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Published in final edited form as: Exp Neurol. 2020 Dec 16;337:113572. doi: 10.1016/j.expneurol.2020.113572

Nerve trauma-caused downregulation of opioid receptors in primary afferent neurons: molecular mechanisms and potential managements

Bi-Xin Zheng 1, Ayma Malik 2, Ming Xiong 1, Alex Bekker 1, Yuan-Xiang Tao 1,3,4
PMCID: PMC7870536  NIHMSID: NIHMS1657447  PMID: 33340498

Abstract

Neuropathic pain is the most common clinical disorder destroying the quality of patient life and leading to a marked economic and social burden. Opioids are still last option for pharmacological treatment of this disorder, but their antinociceptive effects are limited in part due to the downregulation of opioid receptors in the primary afferent neurons after peripheral nerve trauma. How this downregulation occurs is not completely understood, but recent studies have demonstrated that peripheral nerve trauma drives the alterations in epigenetic modifications (including DNA methylation, histone methylation and mciroRNAs), expression of transcription factors, post-transcriptional modifications (e.g., RNA methylation) and protein translation initiation in the neurons of nerve trauma-related dorsal root ganglion (DRG) and that these alternations may be associated with nerve trauma-caused downregulation of DRG opioid receptors. This review presents how opioid receptors are downregulated in the DRG after peripheral nerve trauma, specifically focusing on distinct molecular mechanisms underlying transcriptional and translational processes. This review also discusses how this downregulation contributes to the induction and maintenance of neuropathic pain. A deeper understanding of these molecular mechanisms likely provides a novel avenue for prevention and/or treatment of neuropathic pain.

Keywords: Opioid receptors, downregulation, molecular mechanisms, neuropathic pain, dorsal root ganglion

1. Introduction

Neuropathic pain caused by the damages in the peripheral or central nervous system is the most common disorder in clinic, estimated to affect about 7% of the world population.(van et al., 2014) It significantly impacts the patients’ quality of life and produces a marked social and economic burden.(van et al., 2014) Although non-opioid medications (e.g., antidepressants, skeletal muscle relaxants, non-steroidal anti-inflammatory drugs, and membrane stabilization agents) were used in current therapeutic strategies, opioids are the last option for pharmacological management of this disorder. Unfortunately, about two-thirds of neuropathic pain patients report unsatisfactory pain control.(O’Connor, 2009) Moreover, the majority of the patients need repeated and prolonged administration of opioids and higher doses of opioids to achieve pain relief. Such opioid regimens cause numerous adverse side effects, including nausea and vomiting, respiratory depression, constipation, paradoxical hyperalgesia, analgesic tolerance and addiction.(Bekhit, 2010; Meyer et al., 2014; Reinhart et al., 2018) Over the past few decades, a significant increase in opioid prescriptions in the United States has been associated with robust elevations in the opioid-related mortality and incidence of addition, which constitutes current “opioid crisis”.(Meyer et al., 2014) Therefore, it is highly important to better understand the mechanisms of how opioids present unsatisfactory effects under neuropathic pain conditions.

There are four endogenous opioid receptors (ORs) in the cells of body: μ-opioid receptor (MOR) encoded by Oprm1 gene, δ-opioid receptor (DOR) encoded by Oprd1 gene, κ-opioid receptor (KOR) encoded by Oprk1 gene, and the nociceptin/orphanin FQ receptor (NOR) encoded by Oprl1).(Cox et al., 2015) Among these receptors, approximately 49–58% primary sequences are same and the structures are highly similar.(Cox et al., 2015) ORs belong to the G protein–coupled receptors (GPCRs) with 7-transmembranes and are expressed at virtually all neural loci (from peripheral primary sensory neurons to spinal and brain circuits). ORs are activated by either endogenous opioid peptides (e.g., enkephalins, β-endorphin and dynorphins) or exogenous opioid agonists (such as morphine, heroin, and fentanyl). The ORs regulate neuronal activities and produce the analgesia through OR-triggered activation or inhibition of many intracellular signaling pathways, including G protein-dependent signaling pathways (e.g., inhibition of adenylyl cyclase-mediated cAMP expression/activation, inhibition of Ca2+ current, and activation of G-protein-gated inwardly rectifying potassium).(Liu and Anand, 2001) Thus, the ORs are the key players in opioid-induced analgesic effects.

