Local translation in primary afferents and its contribution to pain

Abstract

Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. Although the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in most of those who suffer. Most notable among the changes in primary afferents is an increase in excitability or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pronociceptive signaling molecules, such as voltage-gated sodium channels, and decreases in antinociceptive signaling molecules, such as voltage-dependent or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules seem to reflect changes in gene expression as well as posttranslational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process not only is dynamically regulated but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology.

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction

“…Interestingly, Calca mRNA can be locally translated outside of the cell body (e.g. in axons/terminals) of primary sensory neurons ( Russell et al, 2014 , Gale et al, 2022 ), taken together with our RNAseq data this suggests the increased Calca transcript abundance detected in the colon likely reflects Calca localized to free nerve endings of colonic DRG neurons. Taken together with prior findings of elevated CGRP in the skin following SCI ( Eller et al, 2022 ), these data point to a critical role for antidromic activity in primary afferents inducing acute expression and release of CGRPα from terminals in close proximity to ENS neurons and leading to subsequent expression of CGRPβ therein.…”

Short-term plasticity in the spinal nociceptive system

“…This results in an increased response latency in both rodents and humans. 58,132,143 In inflammatory and neuropathic conditions, changes in the excitability of primary afferent fibers have been extensively described (reviewed in Refs. 3, 57, 63, 119, 150)as well as changes in activity-dependent slowing.…”

“…58,132,143 In inflammatory and neuropathic conditions, changes in the excitability of primary afferent fibers have been extensively described (reviewed in Refs. 3,57,63,119,150) as well as changes in activity-dependent slowing. 42 These modifications occurring under inflammatory or neuropathic conditions can result in alterations of frequency coding.…”

Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies

“…Here we show that this prototypical synaptic memory induction pathway can also induce LTH in nociceptor somata. While many transcriptional, translational, and post-translational alterations of nociceptors have been linked to persistent pain (Reichling and Levine, 2009;Ferrari et al, 2015;Price and Ray, 2019;Gale et al, 2022;Ghosh and Pan, 2022), this is the first demonstration of an early induction pathway for nociceptor hyperexcitability that is both transcription-and translation-dependent.…”