The importins of pain

doi:10.1126/science.abd4196

GSTDTAP > 气候变化

DOI	10.1126/science.abd4196
	The importins of pain
	Muhammad Saad Yousuf; Theodore J. Price
	2020-08-14
发表期刊	Science
出版年	2020
英文摘要	Neuropathic pain, which is pain that arises from injury or disease affecting the somatosensory nervous system, affects millions of people with devastating consequences to their well-being. Available therapeutics have limited efficacy, and the underlying mechanisms governing the persistence of this disorder are mysterious. On page 842 of this issue, Marvaldi et al. ([ 1 ][1]) reveal that the nuclear import protein, importin α3, plays a crucial role in maintaining neuropathic pain months after a peripheral nerve injury in mice. Their findings demonstrate that activator protein 1 (AP1) family transcription factors require this nuclear transport complex for entrance to the sensory neuronal nucleus, pointing to a defined set of drug targets for the potential disruption of persistent neuropathic pain. An implication of the findings is that even very long-lasting neuropathic pain can be disrupted with disease-modifying therapeutics. An important advance in the work of Marvaldi et al. is the demonstration of a mechanism that may be responsible for the transition to chronic neuropathic pain. The idea of an acute-to-chronic pain transition has received a lot of attention because clinical trials and clinical experience suggest that drugs used for acute pain are rarely effective for chronic pain ([ 2 ][2]). Acute pain typically has a clear cause, and the amount of pain is usually proportional to the injury or the stimulus. Chronic pain does not always have a clear cause, often persists after an injury has healed, and may be disproportionate to the original injury or to the apparent stimulus. These properties of chronic pain are particularly relevant in chronic neuropathic pain, which is often not recognized until it is chronic, because diagnostics to identify peripheral nerve damage are lacking, and treatment options are ineffective and limited. The neurons that are most commonly affected in neuropathic pain are sensory neurons in the dorsal root ganglion (DRG, which connects to the spinal cord); injury to these sensory DRG neurons was studied by Marvaldi et al. Typically, researchers follow neuropathic pain in animal models for 20 to 30 days after induction with an injury to DRG neurons. The phenotype identified by Marvaldi et al. in mice lacking importin α3 does not emerge until 60 days after peripheral nerve injury, a time point that is rarely explored in such studies. Specifically, reducing importin α3 expression in sensory neurons also resolved neuropathic pain 60 days after nerve injury, as did interfering with AP1 transcription factor signaling using a variety of drugs. Notably, the authors demonstrate that reduction of AP1 signaling in sensory neurons of the DRG is the locus of this effect, in agreement with their importin α3 findings. This strongly supports the conclusion that a late wave of importin α3–facilitated, AP1-driven gene expression in DRG neurons is responsible for persistent neuropathic pain (see the figure). One such gene that appears to be regulated by this late wave of AP1 activity is Syngap1 , which encodes a synaptic protein that might increase the strength of connections between the injured peripheral neurons and the first synapses in the pain pathway in the dorsal horn of the spinal cord in the central nervous system (CNS). This importin α3–driven facilitation of gene expression could presynaptically enhance signaling efficacy between DRG neurons and their targets in the CNS in neuropathic pain, representing an exciting candidate mechanism to explain the transition from acute to chronic neuropathic pain. A critical insight from this work is a reconceptualization of the acute-to-chronic neuropathic pain transition. It is broadly accepted that neuropathic pain is initially driven by the emergence of spontaneous or ectopic activity in DRG sensory neurons, including pain-sensing neurons called nociceptors ([ 3 ][3]–[ 5 ][4]). However, once neuropathic pain becomes chronic, it is widely thought that there is a shift from changes in the peripheral nervous system toward independent CNS-mediated mechanisms, suggesting a “centralization” of neuropathic pain when it becomes chronic. The study of Marvaldi et al. does not upend this concept, but it