Several previous studies reveal that potent opioid analgesia is mediated at least in part by peripheral ORs located in primary afferent neurons of dorsal root ganglion (DRG) and trigeminal ganglion following tissue injury or nerve trauma.(Guan et al., 2008; Lewanowitsch et al., 2006; Liu and Anand, 2001; Shinoda et al., 2007) The ORs are expressed on DRG neuronal bodies, central terminals of their primary afferents and peripheral terminals of their peripheral processes.(Coggeshall et al., 1997; Truong et al., 2003) The sensitivity to opiates, particularly MOR agonists, is significantly increased following inflammation.(Stanfa et al., 1992) This increase may be attributed to the activation of endogenous ORs in DRG and spinal cord under the conditions of inflammation.(Hassan et al., 1993; Stein and Lang, 2009) In contrast, preclinical and clinical observations showed reduced efficacy of MOR agonists after peripheral nerve trauma.(Benedetti et al., 1998; Wu et al., 2008) This lower efficacy may be due to nerve trauma-caused OR downregulation in the neurons of nerve trauma-related DRG. Time-dependent reductions of the ORs at both mRNA and protein levels were observed in nerve trauma-related DRG after unilateral fifth lumbar (L5) spinal nerve ligation (SNL), partial sciatic nerve ligation, axotomy, and chronic constriction injury (CCI) of unilateral sciatic nerve.(Kohno et al., 2005; Lee et al., 2011; Obara et al., 2007; Rashid et al., 2004; Zhang et al., 1998) The mechanisms by which the ORs are downregulated in these DRG neurons following peripheral nerve trauma are still elusive, but recent evidence indicates that this downregulation occurs at both transcriptional and translational levels involving distinct molecular mechanism under neuropathic pain conditions. Exploring these molecular mechanisms may provide a new avenue for improving efficacy of OR agonists following peripheral nerve trauma.

In this review, we focus on how peripheral nerve trauma causes the downregulation of the ORs in first-order sensory neurons of DRG. The distinct molecular mechanisms underlying this downregulation are highlighted. We also discuss how this downregulation is involved in the induction and maintenance of neuropathic pain pathogenesis. Potential therapeutic treatments of this disorder in regard to these molecular mechanisms are illustrated.

2. Epigenetic mechanisms of DRG OR downregulation under neuropathic pain conditions

2.1. Role of DNMT3a-triggered DNA methylation in nerve trauma-caused epigenetic silencing of ORs in DRG neurons

DNA methylation, one type of epigenetic modifications, inhibits gene transcriptional expression predominantly by serving as docking sites for transcription repressors (e.g., the family of methyl-CpG-binding domain (MBD) proteins, including MBD1–4 and methyl CpG binding protein 2) and/or physically impeding the binding of transcription factors.(Liang et al., 2015; Poetsch and Plass, 2011) DNA methylation occurs primarily by a group of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a, and DNMT3b.(Liang et al., 2015; Poetsch and Plass, 2011) DNMTs also contain an inactivated isoform DNMT2 and DNMT3L that lacks the conserved catalytic domain.(Chahrour et al., 2008; Siedlecki and Zielenkiewicz, 2006) Conventionally, DNMT3a and DNMT3b are responsible for de novo methylation to reversibly add the methyl group into unmethylated DNA, whereas DNMT1 functions as the primary DNMT to maintain DNA methylation that already exists in the genome.(Jeltsch, 2006; Siedlecki and Zielenkiewicz, 2006) Recent evidence shows that DNMT1, like DNMT3a, might also have de novo methylation activity.(Feng et al., 2010; Sun et al., 2019; Vilkaitis et al., 2005) The level of the DNA methylation in the genes is also controlled by a family of the ten-eleven translocation methylcytosine dioxygenases (TETs) including TET1–3. TET1–3 cause the conversion of 5mC (5-methylcytosine) to 5hmC (5-hydroxymethylcytosine), leading to the promotion of DNA demethylation and gene transcriptional activation.(Bian et al., 2014)

