Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity

Gabriel Rusanescu,Jianren Mao

doi:10.1111/jcmm.12648

Gabriel Rusanescu, Jianren Mao

Open Access

https://doi.org/10.1111/jcmm.12648

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Abstract

Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long-term increase in the number of spinal cord laminae I–II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long-term nociception. TrkB agonists, well-known promoters of nociception in the short-term, significantly inhibit long-term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain.

Highlights

Current chronic pain treatments have only limited effectiveness, largely because of an insufficient understanding of pain mechanisms
Fibromyalgia has been genetically linked to chromosome region 17p11.2-q11.2 [2], which encodes some proteins involved in neuropathic pain, such as Erk5 [9], nitric oxide synthase 2 (NOS2) [10] and transient receptor potential vanilloid 2(TRPV2) [11]
Increased nociceptive sensitivity corresponds to an increased number of spinal cord immature neurons. These results demonstrate that the late-phase of increased nociceptive sensitivity after peripheral nerve injury, which would correspond to chronic pain, correlates closely with the time course of spinal cord neurogenesis and subsequent neuronal differentiation and maturation in the spinal cord nociceptive layers

Summary

Introduction

Current chronic pain treatments have only limited effectiveness, largely because of an insufficient understanding of pain mechanisms. Fibromyalgia has been genetically linked to chromosome region 17p11.2-q11.2 [2], which encodes some proteins involved in neuropathic pain, such as Erk5 [9], nitric oxide synthase 2 (NOS2) [10] and transient receptor potential vanilloid 2(TRPV2) [11] These proteins and many others encoded at this locus are involved in neuronal differentiation, including Erk5 [12], NOS2 [13], TRPV2 [14], kinase suppressor of Ras 1 (KSR1) [15] and Foxn4 [16]. Any genetic variation that interferes with neuronal differentiation would result in incomplete neuronal maturation, including in the spinal cord dorsal horn layers that relay nociceptive information.

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