places focus back on DRG neurons in the peripheral nervous system as the key drivers of chronic neuropathic pain. This work persuasively demonstrates that there are likely distinct transcriptional programs in DRG sensory neurons that are responsible for different phases of neuropathic pain. This complexity may contribute to why the disease is so challenging to treat, especially because most researchers have focused on the acute phase of injury. The work also parallels recent clinical findings demonstrating that peripheral nerve block with regional injection of lidocaine or lidocaine derivatives is almost always effective for alleviating neuropathic pain, even in people who have suffered for long periods of time ([ 6 ][5], [ 7 ][6]). Bringing our understanding of mechanisms in line with clinical observations is promising from the view of developing better therapeutics. Injury to peripheral nerves turns on a regeneration program that is frequently accompanied by emergence of neuropathic pain. One of the earliest signaling events at the site of DRG axon injury is the local translation of the protein kinase mammalian target of rapamycin (mTOR), which then drives reprogramming of translational capacity in the axon ([ 8 ][7]). These events are critical for regeneration, but they also lead to local synthesis of transcription factors, such as cyclic adenosine monophosphate response element-binding protein (CREB) ([ 9 ][8]), and nuclear import factors, such as importin β1 ([ 10 ][9]), which then act as positive, retrograde signals linking axonal injury to transcriptional changes in the neuronal nucleus, paving the way for neuropathic pain. The study of Marvaldi et al. suggests that these transcriptional changes may be coordinated in temporal waves that are ultimately controlled by a nuclear membrane gatekeeper (importin α3). Early signals may be mediated by CREB or other transcription factors, whereas late signals are controlled by importin α3 and AP1 transcription factors, FOS and JUN. Sequencing of DRGs taken from humans with neuropathic pain demonstrate up-regulation in the expression of FOS and JUN in a subset of male neuropathic pain patients ([ 5 ][4]). This clinical parallel emphasizes the translational value of these findings. ![Figure][10] Importin α3 regulates persistent pain following nerve injury Different combinations of activator protein 1 (AP1) transcription factors and importins are likely responsible for early versus chronic phases of neuropathic pain. GRAPHIC: KELLIE HOLOSKI/ SCIENCE Marvaldi et al. lay a new foundation for thinking about neuropathic pain. Focusing on the therapeutic potential of these mechanistic insights has potential for development of long sought-after disease-modifying therapeutics in this clinical space. The work demonstrates that drugs targeting AP1 transcription factors can be effective in reducing neuropathic pain in mice. Some of these drugs are already in existence and could be repurposed for pain treatment. Indeed, Marvaldi et al. intentionally considered drug repurposing when choosing AP1 inhibitors to study. Therefore, Marvaldi et al. have identified some excellent candidates for future study, namely sulmazole and sulfamethizole. 1. [↵][11]1. L. Marvaldi et al ., Science 369, 842 (2020). [OpenUrl][12][Abstract/FREE Full Text][13] 2. [↵][14]1. T. J. Price et al ., Nat. Rev. Neurosci. 19, 383 (2018). [OpenUrl][15][CrossRef][16][PubMed][17] 3. [↵][18]1. L. Djouhri et al ., J. Neurosci. 26, 1281 (2006). [OpenUrl][19][Abstract/FREE Full Text][20] 4. 1. J. Serra et al ., Pain 153, 42 (2012). [OpenUrl][21][CrossRef][22][PubMed][23][Web of Science][24] 5. [↵][25]1. R. Y. North et al ., Brain 142, 1215 (2019). [OpenUrl][26][CrossRef][27][PubMed][28] 6. [↵][29]1. A. Vaso et al ., Pain 155, 1384 (2014). [OpenUrl][30][CrossRef][31][PubMed][32] 7. [↵][33]1. S. Haroutounian et al ., Pain 155, 1272 (2014). [OpenUrl][34][CrossRef][35][PubMed][36][Web of Science][37] 8. [↵][38]1. M. Terenzio et al ., Science 359, 1416 (2018). [OpenUrl][39][Abstract/FREE Full Text][40] 9. [↵][41]1. O. K. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/288066
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Muhammad Saad Yousuf,Theodore J. Price. The importins of pain[J]. Science,2020.
APA	Muhammad Saad Yousuf,&Theodore J. Price.(2020).The importins of pain.Science.
MLA	Muhammad Saad Yousuf,et al."The importins of pain".Science (2020).