Both DNMT1 and DNMt3a (not DNMT3b) in the DRG participate in neuropathic pain induction and maintenance.(Sun et al., 2019; Zhao et al., 2017) DRG neurons, but not satellite cells, express DNMT1 and DNMT3a.(Sun et al., 2019; Zhao et al., 2017) Peripheral nerve trauma increased the levels of their mRNA and protein in nerve trauma-related DRG.(Sun et al., 2019; Zhao et al., 2017) (Fig. 1) Blocking these increases prevented neuropathic pain induction and maintenance.(Sun et al., 2019; Zhao et al., 2017) Additionally, DRG overexpression of DNMT1 or DNMT3a produced the enhanced responses to nociceptive stimuli.(Sun et al., 2019; Zhao et al., 2017) Interestingly, the mechanisms underlying their actions under neuropathic pain conditions are not complete similar. The increased DNMT1 is responsible for nerve trauma-caused de novo methylation within the promoter and 5’-untranslated region (UTR) of the Kcna2 gene, but not Oprm1 and Oprk1 genes, resulting in the reductions of Kcna2 expression and Kv current and an increase in neuronal excitability in the neurons of nerve trauma-related DRG.(Sun et al., 2017) In addition to induction of Kcan2a gene methylation, the increased DNMT3a also participates in the nerve trauma-caused increase in DNA methylation in the promoter and 5’-untranslated region (UTR) of the Oprm1 and Oprk1 genes, consequently reducing their expression in the neurons of nerve trauma-related DRG and augmenting MOR-controlled neurotransmitter release at the primary afferent terminals.(Sun et al., 2017; Zhao et al., 2017) Thus, blocking increased DNMT3a in nerve trauma-related DRG rescued loperamide (a peripheral acting MOR preferring agonist) or morphine analgesic effects and impaired the induction of their analgesic tolerance under the conditions of neuropathic pain.(Sun et al., 2017) Mechanistically, DNMT3a-triggered repression of Oprm1 and Kcna2 gene expression required the MBD1 (an epigenetic repressor), as MBD1 deficiency reduced the interaction of DNMT3a with the promoters of both Oprm1 and Kcna2 genes and removed the DNMT3a-evoked inhibition of their expression in DRG neurons (Fig. 1).(Mo et al., 2018; Sun et al., 2017) It is very likely that both increased DNMT3a and MBD1 block the access of the transcription factor CREB (cyclic AMP response element binding protein) into the promoter region of Oprm1 gene (Fig. 1) (Liang et al., 2016b). MBD1 in the DRG is also critical for the development of neuropathic pain and morphine analgesic tolerance, because DRG MBD1 knockdown or knockout blunted SNL-induced nociceptive hypersensitivity, rescued morphine analgesia and impaired morphine tolerance.(Mo et al., 2018) Given that TETs promote DNA demethylation as discussed above, DRG overexpression of exogenous TET1 attenuated the SNL-caused increase in 5mC and restored the level of 5hmC in the promoter region of Kcna2 gene and in the promoter and 5’-UTR of the Oprm1 gene in nerve trauma-related DRG.(Wu et al., 2019) This overexpression also mitigated SNL-caused nociceptive hypersensitivity.(Wu et al., 2019) Taken together, nerve trauma-caused epigenetic silencing of DRG ORs is attributed at least in part to DNMT3a-triggered DNA methylation in these OR genes in nerve trauma-related DRG neurons. DNMT3a is likely a potential target for adjunctive use with opioids in neuropathic pain management.

Figure 1.

Figure 1.

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Proposed mechanism by which DNMT3a-triggered DNA methylation is involved in nerve trauma-caused mu opioid receptor (MOR) downregulation in dorsal root ganglion (DRG). In normal DRG neurons, the level of Dnmt3a mRNA is relatively low, as miR-143 destabilizes its expression. Oprm1 gene is transcriptionally activated by the transcription factor CREB and MOR is highly expressed in the DRG neurons. In contrast, under neuropathic pain conditions, peripheral nerve trauma reduces the expression of miR-143 and increases the expression of the transcription factor OCT1 and MDB1 in nerve trauma-related DRG. The increased OCT1 activates Dnmt3a gene transcriptional activity and elevates Dnmt3a mRNA and DNMT3a protein. Both increased DNMT3a and MBD1 blocks the access of CREB into the promoter of Oprm1 gene and downregulates the expression of Oprm1 mRNA and MOR protein in nerve trauma-related DRG neurons.

