The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain.
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 (IB4positive) 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.
Cancer Biology, School of Medicine, University of Nottingham, Nottingham, NG7 7UH, United Kingdom; School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. Electronic address: Richard.Hulse@nottingham.ac.uk.
Richard P
RP
Hulse
School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom.
Robert A R
RA
Drake
Cancer Biology, School of Medicine, University of Nottingham, Nottingham, NG7 7UH, United Kingdom; School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom.
David O
DO
Bates
School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom; School of Life Sciences and Arthritis Research UK Pain Centre, University of Nottingham, Nottingham NG7 7UH, United Kingdom. Electronic address: Lucy.Donaldson@nottingham.ac.uk.
Lucy F
LF
Donaldson
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D004195:Disease Models, Animal; D007839:Functional Laterality; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009186:Myelin Sheath / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D010147:Pain Measurement; D010793:Phthalazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
D000906:Antibodies; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000595779:SRSF1 protein, human; D042461:Vascular Endothelial Growth Factor A; D050598:Vesicular Glutamate Transport Protein 1; D000068103:Serine-Arginine Splicing Factors; C404768:vatalanib
Myelinated; Neuropathic pain; SRPK1; SRSF1; Spinal cord; VEGF-A