Emerging roles of microRNAs in chronic pain

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Contents lists available at ScienceDirect

Neurochemistry International journal homepage: www.elsevier.com/locate/nci

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Review

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Emerging roles of microRNAs in chronic pain

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Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan

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a r t i c l e

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Atsushi Sakai, Hidenori Suzuki ⇑

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Article history: Available online xxxx

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Keywords: Astrocyte Cancer pain Hyperexcitability Inflammatory pain Microglia microRNA Neuroinflammation Neuropathic pain Primary sensory neuron Spinal cord

a b s t r a c t Chronic pain is a debilitating syndrome caused by a variety of disorders, and represents a major clinical problem because of the lack of adequate medication. In chronic pain, massive changes in gene expression are observed in a variety of cells, including neurons and glia, in the overall somatosensory system from the sensory ganglia to the higher central nervous system. The protein expressions of hundreds of genes are thought to be post-transcriptionally regulated by a single type of microRNA in a sequence-specific manner. Recently, critical roles of microRNAs in the pathophysiology of chronic pain have been emerging. Genome-wide screenings of microRNA expression changes have been reported in a variety of painful conditions, including peripheral nerve injury, inflammatory diseases, cancer and spinal cord injury. The data obtained suggest that a wide range of microRNAs change their expressions in individual pain conditions, although the pathological significance of individual microRNAs as causal mediators in distinct pain conditions remains to be revealed for a limited number of microRNAs. Insights into the roles of microRNAs in chronic pain will enhance our understanding of the pathophysiology of chronic pain and allow prompt therapeutic application of microRNA-related drugs against intractable persistent pain. Ó 2014 Elsevier Ltd. All rights reserved.

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1. Introduction

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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Although pain is a pivotal alerting system for the body, unnecessary or prolonged (chronic) severe pain is debilitating and reduces patients’ quality of life. Therefore, effective intervention is required for such inappropriate pain. However, the current therapeutic options are far from satisfactory. Conventional analgesics such as nonsteroidal anti-inflammatory drugs and opioids have associated problems in long-term treatment for chronic inflammatory pain conditions such as arthritis. Chronic pain also arises from a variety of other causes, including damage to the somatosensory system, cancer and genetic diseases. In particular, neuropathic pain caused by lesions or diseases of the somatosensory system, as observed in traumatic injury, herpes zoster, diabetes or chemotherapy, is poorly controlled by the currently available analgesics (Dworkin et al., 2013). Thus, chronic pain is a major clinical problem and the development of safer and more effective analgesics is awaited. A nociceptive stimulus applied to the body is initially detected by nociceptors on the peripheral axons of primary sensory

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⇑ Corresponding author. Tel.: +81 3 3822 2131x5277; fax: +81 3 5814 1684. E-mail addresses: [email protected] (A. Sakai), [email protected] (H. Suzuki).

neurons. These primary sensory neurons, whose cell bodies are located in the dorsal root ganglion (DRG) or trigeminal ganglion (TG), transmit nociceptive information to secondary neurons in the spinal or medullary dorsal horn. In the dorsal horn, the nociceptive and non-nociceptive information is integrated and processed by complex circuits involving excitatory and inhibitory interneurons and descending axons from the brainstem as well as glial cells (Kuner, 2010; Todd, 2010). The processed information is then transmitted via the ascending pathway to multiple brain areas where pain sensation and associated negative affects and emotions are elicited. These brain areas include not only somatosensory cortices, which are mainly involved in the sensory aspect of pain, but also limbic systems and other cortices such as the amygdala, anterior cingulate cortex, insular cortex and prefrontal cortex, which are considered to be involved in the affective and emotional aspects of pain as well as pain perception (Apkarian et al., 2011). Thus, higher brain functions such as mood and cognition can be negatively affected by a nociceptive stimulus, most notably in the chronic pain state. In fact, chronic pain is correlated with comorbid cognitive, mood and anxiety disorders (McWilliams et al., 2003) and can be actively modulated by cognitive and emotional processes (Bushnell et al., 2013). MicroRNAs (miRNAs) are non-coding functional RNAs that negatively regulate multiple gene expressions. The sequences of miRNAs and their target sites in mRNAs are extensively conserved across species (Friedman et al., 2009). A single miRNA is generally

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Please cite this article in press as: Sakai, A., Suzuki, H. Emerging roles of microRNAs in chronic pain. Neurochem. Int. (2014), http://dx.doi.org/10.1016/ j.neuint.2014.05.010

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thought to recognize the 30 -UTR of mRNAs in a sequence-specific manner to post-transcriptionally inhibit the protein expressions of hundreds of targeted mRNAs (Bartel, 2009). Thus, the expression changes of miRNAs concurrently modulate many gene expressions and have considerable effects on cellular functions, as well described for development and tumorigenesis (Sayed and Abdellatif, 2011). Critical roles of miRNAs in the development and pathophysiology of the nervous system have also become increasingly evident (Bhalala et al., 2013). In this review, we provide an overview of the roles of miRNAs expressed in the nervous system with chronic pain. The roles of miRNAs expressed in peripheral cells or tissues in painful diseases have been reviewed elsewhere, including bladder pain syndrome (Gheinani et al., 2013), osteoarthritis (Yu et al., 2011c) and rheumatoid arthritis (Ammari et al., 2013).

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2. Expression changes in miRNAs in animal models of pain

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Dynamic changes in the nociceptive circuit can occur over several temporal scales (acute to chronic) and at the molecular, synaptic, cellular and network levels (Kuner, 2010). Given that expression and functional changes in a wide variety of molecules are induced in nociceptive neurons in chronic pain states (Basbaum et al., 2009; Ji and Strichartz, 2004; Kuner, 2010; Stemkowski and Smith, 2012), miRNAs may orchestrate such pathological expression changes. To date, genome-wide screenings of miRNA expression changes have been conducted in a variety of painful conditions, including peripheral nerve injury (axotomy or nerve ligation), inflammatory disease, cancer and spinal cord injury (Table 1). The data obtained indicate that many miRNAs undergo expression changes in individual pain conditions, although the patterns of the expression changes differ among the causative disorders. It is also noteworthy that miRNAs show dynamic changes during the time course after the initial event in both the DRG and spinal cord. The molecular mechanisms underlying the initiation and maintenance of chronic pain are possibly distinct (Crown, 2012; Ji et al., 2003). These time-dependent changes may also reflect certain aspects of the regenerative processes seen in the chronic phases of pain conditions. Furthermore, anatomically widespread changes in miRNA expressions are induced in chronic pain states. Notably, miRNA expressions are changed not only in the somatosensory system, but also in other brain regions such as the limbic system and prefrontal cortex (PFC). Since these brain areas represent cognitive, affective and emotional components of pain, miRNAs may also play roles in higher brain dysfunctions associated with chronic pain. Although inflammatory and neuropathic pain can both take a chronic course and partly share some molecular mechanisms, they are distinct in their characteristics. Inflammatory pain, as well as physiological pain, works in some cases as an alerting system for organisms to protect themselves against potential damage and to promote rest and healing. In contrast, chronic neuropathic pain is no longer beneficial, but fully pathological. Kusuda et al. (2011) showed that miR-16 expression was decreased in the DRG in inflammatory pain, but not neuropathic pain. miR-143 was decreased in the DRG in inflammatory pain caused by complete Freund’s adjuvant (CFA) injection, but not nerve damage (Tam Tam et al., 2011). miR-21 and miR-7a expressions were upregulated and downregulated, respectively, in neuropathic pain, but remained unchanged in inflammatory pain (Sakai et al., 2013; Sakai and Suzuki, 2013). In addition, miR-7a alleviated neuropathic pain, but not inflammatory pain (Sakai et al., 2013). miR-1a-3p was upregulated in bone cancer, axotomy and capsaicin injection, but downregulated in CFA injection and partial sciatic nerve ligation (Bali et al., 2013; Kusuda et al., 2011). DRG neuron-specific deletion of Dicer, an enzyme that produces mature miRNAs via cleavage of

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109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155

pre-miRNAs, attenuated inflammatory pain, but not neuropathic pain (Zhao et al., 2010). Furthermore, traumatic injury differentially affects miRNA expressions depending on the types of injury. miR-1 was downregulated in the DRG following ligation of the sciatic nerve, but upregulated by axotomy. Similarly, miR-206 was downregulated in the DRG by ligation, but not axotomy, of the sciatic nerve (Kusuda et al., 2011). miRNA expression changes may also contribute to functional recovery from nerve damage. Upregulation of miR-21 after nerve injury is involved in both axon growth and neuropathic pain (Sakai and Suzuki, 2013; Strickland et al., 2011b). miR-222 upregulation after sciatic nerve transection promotes neurite outgrowth (Zhou et al., 2012). As described above, a variety of expression changes in miRNAs occur in a wide range of animal models of pain, suggesting the importance of miRNAs as pain regulators. Therefore, focusing on the miRNAs commonly changed in most of these animal models would be an efficient strategy to elucidate the pathophysiology of pain. Alternatively, investigations of the roles of miRNAs specifically changed in certain pain conditions would be effective for characterizing individual pain states, thereby providing information toward the development of analgesics suitable for individual disorders. The miRNAs reported to be involved in pain behaviors in animal models are summarized in Table 2.

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3. miRNAs in the sensory ganglia

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DRG and TG neurons are first-line sensory neurons that detect noxious stimuli and inflammation and transmit their information to the spinal and medullary dorsal horns, respectively. Persistent noxious stimulation and/or inflammation cause long-lasting sensitization and hyperexcitability in these sensory neurons, resulting in hyperalgesia. In clinical practice, DRG and TG neurons are the principal origins of neuropathic pain, and are therefore involved in both the initiation and maintenance of chronic neuropathic pain (Devor, 2006). Thus, DRG and TG neurons are important analgesic targets. Accordingly, microarray data have shown massive expression changes of miRNAs in the DRG after peripheral nerve injury (Sakai et al., 2013; von Schack et al., 2011; Yu et al., 2011a; Zhang et al., 2011; Zhou et al., 2011, 2012), osteoarthritis (Li et al., 2013) and bone cancer (Bali et al., 2013).

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3.1. Roles of miRNAs in neuronal excitability in chronic pain

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Hyperexcitability of primary sensory neurons is a common cause of chronic pain. It has been revealed that the expression level, intracellular distribution and posttranslational modulation of ion channels, such as voltage-gated sodium channels, are changed in chronic pain states (Waxman and Zamponi, 2014). miRNA dysregulation leads to abnormal neuronal excitability through direct inhibition of ion channel expressions (Wang, 2013). Consistently, several miRNAs in DRG neurons were shown to be involved in ion channel expressions in chronic pain states. Specific deletion of Dicer in nociceptive DRG neurons resulted in expression changes of nociceptor-enriched voltage-gated sodium channels, NaV1.7, NaV1.8 and NaV1.9 (Zhao et al., 2010), suggesting a possible regulatory role of certain mature miRNAs. Another voltage-gated sodium channel modulated by an miRNA is NaV1.3, which is upregulated in DRG neurons after axotomy (Waxman et al., 1994). Chen et al. (2014) suggested that NaV1.3 upregulation in the DRG was mediated by miR-96. They showed that miR-96 was decreased in parallel with NaV1.3 upregulation in the neuropathic pain state. Furthermore, intrathecal miR-96 suppressed NaV1.3 expression in association with alleviation of neuropathic pain. With regard to the relationship between miRNAs and neuronal excitability, we

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Please cite this article in press as: Sakai, A., Suzuki, H. Emerging roles of microRNAs in chronic pain. Neurochem. Int. (2014), http://dx.doi.org/10.1016/ j.neuint.2014.05.010

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A. Sakai, H. Suzuki / Neurochemistry International xxx (2014) xxx–xxx Table 1 Comprehensive analyses of miRNA expression profiles in pain-related conditions. Condition

Region

Platform

Time examined

Number of miRNA

Reference

Axotomy

DRG

7d

8up,12down/375

Bone cancer

DRG

Microarray (Atactic Technologies) Microarray (Illumina)

Carrageenan

CCI

PFC (left) PFC (right) Dorsal spinal cord Spinal cord

4d 8d 3d

CCI

Hippocampus

7d 14 d 4h 24 h 6d 12 d 7d 15 d 7d

0/655 (>2.5-fold) 26up,31down/655 (>2.5-fold) 2up,1down 13up,1down 8up,13down/375 20up,45down/375 5down/349 1down/349 0/349 0/349 34/373 31/373 47up,7down/373

Strickland et al. (2011b) Bali et al. (2013)

7d

15up,25down/373

Hori et al. (2013)

Unexplained

4up,14down

Orlova et al. (2011)

1d 9 y (median)

2up,9down 9down/742

Tam Tam et al. (2011) Bjersing et al. (2013)

Microarray (NanoString)

Unexplained

2up

Fourie et al. (2014)

Microarray (Affymetrix) Deep sequencing (Illumina) Microarray (Affymetrix)

Unexplained

61down 27down (>2-fold) 8up,4down

Zhao et al. (2010)

7up,18down in both time points and both arrays

Wu et al. (2011)

Yu et al. (2011b)

1d 4d 7d 14 d 3d 1, 4, 7, 14 d 1h 3h 6h 9h 8 wk

201 225 4up,1down/350 23up,6down/350 13up,5down/350 8up,16down/350 10up,21down/955 (>1.5-fold) 26 6up,1down/350 4up,2down/350 1up,2down/350 7up,5down/350 2up,7down

Li et al. (2013)

7d

17/384

Imai et al. (2011)

12 h 4 h, 1, 7 d

Unexplained Unexplained 5up,5down 97/350

Nakanishi et al. (2010) Liu et al. (2009)

4, 14 d

4up,32down

1d 3d 7d 14 d 14 d

10-28/1773 depending on statistical method 13-43/1773 13-203/1773 102up,6down/350 0/350

4 wk 4 wk

Unexplained 4up,59down/365

CCI

CFA

Hippocampus

CRPS (human)

Whole blood

Culturing Fibromyalgia (human)

DRG Cerebrospinal fluid Whole blood

Irritable bowel syndrome (human) NaV1.8-Cre mediated Dicer KO Neonatal zymosan-induced cystitis Nerve crush

DRG Dorsal spinal cord Sciatic nerve

Microarray (Agilent) TaqMan array (Life Technologies) Microarray (Exiqon)

TaqMan array (Life Technologies) TaqMan array (Life Technologies) TaqMan array (Life Technologies) TaqMan array (Life Technologies) Microarray (Exiqon) Microarray (Exiqon)

Microarrays

Nerve transection

DRG Sciatic nerve DRG

(Custom & Agilent) Deep sequencing (Illumina) Microarray (Agilent)

Nerve transection Nerve transection Nerve transection

DRG DRG DRG

Microarray (Exiqon) Microarray (Agilent) Microarray (Agilent)

Osteoarthritis

Microarray (Exiqon)

SCI SCI

Spinal cord, dorsal? Limbic forebrain Amygdala Hippocampus Spinal cord Spinal cord

SCI

Spinal cord

Microarray (Invitrogen) Microarray (Atactic Technologies) Microarray (Exiqon)

