Importin α3 regulates chronic pain pathways in peripheral sensory neurons

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6505; pp. 842 - 846
• Main Authors: Marvaldi, Letizia, Panayotis, Nicolas, Alber, Stefanie, Dagan, Shachar Y., Okladnikov, Nataliya, Koppel, Indrek, Di Pizio, Agostina, Song, Didi-Andreas, Tzur, Yarden, Terenzio, Marco, Rishal, Ida, Gordon, Dalia, Rother, Franziska, Hartmann, Enno, Bader, Michael, Fainzilber, Mike
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 14.08.2020; American Association for the Advancement of Science (AAAS)
• Subjects: Analgesia; Analgesics; Animal models; Axonal transport; c-Fos protein; c-Jun protein; Cellular Biology; Chronic pain; Drug development; Drugs; Fear of Success; Imports; Life Sciences; Localization; Narcotics; Neurobiology; Neurons; Neurons and Cognition; Nuclear transport; Pain; Pain perception; Peripheral neuropathy; Perturbation; Pharmaceutical sciences; Pharmacology; Quantitative Methods; Regulators; Sensory neurons; Subcellular Processes; Transcription factors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaz5875

Nuclear transport controls chronic pain Chronic neuropathic pain is debilitating and difficult to treat. Marvaldi et al. now show that chronic pain is regulated by a specific nuclear import factor in peripheral sensory neurons (see the Perspective by Yousuf and Price). Importin α3 is required for nuclear import of the transcription factor c-Fos in sensory neurons, and perturbation of this pathway ameliorates sustained neuropathic pain in mice. Candidate drugs were identified that mimic this pathway and alleviate neuropathic pain in mouse models. Identification of a nuclear transport factor that regulates pain mechanisms offers opportunities for future analgesic development. Science , this issue p. 842 ; see also p. 774 Perturbing c-Fos nuclear import by importin α3 in sensory neurons reduces sensitivity to noxious stimuli and thus leads to analgesia. How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron–specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3–bound c-Fos and importin α3–deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.