2.2. Role of histone methylation in nerve trauma-caused epigenetic silencing of ORs in DRG neurons

Histone methylation, one type of histone modifications, can either increase or decrease the gene expression, depending on the content and sites being methylated in amino acids of histone proteins in chromosomes. In general, methylation of histone H3 at Lys27 (H3K27) or Lys9 (H3K9) and histone H4 at Lys20 (H4K20) causes transcriptional repression, whereas methylation of H3K36, H3K4 and H3K79 leads to transcriptional activation.(Kouzarides, 2007) G9a, a histone methyltransferase, encoded by Ehmt2 gene, produces histone H3 dimethylation at Lys9 (H3K9me2) (Shinkai and Tachibana, 2011). This methylation causes condensed chromatin, resulting in transcriptional repression of genes.(Kouzarides, 2007)

G9a was detected in neurons, but not in satellite cells, in DRG.(Laumet et al., 2015; Liang et al., 2016a) SNL or CCI consistently increased the amounts of Ehmt2 mRNA and G9a protein as well as its catalyzed H3K9m2 in nerve trauma-related DRG.(Laumet et al., 2015; Liang et al., 2016a) These increases contributed to SNL- or CCI-caused downregulation of Oprm1, Oprk1, and Oprd1 genes as well as potassium (K+) channel (e.g., Kcan2) genes in the neurons of nerve trauma-related DRG.(Laumet et al., 2015; Liang et al., 2016a; Liang et al., 2016b; Zhang et al., 2016b) Mechanistically, the G9a/H3K9me2 binds to the promoter region and 5’-UTR of the Oprm1 gene in DRG (Fig. 2).(Liang et al., 2016b) Peripheral nerve trauma strikingly increased these interaction, resulting in the blockade in the access of CREB to the promoter region of Oprm1 gene and consequent silence of Oprm1 transcriptional activity in nerve trauma-related DRG (Fig. 2).(Liang et al., 2016b) Thus, blocking the increased DRG G9a attenuated the induction of loperamide- or morphine-evoked analgesic tolerance after SNL.(Liang et al., 2016b; Zhang et al., 2016b) G9a is likely an endogenous instigator of neuropathic pain, as genetic knockdown/knockout or pharmacological inhibition of DRG G9a blocked the induction and maintenance of neuropathic pain.(Laumet et al., 2015; Liang et al., 2016a; Liang et al., 2019)

Figure 2.

Figure 2.

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Proposed mechanism by which G9a- or SUV39H1-triggered histone methylation participates in nerve trauma-caused mu opioid receptor (MOR) downregulation in dorsal root ganglion (DRG). In normal DRG neurons, the level of Ehmt2 mRNA is relatively low, as YTHDF2 binds to m6A within Ehmt2 RNA and destabilizes its expression. Oprm1 gene is transcriptionally activated by the transcription factor CREB and MOR is highly expressed in the DRG neurons. In contrast, under neuropathic pain conditions, peripheral nerve trauma increases the expression of FTO, SUV39H1 and C/EBPβ in nerve trauma-related DRG. The increased C/EBPβ activates Ehmt2 gene transcriptional activity and elevates Ehmt2 mRNA and G9a protein. The increased FTO erases m6A within Ehmt2 RNA and further stabilizes nerve trauma-caused increases in Ehmt2 mRNA and G9a protein in nerve trauma-related DRG. The elevated G9a leads to H3K9me2, whereas the increased SUV39H1 produces H3K9me3. These histone modifications block the access of CREB into the promoter of Oprm1 gene, resulting in the reductions of Oprm1 mRNA and MOR protein in nerve trauma-related DRG.

Besides G9a, another histone lysine methyltransferase SUV39H1 (the suppressor of variegation 3–9 homolog 1) produces histone H3 trimethylation at Lys9 (H3K9me3).(Rea et al., 2000) SUV39H1 was expressed mainly in small DRG neurons and co-existed with MOR in these neurons.(Zhang et al., 2016a) The levels of SUV39H1 mRNA and protein were time-dependently increased in the ipsilateral lumbar 5 (L5) DRG of the rats following SNL.(Zhang et al., 2016a) DRG SUV39H1 knockdown not only attenuated the SNL-caused nociceptive hypersensitivity but also rescued SNL-caused MOR downregulation in the ipsilateral L5 DRG (Fig. 2).(Zhang et al., 2016a) SUV39H1 may participate in neuropathic pain by epigenetically silencing MOR expression in nerve trauma-related DRG.

Taken together, nerve trauma-caused downregulation of MOR is likely attributed to the disruption of the interaction between CREB and the promoter of Oprm1 gene caused by the increases in G9a/H3K9me2 and SUV39H1/H3K9me3 in the neurons of nerve trauma-related DRG (Fig. 2).

2.3. Role of microRNAs in nerve trauma-caused epigenetic silencing of ORs in DRG neurons

The microRNA (miR) is an endogenous small non-coding RNA molecule. It is about 18–25 nucleotides in size. The miR has the functions in RNA repression and post-transcriptional regulation of gene expression by base-pairing with complementary sequences within targeted RNA molecules.(Lutz et al., 2014) It was predicted that miR-143 targets Dnmt3a gene.(Ng et al., 2009) Expression of Dnmt3 mRNA and protein was reduced in breast cancer cells ectopically expressing miR-143 or in colorectal cancer cell lines restoring miR-143 expression.(Ng et al., 2014; Ng et al., 2009) The luciferase reporter assay revealed that miR-143 directly inhibited Dnmt3a promoter activity.(Ng et al., 2014; Ng et al., 2009) Peripheral nerve trauma caused by SNL decreased the level of miR-143 in the ipsilateral L5 DRG of the rats.(Xu et al., 2017) SNL-caused DRG Dnmt3a increase required this decrease, because restoring DRG miR-143 expression attenuated the SNL-caused elevation in Dnmt3a and rescued the expression of Oprm1 mRNA and MOR in these DRG neurons. (Xu et al., 2017) Rescuing DRG miR-143 expression also impaired the SNL-evoked nociceptive hypersensitivity and restored morphine analgesic effects under the conditions of SNL-caused neuropathic pain.(Xu et al., 2017) In contrast, knocking down expression of DRG miR-143 in animals with absence of peripheral nerve trauma increased the amounts of Dnmt3a mRNA and protein and correspondingly decreased the levels of Oprm1 mRNA and MOR in injected DRG, leading to nociceptive hypersensitivity in response to evoked stimuli.(Xu et al., 2017) Thus, the downregulated DRG miR-143 participates in nerve trauma-evoked epigenetic silencing of MOR likely through negative regulation of Dnmt3a gene expression in nerve trauma-related DRG (Fig. 1).

3. Transcription factor-mediated mechanisms of DRG OR downregulation under neuropathic pain conditions

Transcription factors are sequence-specific DNA-binding proteins that act as the primary regulators of gene transcription. The transcriptional repressor neuron-restrictive silencer factor (NRSF) inhibits the expression of genes that contain neuron-restrictive silencer element (NRSE). After NRSF interacts with NRSE within the targeted genes, histone deacetylase (HDAC) is recruited through NRSF’s core-pressors, mSin3 and CoREST, and repressive chromatin environment is generated.(Ballas et al., 2005) A previous study revealed that NRSF decreased the expression of Oprm1 gene via HDAC-involved mechanisms.(Kim et al., 2004) Peripheral nerve trauma upregulated NRSF expression, resulting in the enhanced interaction of NRSF with the NRSE within Oprm1 gene and consequently epigenetic silence of Oprm1 gene in nerve trauma-related DRG neurons (Fig. 3).(Uchida et al., 2010) DRG NRSF knockdown significantly rescued the SNL-caused MOR downregulation in the ipsilateral L4 DRG of mice and restored the losses of peripheral morphine analgesia.(Uchida et al., 2010) Therefore, NRSF is one of key regulators in nerve trauma-caused epigenetic silence of DRG MOR through recruitment of HDAC and subsequent blockage of CREB access into Oprm1 gene (Fig. 3).

Figure 3.

Figure 3.

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Proposed mechanism by which the transcriptional repressor neuron-restrictive silencer factor (NRSF) causes mu opioid receptor (MOR) downregulation in dorsal root ganglion (DRG) under neuropathic pain conditions. In normal DRG neurons, the histone deacetylase (HDAC) does not bind to the promote region of Oprn1 gene due to low levels of NRSF protein. Oprm1 gene is transcriptionally activated by the transcription factor CREB and MOR is highly expressed in the DRG neurons. In contrast, under neuropathic pain conditions, peripheral nerve trauma increases the expression of Nrsf mRNA and its coding NRSF protein in nerve trauma-related DRG. The increased NRSF binds to the neuron-restrictive silencer element within the promoter region of Oprm1 gene and recruits HDAC into this region, resulting in the blockade of CREB access into the promoter of Oprm1 gene and subsequent downregulation of Oprm1 mRNA and MOR protein in nerve trauma-related DRG neurons.

The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is one member of a family of six structurally related basic leucine-zipper DNA binding proteins. C/EBPβ transcriptionally activated the Ehmt2 gene once C/EBPβ bound to its consensus binding motif within the promoter region of Ehmt2 gene in human embryonic kidney (HEK)-293T cells.(Li et al., 2013) CCI upregulated the expression of C/EBPβ in the ipsilateral L3/4 DRG neurons of mice.(Li et al., 2017) This upregulation produced a marked decrease in the amounts of Oprm1 mRNA and MOR protein in these DRGs (Fig. 2).(Li et al., 2017) This effect required the C/EPBβ-mediated transcriptional activation of Ehmt2 gene and G9a production (Fig. 2).(Li et al., 2017) Blocking increased DRG C/EBPβ restored morphine analgesia under the conditions of CCI-induced neuropathic pain and attenuated the induction and maintenance of CCI-induced nociceptive hypersensitivities.(Li et al., 2017) Therefore, DRG C/EBPβ is likely a key player in neuropathic pain and may be a potential target for therapeutic management of this disorder.

Octamer transcription factor 1 (OCT1) is also a transcription activator that interacts with the “ATTTGCAT” motif. This consensus binding motif was found within the promoter region of the Dnmt3a gene.(Zhao et al., 2017) The activity of Dnmt3a promoter could be activated by OCT1 in HEK-293 cells.(Zhao et al., 2017) The level of OCT1 protein was time-dependently increased in the ipsilateral L4/5 DRGs of the rats after CCI.(Yuan et al., 2019) This increase is responsible for CCI-caused upregulation of Dnmt3a mRNA and protein as well as DNMT3a-triggered downregulation of Oprm1 mRNA and MOR protein in the ipsilateral L4/5 DRGs.(Yuan et al., 2019) (Fig. 1) Blocking this increase prevented the development and maintenance of CCI-caused nociceptive hypersensitivity and rescued morphine analgesia following CCI.(Yuan et al., 2019) Thus, DRG OCT1 contributes to neuropathic pain likely through OCT1-mediated transcriptional activation of Dnmt3a gene and consequent downregulation of Oprm1 triggered by increased DNMT3a in the neurons of nerve trauma-related DRG (Fig. 1).

4. Post-transcriptional mechanisms of DRG OR downregulation under neuropathic pain conditions

4.1. Role of RNA m6A methylation in nerve trauma-caused epigenetic silencing of ORs in DRG neurons

Gene expression is also regulated by RNA modifications.(Lence et al., 2017; Patil et al., 2018; Roignant and Soller, 2017; Wei et al., 2017; Yue et al., 2015) Until now, more than 100 distinct chemical modifications have been identified in RNAs. One of the most prevalent modifications on RNA is N6-methyladenosine (m6A). The level of m6A on RNA is regulated reversibly by m6A writers including methyltransferase-like 3 and 14 (METTL3 and METTL14) and Wilms’ tumor 1-associating protein (WTAP) and m6A eraser proteins including fat-mass and obesity-associated proteins (FTO) and AlkB homolog 5 (ALKBH5)). m6A modification is recognized by m6A reader proteins including YTH N6-methyladenosine RNA binding proteins 1/2/3 (YTHDF1/2/3). RNA m6A modification affects all stages of RNA biogenesis, such as splicing, export, transcription, translation, and degradation.(Adhikari et al., 2016; Genenncher et al., 2018; Ke et al., 2015; Ke et al., 2017; Wang et al., 2014)

FTO-triggered removal of Ehmt2 RNA m6A may participate in nerve trauma-caused DRG MOR downregulation. The levels of Fto mRNA and FTO protein were time-dependently increased in the ipsilateral L5 DRG after SNL or in the ipsilateral L4/5 DRGs after CCI in rats.(Li et al., 2020) Interestingly, no changes in the amounts of METTL3, METTL14, ALKBH5, WTAP and YTHDF2 proteins were observed in the ipsilateral L5 DRG following SNL.(Li et al., 2020) Mimicking nerve trauma-caused DRG FTO increase erased m6A in Ehmt2 mRNA, reduced the binding of YTHDF2 to 3-UTR of Ehmt2 mRNA, stabilized the increased expression of Ehmt2 mRNA/G9a and downregulated MOR in DRG (Fig. 2), resulting in neuropathic pain symptoms.(Li et al., 2020) Genetic knockdown or knockout of DRG FTO reversed a loss of m6A sites within Ehmt2 mRNA, enhanced the YTHDF2 binding to 3-UTR of Ehmt2 mRNA, destabilized the nerve trauma-caused G9a upregulation and restored the nerve trauma-caused decrease of MOR in nerve trauma-related DRG, attenuated the induction and maintenance of neuropathic pain and alleviated morphine analgesic tolerance after SNL.(Li et al., 2020) Therefore, FTO participates in neuropathic pain likely by maintaining nerve trauma-caused increase in G9a expression and consequent downregulation of G9a-determined MOR in nerve trauma-related DRG neurons (Fig. 2).

