactile allodynia in the spinal nerve ligation (SNL) model, than the companion low autotomy (LA) line. Changes in calcitonin gene-related peptide (CGRP) and Substance P expression were evaluated immunohistochemically in L4 and L5 dorsal root ganglia 7 days after SNL surgery. Expression of CGRP was decreased in axotomized small- and medium-diameter neurons in both rat lines. However, in HA but not in LA rats, there was a tenfold increase in CGRP immunoreactivity (CGRP-IR) in large-diameter neurons. Corresponding changes in CGRP-IR in axon terminals in the nucleus gracilis were also seen. Finally, there were indications of enhanced CGRP neurotransmission in deep laminae of the dorsal horn. Substance P immunoreactivity was also upregulated in large-diameter neurons, but this change was similar in the 2 lines. Our findings suggest that phenotypic switching contributes to the heritable difference in pain behavior in HA vs LA rats. Specifically, we propose that in HA rats, but less so in LA rats, injured, spontaneously active Aβ afferents both directly drive CGRP-sensitive central nervous system pain-signaling neurons and also trigger and maintain central sensitization, hence generating spontaneous pain and tactile allodynia.
authors.affiliation: Department of Medical Neurobiology, Faculties of Medicine and Dentistry, The Hebrew University of Jerusalem, Jerusalem, Israel Department of Cell and Developmental Biology, Institute of Life Science, Faculty of Natural Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Nitzan-Luques
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
authors.forename: Michael
authors.initials: M
authors.lastname: Tal
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D005838:Genotype; D006930:Hyperalgesia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009437:Neuralgia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D010641:Phenotype; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity