The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

Hulse, RP ORCID: https://orcid.org/0000-0002-5193-9822, Drake, RAR, Bates, DO and Donaldson, LF, 2016. The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain. Neurobiology of Disease, 96, pp. 186-200. ISSN 0969-9961

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Abstract

Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord.
Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons. Serine arginine protein kinase 1 (SRPK1) is the principal route of SRSF1 activation. Spinal SRPK1 inhibition attenuated SRSF1 activity, abolished neuropathic pain behaviors and suppressed central sensitization. SRSF1 was principally expressed in large diameter myelinated (NF200-rich) dorsal root ganglia sensory neurons and their excitatory central terminals (vGLUT1 + ve) within the dorsal horn of the lumbar spinal cord.
Expression of pro-nociceptive VEGF-Axxxa within the spinal cord was increased after nerve injury, and this was prevented by SRPK1 inhibition. Additionally, expression of anti-nociceptive VEGF-Axxxb isoforms was elevated, and this was associated with reduced neuropathic pain behaviors. Inhibition of VEGF receptor-2 signaling in the spinal cord attenuated behavioral nociceptive responses to mechanical, heat and formalin stimuli, indicating that spinal VEGF receptor-2 activation has potent pro-nociceptive actions. Furthermore, intrathecal VEGF-A165a resulted in mechanical and heat hyperalgesia, whereas the sister inhibitory isoform VEGF-A165b resulted in anti-nociception. These results support a role for myelinated fiber pathways, and alternative pre-mRNA splicing of factors such as VEGF-A in the spinal processing of neuropathic pain. They also indicate that targeting pre-mRNA splicing at the spinal level could lead to a novel target for analgesic development.

Item Type:	Journal article
Publication Title:	Neurobiology of Disease
Creators:	Hulse, R.P., Drake, R.A.R., Bates, D.O. and Donaldson, L.F.
Publisher:	Academic Press
Date:	December 2016
Volume:	96
ISSN:	0969-9961
Identifiers:	Number Type 10.1016/j.nbd.2016.09.009 DOI
Rights:	Crown Copyright © 2016 Published by Elsevier Inc. This is an open access article under the CC BY license
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	09 Jan 2018 14:05
Last Modified:	09 Jan 2018 14:05
URI:	https://irep.ntu.ac.uk/id/eprint/32361

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