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Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord.

ABSTRACT: Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontaneous. Given that one in three chronic pain patients do not respond to the treatments currently available, the need for more effective analgesics is evident. Two principal obstacles to the development of novel analgesic therapies are our limited understanding of how neuronal circuits that comprise these pain pathways transmit and modulate sensory information under normal circumstances and how these circuits change under pathological conditions leading to chronic pain states. In this review, we focus on the role of inhibitory interneurons in setting pain thresholds and, in particular, how disinhibition in the spinal dorsal horn can lead to aberrant sensory processing associated with chronic pain states.

SUBMITTER: Hughes DI

PROVIDER: S-EPMC7641291 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord.

Hughes David I DI Todd Andrew J AJ

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20200701 3

Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontan ...[more]

PMID: 33029722

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Project description:Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2 (CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury (SCI). We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in (CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system. Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice. Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI. However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice. Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated. Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses. Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522. All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan (2017-A027 approved on March 21, 2017; 2018-A003 approved on March 25, 2018; 2019-A026 approved on March 25, 2019).

Dataset Information

Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord.

Publications

Central Nervous System Targets: Inhibitory Interneurons in the Spinal Cord.

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