4.2. Role of eIF4G2 in nerve trauma-caused downregulation of ORs in DRG neurons

Eukaryotic initiation factor 4F (eIF4F) is one of the protein complexes involved in protein translation initiation and is a key effector of post-transcriptional gene regulation.(Prevot et al., 2003) There are three subunits in the eIF4F complex: cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A and scaffolding protein eIF4G.(Hinnebusch and Lorsch, 2012) eIF4G consists of three isoforms: eIF4G1, eIF4G2 and eIF4G3.(Henis-Korenblit et al., 2002) eIF4G2 (also known as DAP-5, p97 and NAT1) shares similarities in its C-terminal region with eIF4G1.(Hinnebusch and Lorsch, 2012; Imataka et al., 1997; Imataka and Sonenberg, 1997; Yamanaka et al., 1997) Unlike eIF4G1, which augments cap-dependent and -independent RNA translation, eIF4G2 functions as a general inhibitor of cap-dependent translation of most RNAs by establishing translationally inactive complexes. Interestingly, eIF4G2 was also demonstrated to promote noncanonical, cap-independent initiation of protein translation and cap-dependent protein translation of select mRNAs.(Lee and McCormick, 2006; Nousch et al., 2007; Sugiyama et al., 2017)

DRG eIF4G2 may involve in nerve trauma-caused downregulation of MOR in the DRG neurons. Although eIF4G2 was distributed in all types of DRG neurons, it co-expressed with MOR in small DRG neurons.(Zhang et al., 2021) Amounts of eIF4G2 mRNA and protein in the ipsilateral L4 DRG of mice were time-dependently increased after SNL.(Zhang et al., 2021) Blocking this increase through DRG microinjection of eIF4G2 siRNA restored the SNL-caused downregulation of DRG MOR and attenuated the development and maintenance of the SNL-caused nociceptive hypersensitivities to mechanical, heat and cold stimuli.(Zhang et al., 2021) DRG overexpression of eIF4G2 through microinjection of AAV5 expressing full-length eIF4G2 decreased DRG MOR expression and elicited hypersensitivities to mechanical, heat and cold stimuli.(Zhang et al., 2021) Thus, DRG eIF4G2 contributes to neuropathic pain likely by negatively regulating MOR expression in the neurons of nerve trauma-related DRG.

5. Conclusion

In summary, this review revealed several mechanisms at transcriptional and translational levels that underlie nerve trauma-caused downregulation of ORs in nerve trauma-related DRG neurons. It is evident that these mechanisms do not compensate each other, because targeting each mechanism can rescue the expression of OR mRNAs and proteins in nerve trauma-related DRG. How these mechanisms co-work together to contribute to the nerve trauma-caused downregulation of ORs merits to be investigated in further studies. Given that targeting these mechanisms restores loperamide or morphine analgesia, decreases primary afferent transmitter release, and blocks loperamide- or -morphine induced analgesic tolerance, and relieves nerve trauma-caused nociceptive hypersensitivity under neuropathic pain conditions, developing the drugs that target these mechanisms will likely provide the benefits of anti-nociceptive effects, maintaining opioid analgesia and anti-opioid analgesic tolerance in management of neuropathic pain. It should be noted that these key targets (such as DNMT3a, G9a, OCT1, C/EBPβ, NRSF, FTO and eIF4G2) within these mechanisms are also expressed in other body tissues besides the DRG as well as may target other genes in addition to opioid receptors. The possible adverse effects caused by targeting these key players should be paid an attention when therapeutic models are developed in future.

Acknowledgments

This work was supported by the NIH grants (R01NS111553, R01NS094664, R01NS094224 and RFNS113881).

Footnotes

Conflict of interest statement

All authors have no conflicts of interest to declare.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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