Reversal of peripheral nerve injury-induced neuropathic pain and cognitive dysfunction via genetic and tomivosertib targeting of MNK.

Abstract

Neuropathic pain caused by nerve injury presents with severe spontaneous pain and a variety of comorbidities, including deficits in higher executive functions. None of these clinical problems are adequately treated with current analgesics. Targeting of the mitogen-activated protein kinase-interacting kinase (MNK1/2) and its phosphorylation target, the mRNA cap binding protein eIF4E, attenuates many types of nociceptive plasticity induced by inflammatory mediators and chemotherapeutic drugs but inhibiting this pathway does not alter nerve injury-induced mechanical allodynia. We used genetic manipulations and pharmacology to inhibit MNK-eIF4E activity in animals with spared nerve injury, a model of peripheral nerve injury (PNI)-induced neuropathic pain. We assessed the presence of spontaneous pain using conditioned place preference. We also tested performance in a medial prefrontal cortex (mPFC)-dependent rule-shifting task. WT neuropathic animals showed signs of spontaneous pain and were significantly impaired in the rule-shifting task while genetic and pharmacological inhibition of the MNK-eIF4E signaling axis protected against and reversed spontaneous pain and PNI-mediated cognitive impairment. Additionally, pharmacological and genetic inhibition of MNK-eIF4E signaling completely blocked and reversed maladaptive shortening in the length of axon initial segments (AIS) in the mPFC of PNI mice. Surprisingly, these striking positive outcomes on neuropathic pain occurred in the absence of any effect on mechanical allodynia, a standard test for neuropathic pain efficacy. Our results illustrate new testing paradigms for determining preclinical neuropathic pain efficacy and point to the MNK inhibitor tomivosertib (eFT508) as an important drug candidate for neuropathic pain treatment.

• Authors: Stephanie Shiers, Juliet Mwirigi, Grishma Pradhan, Moeno Kume, Bryan Black, Paulino Barragan-Iglesias, Jamie K Moy, Gregory Dussor, Joseph J Pancrazio, Sven Kroener, Theodore J Price
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 45 Issue 3 Pg. 524-533 (02 2020) ISSN: 1740-634X [Electronic] England
• PMID: 31590180 (Publication Type: Journal Article)

Chemical References

• Pyridines
• Pyrimidines
• Mitogen-Activated Protein Kinases
• tomivosertib

Topics

• Animals
• Cognitive Dysfunction (enzymology, genetics, therapy)
• Drug Delivery Systems (methods)
• Female
• Gene Targeting (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Neuralgia (enzymology, genetics, therapy)
• Peripheral Nerve Injuries (enzymology, genetics, therapy)
• Prefrontal Cortex (drug effects, enzymology)
• Pyridines (administration & dosage)
• Pyrimidines (administration & dosage)