Revisiting PNS Plasticity: How Uninjured Sensory Afferents Promote Neuropathic Pain

Abstract

Despite the widespread study of how injured nerves contribute to chronic pain, there are still major gaps in our understanding of pain mechanisms. This is particularly true of pain resulting from nerve injury, or neuropathic pain, wherein tactile or thermal stimuli cause painful responses that are particularly difficult to treat with existing therapies. Curiously, this stimulus-driven pain relies upon intact, uninjured sensory neurons that transmit the signals that are ultimately sensed as painful. Studies that interrogate uninjured neurons in search of cell-specific mechanisms have shown that nerve injury alters intact, uninjured neurons resulting in an activity that drives stimulus-evoked pain. This review of neuropathic pain mechanisms summarizes cell-type-specific pathology of uninjured sensory neurons and the sensory ganglia that house their cell bodies. Uninjured neurons have demonstrated a wide range of molecular and neurophysiologic changes, many of which are distinct from those detected in injured neurons. These intriguing findings include expression of pain-associated molecules, neurophysiological changes that underlie increased excitability, and evidence that intercellular signaling within sensory ganglia alters uninjured neurons. In addition to well-supported findings, this review also discusses potential mechanisms that remain poorly understood in the context of nerve injury. This review highlights key questions that will advance our understanding of the plasticity of sensory neuron subpopulations and clarify the role of uninjured neurons in developing anti-pain therapies.

Neurodynamic Treatment Promotes Mechanical Pain Modulation in Sensory Neurons and Nerve Regeneration in Rats

“…We have also defined that NDT promotes neuronal cell survival in the DRG cultures, speeds up neurites outgrowth and reduces intraneural fibrosis, according to the available evidence reported in the literature on NDT used in clinical and preclinical studies [ 36 , 42 , 48 , 58 , 59 , 78 , 79 , 80 , 81 ]. In addition, our data show that NDT prevents ipsilateral and contralateral mechanical threshold lowering induced by the nerve crush injury, which is a phenomenon sustained by a multilevel PNS plasticity and systemic processes [ 82 , 83 , 84 , 85 ].…”

“…Our data provide evidence that NDT prevents sensitization to normal mechanical stimuli that we observed by the significantly lowered mechanical threshold in the untreated rats on both sides, suggesting that NDT may activate metameric or systemic processes, avoiding nerve sensitization to mechanical stimuli. Even if some pain behaviours related to contralateral DRG changes after a nerve injury, as described in the literature [ 82 , 84 , 85 , 104 ], only a few clinical studies have shown in healthy subjects that NDT improves the mobility of the contralateral untreated limb [ 105 , 106 ]. We provide evidence that NDT administered before nerve injury modulates pain with a significant antiallodynic effect for mechanical stimuli 19 days after nerve injury, with no significant difference in TACAN gene expression in the ipsilateral and contralateral DRG assessed 24 days after the injury when compared to controls.…”

Targeted ubiquitination of sensory neuron calcium channels reduces the development of neuropathic pain

“…1 ) ( 21 , 22 ). In neuropathic pain, injured nerves and nonneuronal cells such as glia and mast cells release factors (e.g., substance P, CGRP, bradykinin) that cause uninjured nearby neurons to undergo neurophysiological and neurochemical changes that increase their intrinsic excitability and expression of pain-associated molecules ( 23 ). Signal integration occurs in the spinal cord and involves complex circuits and cell types including numerous excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) interneurons and descending inhibitory inputs ( 24 , 25 ).…”

scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons ofPirt-EGFPfmice in neuropathic pain condition

“…Increasing evidence has suggested that uninjured DRG neurons also play important roles in neuropathic pain, and show robust neurochemical and functional changes after nerve injury (Kalpachidou et al, 2021; Obata et al, 2003; Pertin et al, 2005; Tran & Crawford, 2020). Strikingly, our analysis showed for the first time that uninjured ( Sprr1a − ) neurons in NP1, PEP5, NF1, and NF2 clusters also undergo subtype-specific changes in gene expression after CCI, as compared to those in the sham group.…”

“…Axotomized neurons may exhibit the most profound gene expression changes that are important for regeneration. Nevertheless, neighboring uninjured DRG neurons also show significant functional changes (e.g., hyperexcitability) and contribute to dysesthesia and evoked pain hypersensitivity as a result of the remaining peripheral innervations (Djouhri et al, 2012; Kalpachidou et al, 2021; Obata et al, 2003; Tran & Crawford, 2020). Details of subtype-specific changes in DRG neurons under neuropathic pain conditions are currently only partially known.…”