SCI

Spinal cord

Microarray (Exiqon)

Nerve transection

PSNL

SNL

SNL

Injured DRG Injury-spared DRG Injured DRG Injury-spared DRG

TaqMan array (Life Technologies)

Microarray (Agilent)

TaqMan array (Life Technologies)

Postnatal day 30, 60 4d 7d 1, 4, 7, 14 d

Poh et al. (2011) Genda et al. (2013) Brandenburger et al. (2012)

Arai et al. (2013) Hori et al. (2013)

Sengupta et al. (2013)

Yu et al. (2011a)

Zhang et al. (2011) Zhou et al. (2012) Zhou et al. (2011)

Strickland et al. (2011a) Yunta et al. (2012)

Sakai et al. (2013)

von Schack et al. (2011)

CCI, chronic constriction injury; CRPS, complex regional pain syndrome; PSNL, partial sciatic nerve injury; SCI, spinal cord injury; SNI, spared nerve injury; SNL, spinal nerve injury. 217 218 219 220 221 222

clearly showed that miR-7a suppressed long-lasting hyperexcitability of nociceptive afferents, possibly by targeting the b2 subunit of voltage-gated sodium channels (see below) (Sakai et al., 2013). Therefore, hyperexcitability of nociceptive DRG neurons in the chronic pain state is controlled, at least partly, by miRNA-mediated posttranscriptional modulation of gene expression.

3.2. miR-7a

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Recently, we showed that miR-7a in DRG neurons plays a key role in sustaining the late phase of neuropathic pain through regulation of neuronal excitability (Sakai et al., 2013). miR-7a was mainly expressed in small cell-sized neurons that are considered

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4

Region

Cell type

Time examined

Expression change

Pain

Validated functional target

Reference

miR-let-7a,c,g

Opioid tolerance

Brain

N/D

3, 5 d

Up

Potentiated morphine antinociception

l opioid receptor

He et al. (2010)a

miR-1a-3p

Bone cancer CFA

DRG DRG Dorsal spinal cord DRG

N/D N/D N/D

1d 8d 12 h, 1, 3, 7 d 12 h 1, 3, 7 d 1d 3, 7, 14 d 1, 3, 7 d 14 d 1, 3, 7 d 1, 3, 7 d

N/C Up Down N/C Up N/C Down N/C Down Up Down

Improved N/D

Chloride channel 3 –

Bali et al. (2013)a Kusuda et al. (2011)a

N/D

–

N/D

–

10 min 10 min

Up N/C

N/D

–

PSNL

Neuron

24 h 4, 14 d

N/C Down

N/D

–

Strickland et al. (2011a)b,d

SNL, CCI

DRG

Neuron

DRG

N/C Down N/C

Unaffected Improved Unaffected

– NaV b2 –

Sakai et al. (2013)a,d

CFA

3d 7, 14d 3, 7, 14 d

SNL

DRG

Neuron

DRG

IL-1b CFA Axotomy

DRG DRG DRG

Neuron

N/C Up N/C Up Up N/C Up

N/D Improved N/D N/D N/D N/D N/D

– Unknown – – – – –

Sakai and Suzuki, (2013)a,d

CCI

3d 7, 14 d 3d 7, 14 d 3d 3, 7, 14 d 2, 7, 14, 28 d

Nerve resection

DRG

N/D

N/C Up

N/D N/D

– –

Nerve crush SCI

Sciatic nerve Spinal cord

Axon Neuron

– –

Wu et al. (2011)c Strickland et al. (2011a)b,d

Spinal cord Spinal cord

Astrocyte N/D

Up N/C Up Down Up Up

N/D N/D

SCI SCI

1d 4, 7, 14,21, 28d Unexplained 24 h 4d 14 d 4, 14, 35 d 3, 7 d

N/D N/D

– –

Bhalala et al. (2012)a,d Yunta et al. (2012)a

miR-23b

SCI

Spinal cord

3d

Down

Improved

NADPH oxidase 4

Im et al. (2012)c,e

miR-34c-5p

Bone cancer

DRG

GABAergic neuron N/D

8d

Up

Improved

Unknown

Bali et al. (2013)a

miR-96

SNL CCI

Injured DRG DRG DRG

Neuron N/D

14 d 7, 14, 21 d 1d

Down Down N/C

N/D Improved

– NaV1.3

Aldrich et al. (2009)a,d Chen et al. (2014)a

miR-103

SNL

Dorsal spinal cord

Neuron

Unexplained

Down

Improved

CaV1.2-a1, -a2d1, b1 subunits

Favereaux et al. (2011)c,d

miR-124a

CFA

TG

N/D

–

Bai et al. (2007)a,d

Dorsal spinal

Neuron

Down N/C Up N/C

N/D

Formalin

0.5, 1, 4, 24 h 4d 12 d 1, 48 h

Improved

MeCP2

Kynast et al. (2013)a,d

Axotomy

Capsaicin

miR-7a

miR-21

(unpublished data)a Strickland et al. (2011b)a,d Yu et al. (2011a)a

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SCI

Dorsal spinal cord DRG Dorsal spinal cord DRG Dorsal spinal horn Spinal cord

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Table 2 miRNAs validated in pain behaviors.

