Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain

Abstract

Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptors before SCI mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations from contusion SCI mice 7 days after injury makes a significant direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

Magnetic resonance neurography in spinal cord injury: Imaging findings and clinical significance

“…The enlargement of DRG in individuals with SCI and BLP suggests that changes at the level of the junction between PNS and CNS are of relevance for the development of neuropathic pain below the level of injury. This assumption of direct PNS involvement in BLP is supported by recent studies that revealed neuronal nociceptive hyperexcitability after SCI in animal models [11, 36]. An association between pain and structural changes of the sciatic nerve could not be found for MRN parameters of the sciatic nerve in our cohort, which may be due to the fact that it is not yet possible to discriminate between sensory and motor fiber lesions in mixed peripheral nerves using MRN.…”

“…The enlargement of DRG in individuals with SCI and BLP suggests that changes at the level of the junction between PNS and CNS are of relevance for the development of neuropathic pain below the level of injury. This assumption of direct PNS involvement in BLP is supported by recent studies that revealed neuronal nociceptive hyperexcitability after SCI in animal models [11,36].…”

“…Among these factors, which include peripheral, spinal, and not least supraspinal mechanisms, central sensitization is considered one of the crucial consequences and a key process in developing neuropathic pain after SCI [10]. In animal studies, the PNS has recently come into focus in BLP, with hyperexcitability in the pain‐mediating sensory system being discussed as a significant factor [11]. In humans, electrophysiological studies only provide limited information about the location, pattern, and extent of nerve lesions, particularly in proximal regions of the PNS [12].…”