Genotype-selective phenotypic switch in primary afferent neurons contributes to neuropathic pain

Pain is normally mediated by nociceptive A delta and C fibers, while A beta fibers signal touch. However, after nerve injury, A beta fibers may signal pain. Using a genetic model, we tested the hypothesis that phenotypic switching in neurotransmitters expressed by A beta 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 A beta 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. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.