Region cord DRG

Cell type

Time examined

Expression change Down N/C Down N/C Down N/C Down Down

SCI

Spinal cord

Myelinated neuron N/D

SCI

Spinal cord

Neuron

Intraplantar IL-1b in LysM-GRK2+/ mice Carrageenan SNI Nerve crush

Spinal cord

Microglia

8, 24 h 1, 2, 8, 48 h 24 h 6, 12 h 1, 3, 7 d 24 h 4, 14 d 24 h

– – Sciatic nerve

– – N/D

– – Unexplained

miR-183 miR-195

SNL SNL

N/D Microglia

miR-291b-5p miR-370-3p miR-483-3p miR-544-3p

Bone Bone Bone Bone

DRG Dorsal spinal cord DRG DRG DRG DRG

N/D N/D N/D N/D

cancer cancer cancer cancer

Pain

Validated functional target

Reference

Unknown N/D

–

N/D

–

Improved

Unknown

Nakanishi et al. (2010)a,d Strickland et al. (2011a)b,d Willemen et al. (2012)a

N/D N/D Down

Improved Improved –

Unknown Unknown –

Wu et al. (2011)b

7, 14 d 2, 5, 10, 14 d

Down Up

Improved Improved

NaV1.3, BDNF ATG14

Lin et al. (in press)a,d Shi et al. (2013)c,f

8 8 8 8

Down Down Down Up

Unaffected Worsened Improved Unaffected

– Unknown Unknown –

Bali Bali Bali Bali

d d d d

N/D, not determined; N/C, not changed. CCI, chronic constriction injury; PSNL, partial sciatic nerve injury; SCI, spinal cord injury; SNI, spared nerve injury; SNL, spinal nerve injury. a TaqMan. b Locked nucleic acid. c Sybr Green-based quantitative PCR. d Locked nucleic acid. e Oligonucleotide-based in situ hybridization. f Nothern blot.

et et et et

al. al. al. al.

(2013)a (2013)a (2013)a (2013)a

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Table 2 (continued)

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to be nociceptive neurons. miR-7a expression was drastically decreased in injured DRG neurons only in the late phase of neuropathic pain. Overexpression of miR-7a in injured DRG neurons suppressed the maintenance, but not the development, of neuropathic pain. Functional blockade of miR-7a in intact rats caused painrelated behaviors. On the other hand, miR-7a overexpression had no effect on acute physiological or inflammatory pain, consistent with the lack of expression change of miR-7a in inflammatory pain. These data suggest that miR-7a may be a preferred target for chronic neuropathic pain treatment owing to its selectivity, as it specifically suppressed neuropathic pain, but not other pain conditions such as physiological and inflammatory pain. In addition, miR-7a offers an advantage in the alleviation of established chronic pain, because its expression is progressively decreased. miR-7a targets the b2 subunit of voltage-gated sodium channels, which affects the cell surface expression of these channels and leads to increased neuronal excitability (Isom et al., 1995; Lopez-Santiago et al., 2006). As predicted, the protein expression of the b2 subunit was increased by nerve injury or miR-7a blockade. Consistent with the miR-7a effect on b2 subunit expression, miR-7a overexpression normalized long-lasting hyperexcitability of nociceptive neurons in the neuropathic pain state. Targeting voltage-gated sodium channels is a promising strategy for treating neuropathic pain, although the currently available voltage-gated sodium channel blockers have significant adverse effects (Devor, 2006). miR-7a-induced normalization of neuronal excitation, rather than blockade with voltagegated sodium channel blockers, may be an effective route for treatment of established neuropathic pain. In addition to its regulation of excitability, miR-7a may have an important role in damaged neurons because miR-7 was found to be downregulated in neurological disorders associated with degeneration, such as Parkinson’s disease (Junn et al., 2009) and spinal cord injury (Liu et al., 2009). miR-7-1 was recently shown to potentiate the action of estrogen receptor agonists for neuroprotection of motoneurons (Chakrabarti et al., 2014). miR-7 also protected the neuroblastoma cell line NS20Y against oxidative stress (Junn et al., 2009). miR-7a is known to be an important regulator for determination of the dopaminergic phenotype during development (de Chevigny et al., 2012). Therefore, further insights into miR-7a function will enhance our understanding of the pathophysiology of neuropathic pain.

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3.3. miR-1a-3p

270

286

miR-1 expression has been examined in a number of pain conditions and found to be highly dependent on the pain context. Kusuda et al. (2011) first showed that miR-1 was downregulated in the DRG after intraplantar CFA injection and partial sciatic nerve ligation, but upregulated after axotomy and intraplantar injection of capsaicin, a TRPV1 agonist. However, its function in pain modulation had not been analyzed. Recently, Bali et al. (2013) found that miR-1a-3p was upregulated in the DRG in a bone metastatic pain model and that miR-1a-3p inhibitor treatment attenuated the tumor-associated pain. They also identified chloride channel 3, which is decreased in DRG neurons, as a miR-1a-3p target gene responsible for the pain modulation, although the mechanism underlying how decreased chloride channel 3 levels cause hyperalgesia is unknown. miR-1a-3p inhibitor treatment may also alleviate other pain conditions associated with miR-1a-3p upregulation, including axotomy-induced pain such as phantom limb pain and acute pain associated with TRPV1 activation.

