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.

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

“…78 Studies performed with genetically similar rats that expressed either a high (HA) or low (LA) propensity to develop allodynia after peripheral nerve injury showed that the HA rats showed a 10-fold increase in CGRP in large-diameter DRG neurons. 143,144 The increase in CGRP in these neurons corresponded to the development of behavioral signs of tactile allodynia and central sensitization in the HA rats. 143,144 The intrathecal administration of the CGRP receptor antagonist BIBN4096BS (olcegepant) blocked behavioral and neurochemical signs of central sensitization without altering baseline nociceptive thresholds.…”

Nerve injury‐induced calcium channel alpha‐2‐delta‐1 protein dysregulation leads to increased pre‐synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia

“…These changes may include, but are not limited to, dysregulation of genes (Dobremez et al, 2005), suppressing inhibitory and/or enhancing facilitatory descending modulations (Suzuki et al, 2004; Rahman et al, 2008), attenuated glutamate uptake (Binns et al, 2005), and increased pain-inducing peptides in DDH neurons (Nitzan-Luques et al, 2011). However, to the best of our knowledge, it is not yet known if peripheral nerve injury alters excitatory and/or inhibitory miniature synaptic transmission in deep dorsal horn, which can play a critical role in mediating neuropathic allodynia.…”

The influence of spatial pulsed magnetic field application on neuropathic pain after tibial nerve transection in rat

“…Those cells secrete substances involved in the process of degeneration and regeneration and they also can increase sensitivity of nerve endings. Following a peripheral nerve injury, pathological changes can also occur within CNS (Nitzan-Luques et al, 2011) and metabolism of spinal cord neurons changes. Some changes in CNS appear to be associated with enhanced neurotransmission via the NMDA, AMPA and NK-1 receptors (Pickering et al, 2011;Zhuo, 2007).…”