Dynamic genotype-selective "phenotypic switching" of CGRP expression contributes to differential neuropathic pain phenotype.
Using a genetic model we demonstrate the role played by "phenotypic switching" of calcitonin gene related peptide (CGRP) expression in axotomized large Aβ afferents in the development of neuropathic pain behavior in rats. After nerve injury both substance P and CGRP are upregulated in Aβ afferents in the corresponding DRGs. It has been proposed that intraspinal release of these neurotransmitters upon gentle stroking of skin drives ascending pain signaling pathways resulting in tactile allodynia. We reported previously that in rat lines genetically selected for high (HA) vs. low (LA) pain phenotype, SP is upregulated equally in both strains, but that CGRP is upregulated exclusively in the pain prone HA line (Nitzan-Luques et al., 2011). This implicates CGRP as the principal driver of tactile allodynia. Here we confirm this conclusion by showing: 1) that the time of emergence of CGRP-IR in DRG Aβ neurons and their central terminals in HA rats matches that of pain behavior, 2) that following spinal nerve lesion (SNL) selective activation of low threshold afferents indeed drives postsynaptic pain-signaling neurons and induces central sensitization in HA rats, as monitored using c-Fos as a marker. These changes are much less prominent in LA rats, 3) that intrathecal (i.t.) administration of CGRP induces tactile allodynia in naïve rats and 4) that i.t. administration of the CGRP-receptor antagonist BIBN4096BS (Olcegepant) attenuates SNL-evoked tactile allodynia, without blocking baseline nociception. Together, these observations support the hypothesis that genotype-selective phenotypic switching of CGRP expression in Aβ afferents following nerve injury is a fundamental mechanism of neuropathic tactile allodynia.
Department of Medical Neurobiology, Faculties of Medicine and Dentistry, The Hebrew University of Jerusalem, Israel. Electronic address: nitzan_a@yahoo.com.
Adi
A
Nitzan-Luques
Anne
A
Minert
Marshall
M
Devor
Michael
M
Tal
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D059333:Central Nervous System Sensitization / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism; D005838:Genotype; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D010641:Phenotype; D051381:Rats
D015740:Calcitonin Gene-Related Peptide