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3.4. miR-182-96-183 cluster

288

In contrast to the above-mentioned miRNAs, the miR-182-96183 cluster, in which three distinct miRNAs (miR-182, miR-96

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271 272 273 274 275 276 277 278 279 280 281 282 283 284 285

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and miR-183) are located near each other on the genome and possibly transcribed as a single common primary transcript, is consistently downregulated in pain conditions with distinct causes. In inflammatory muscle pain, miR-183 was downregulated in the TG within hours after CFA injection into the rat masseter muscle (Bai et al., 2007). The miR-182-96-183 cluster was reduced in the DRG in osteoarthritic pain (Li et al., 2013). In addition to pain conditions with peripheral tissue origins, the miR-182-96-183 cluster was downregulated in injured DRG neurons in neuropathic pain (Aldrich et al., 2009). Although the pathophysiological relevance of the cluster for pain is less clear, several pain-related genes, including brain-derived neurotrophic factor (BDNF) and substance P, were predicted in silico to be targets for cluster members (Aldrich et al., 2009). Furthermore, voltage-dependent sodium channels (NaV1.3 and NaV1.7) and voltage-dependent calcium channel subunit a2d1, which are key ion channels for pain transmission, were predicted to be targets for multiple miRNAs in this cluster. In this regard, the cluster member miR-96 and miR-183 were shown to inhibit NaV1.3 and BDNF expressions in the DRG in association with alleviation of neuropathic pain (Chen et al., 2014; Lin et al., in press). Given that each miRNA has a unique set of target genes, downregulation of the miR-182-96-183 cluster would have synergistic impacts on pain modulation.

290

3.5. miR-21

313

miR-21 is one of the well-characterized oncogenic miRNAs in almost all kinds of carcinoma cells (Selcuklu et al., 2009). miR-21 also has a wide range of physiological and pathological functions, including roles in the immune system and cardiovascular diseases (Kumarswamy et al., 2011). In the nervous system, miR-21 expression was reported to be upregulated in response to various types of damage, including ischemia (Buller et al., 2010), ionizing radiation (Shi et al., 2012) and traumatic brain injury (Redell et al., 2011). Consistently, miR-21 was upregulated in DRG neurons after various nerve injuries (Sakai et al., 2013; Sakai and Suzuki, 2013; Strickland et al., 2011b; Wu et al., 2011; Yu et al., 2011a). On the other hand, miR-21 expression in the DRG was unchanged in the inflammatory pain condition induced by intraplantar CFA injection in rats (unpublished data). These results suggest that miR-21 is consistently upregulated by a variety of damage situations and therefore plays an important role in the functional changes observed in damaged neurons. In fact, miR-21 was shown to modulate axon growth of DRG neurons in vitro (Strickland et al., 2011b). With regard to pain, we recently showed that miR-21 was involved in the maintenance of neuropathic pain (Sakai and Suzuki, 2013). However, the detailed molecular mechanisms of miR-21 upregulation after nerve injury remain unclear. miR-21 expression is speculated to be controlled in a complicated manner, because many enhancer elements are present in the miR-21 promoter region (Fujita et al., 2008). Interestingly, miR-21 expression in the DRG was upregulated in intact rats following intrathecal injection of interleukin (IL)-1b (Sakai and Suzuki, 2013), which is causally involved in neuropathic pain. In addition, nerve growth factor, a well-known neurotrophic factor for a subpopulation of DRG neurons, was shown to increase miR-21 expression in PC12 cells (Mullenbrock et al., 2011). Although the miR-21 target genes responsible for neuropathic pain have not been fully identified, several genes are speculated to be candidate targets. For example, miR-21 was shown to target negative regulators of matrix metalloproteinases (Reck and timp-3) and extracellular signal-regulated kinase (sprouty 1, sprouty 2 and Btg2) (Huang et al., 2013), which underlie neuropathic pain (Kawasaki et al., 2008; Obata et al., 2004). miR-21 also targeted an endogenous inhibitor of phosphatidylinositol 3-kinase, PTEN (Meng et al., 2007), which is involved in neuropathic pain (Xu et al., 2007). Considering the importance of the miR-21 roles in a

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was downregulated in spinal dorsal horn neurons in neuropathic pain, and intrathecal miR-103 injection alleviated the neuropathic pain. Therefore, miR-103 represents a possible therapeutic target in chronic neuropathic pain.

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variety of organs (Kumarswamy et al., 2011), clarification of the nerve injury-specific mechanisms for miR-21 upregulation and identification of the miR-21 target genes will reveal key molecules for the pathophysiology of nerve injury-specific neuropathic pain.

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4.2. miR-124a

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miR-146a is another miRNA that frequently shows changes in expression in a variety of diseases associated with pain. miR146a expression was decreased in the DRG after induction of osteoarthritic pain (Li et al., 2011, 2013). In a diabetic peripheral neuropathy model, miR-146a was decreased in DRG neurons, possibly contributing to neuronal apoptosis under high-glucose conditions (Wang et al., 2013). Microarray analyses showed that miR-146a was upregulated in the DRG after sciatic nerve axotomy (Yu et al., 2011a) and spinal nerve injury (Sakai et al., 2013). However, the miR-146a contribution to chronic pain has not yet been reported. Given its involvement in innate immune responses and inflammation (Chan et al., 2013; Montagner et al., 2013), miR146a may be a good target for the development of analgesics against chronic pain. In humans, functional single-nucleotide polymorphisms found in miR-146a were reported to be associated with the risk of hepatocellular carcinoma development (Xu et al., 2013). It will be intriguing to determine whether these polymorphisms affect variability in chronic pain predisposition, as shown for the P2X7 receptor (Sorge et al., 2012).

miR-124a has been shown to play multiple roles in the spinal cord. After intraplantar formalin injection which is commonly used to induce acute spontaneous pain behaviors, miR-124a was significantly decreased in putative nociceptive spinal neurons (Kynast et al., 2013). Intrathecal administration of a miR-124 mimic reduced the second phase of formalin-induced pain. miR124 directly modulated the expression of MeCP2, a transcriptional regulator involved in inflammatory pain (Géranton et al., 2007, 2008). Consistently, MeCP2 protein is expressed in the same cells expressing miR-124, unequivocally supporting the direct interaction between MeCP2 and miR-124. Furthermore, BDNF, a wellknown MeCP2 target gene that promotes nociceptive transmission in the dorsal horn, was downregulated by miR-124 in intact mice. Since miR-124 was decreased in spinal neurons after spinal cord injury (Strickland et al., 2011a), miR-124 downregulation may also contribute to neuropathic pain after spinal cord injury. On the other hand, miR-124 was shown to promote microglia quiescence (Ponomarev et al., 2011). miR-124 was reported to be decreased by intraplantar IL-1b injection in spinal microglia of microglia/macrophage-specific GRK2 heterozygous (LysM-GRK2+/) mice, which develop prolonged inflammatory hyperalgesia concomitant with ongoing spinal microglia activation by IL-1b treatment (Willemen et al., 2012). Consistently, intrathecal miR-124 treatment prevented the transition to persistent pain in response to IL-1b in LysM-GRK2+/ mice. Interestingly, miR-124 also normalized the expressions of markers for pro-inflammatory (M1-type) and antiinflammatory (M2-type) macrophages in the spinal cord. In addition, intrathecal miR-124 treatment reversed carrageenan-induced hyperalgesia and prevented neuropathic pain in wild-type mice, although it was not shown whether miR-124 expression was reduced in these pain conditions. Microarray data showed that miR-124 was highly expressed in the spinal cord, but remained unchanged in the neuropathic pain state (Brandenburger et al., 2012). miR-124 was reported to be decreased in sensory ganglia after formalin and CFA injection (Bai et al., 2007; Kynast et al., 2013), suggesting the possibility that miR-124 supplementation may alleviate hyperalgesia through actions on the DRG.

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4.3. Spinal glial cells

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Spinal glial cells, especially microglia and astrocytes, have been increasingly recognized as major players in chronic pain through modulation of neurotransmission and neuroinflammation. They are activated in a variety of chronic pain states and release cytokines to facilitate nociceptive transmission (Ji et al., 2013). In the periphery, miRNAs are well-known to modulate inflammatory and immune processes (Rebane and Akdis, 2013). Consistently, several miRNAs have also been shown to modulate spinal glial functions. As described above, miR-124 was reduced by intraplantar IL-1b injection in spinal microglia of LysM-GRK2+/ mice. miR195 was upregulated in isolated spinal microglia after spinal nerve ligation (Shi et al., 2013). Intrathecal administration of a miR-195 inhibitor suppressed neuropathic pain and decreased lipopolysaccharide-induced expression of proinflammatory cytokines (IL-1b and tumor necrosis factor-a) in primary spinal microglia. These analgesic and anti-inflammatory effects of a miR-195 inhibitor were possibly mediated by regulation of autophagy, which is involved in the inflammatory response (Deretic et al., 2013). Putative autophagic activity in primary spinal microglia was decreased

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Integration and processing of sensory inputs occur in the spinal dorsal horn, and the net output from the spinal network is carried to the brain (Kuner, 2010). Such information processing occurs through not only neuron-neuron communication, but also neuron-glia (microglia and astrocyte) communication. Notably, aberrant processing of sensory inputs at the spinal cord level is considered to be a major contributor to chronic pain with both spinal and peripheral origins. As shown in Table 1, TaqMan array analyses revealed that miRNA expressions were significantly changed in the dorsal spinal cord in neuropathic pain induced by peripheral nerve injury (Genda et al., 2013). On the other hand, although the let-7 family members and miR-124 were highly expressed in the spinal cord, these miRNAs did not undergo marked expression changes in the same neuropathic pain model (Brandenburger et al., 2012). In the spinal cord injury model, massive miRNA expression changes were observed in the spinal cord. Interestingly, several miRNA expressions were concurrently changed in pain states in the spinal cord as well as in the DRG. miR146a and the miR-182-96-183 cluster were markedly reduced in both the DRG and spinal cord after induction of osteoarthritic pain (Li et al., 2013). Kusuda et al. (2011) showed that miR-1, miR-16 and miR-206 were differentially modulated in both the DRG and dorsal spinal cord in inflammatory and neuropathic pain. However, there are only sparse data on the function of miRNAs in spinal pain processing during chronic pain.

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4.1. miR-103

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miR-103 is the first well-characterized miRNA in neuropathic pain (Favereaux et al., 2011). Favereaux et al. (2011) found that all three subunits (Cav1.2-a1, -a2d1 and -b1) comprising CaV1.2 L-type calcium channels, which underlie the long-term plastic changes in chronic neuropathic pain (Fossat et al., 2010), were targets for miR-103 in spinal neurons and that miR-103 modulated their expressions. Consistently, miR-103 functionally modulated neuronal calcium transients. In line with these results, miR-103

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by spinal nerve ligation and increased by a miR-195 inhibitor. The effects of a miR-195 inhibitor on autophagic activity and neuropathic pain were impaired by the autophagy inhibitor 3-methyladenine. ATG14, an important regulator of autophagy (Obara and Ohsumi, 2011), was identified as a target for miR-195. Thus, miR195 upregulation appears to contribute to neuropathic pain via enhancement of neuroinflammation by autophagy inhibition. Although their involvement in pain remains to be determined, miR-21 and miR-146a were reported to be involved in glial modulation. miR-21 was upregulated in astrocytes following spinal cord injury (Bhalala et al., 2012). Astrocyte-specific miR-21 inhibition augmented astrocytic hypertrophy and increased axon density within the lesion site after spinal cord injury. On the other hand, miR-146a was decreased and increased in the spinal cord in osteoarthritis and spinal cord injury, respectively (Li et al., 2013; Yunta et al., 2012). Li et al. (2013) found that miR-146a suppressed the upregulation of inflammation-related genes induced by lipopolysaccharide or IL-1b treatment in the microglial cell line BV2 and primary astrocytes. Although the cell type expressing miR-146a in the spinal cord is unknown, miR-146a may provide an efficient means to concurrently suppress glia-mediated neuroinflammation.

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5. miRNAs in the brain

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Chronic pain affects higher brain functions including cognitive, mood and anxiety disorders (McWilliams et al., 2003). Functional MRI studies in humans have indicated that brain activity is extensively affected in individuals with chronic pain (Apkarian et al., 2011). Pain-related changes have been documented at the single cell level in the brain (Saab, 2012). Therefore, through modulation of cellular functions, miRNAs potentially underlie the altered brain functions in chronic pain. There have been several reports to date demonstrating miRNA expression changes in chronic pain, although the functional significance of miRNAs remains to be fully clarified. Many miRNA expressions, such as miR-132 and miR125b, were changed in the hippocampus in neuropathic and inflammatory pain conditions (Arai et al., 2013; Hori et al., 2013). Interestingly, marked overlapping of modulated miRNAs was observed in the hippocampus between neuropathic and inflammatory pain conditions, suggesting that chronic pain causes common miRNA dysregulation at the higher central nervous system level independently of the causes of pain, in contrast to the case for the DRG and spinal cord. Massive expression changes in miRNAs were also reported in the nucleus accumbens, which is thought to be a region that predicts the value of a noxious stimulus and its offset, and then causes changes in the motivational state (Baliki et al., 2010). In the nucleus accumbens, miR-200b and miR-429 expressions were decreased in the neuropathic pain state with a concomitant increase in the protein expression of DNA methyltransferase 3a, a putative target for the miRNAs (Imai et al., 2011). In the prefrontal cortex, miR-155 and miR-223 expressions were reported to increase after facial carrageenan injection (Poh et al., 2011). The let-7 family members were upregulated in the brain after morphine treatment and modulated opioid tolerance by targeting the l opioid receptor (He et al., 2010).

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As described above, miRNA expression changes are extensively induced in chronic pain conditions and are involved in the underlying mechanisms of chronic pain, ranging from neuronal hyperexcitability and neuroinflammation to possibly the altered higher brain function. The miRNA functions can be modulated by miRNA mimics and inhibitors in efficient and stable forms. However, there are associated obstacles, such as drug delivery, to the clinical use of miRNA-related drugs. Oral administration is well-tolerated and

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preferable in most patients on cancer pain management recommended by the WHO, but the current miRNA-related drugs are not available as oral formulations. Intravenous administration is not expected to deliver sufficient amounts of miRNA-related drugs into sensory neurons, especially central nervous system neurons, although systemically injected exosomes were reported to cross the blood–brain barrier and deliver a small-interfering RNA to neurons, microglia and oligodendrocytes in the mouse brain (AlvarezErviti et al., 2011). In most of the studies, miRNA-modifiers were intrathecally administered to alleviate chronic pain in animal experiments. Gene transfer may provide a preferable means for long-term treatment, although safety is a critical concern (Vannucci et al., 2013). Viral vectors modified from lentivirus, adeno-associated virus and herpes simplex virus were shown to be efficiently and specifically transduced to sensory neurons and to express their transgene persistently (Beutler and Reinhardt, 2009; Goss et al., 2014; Sakai et al., 2013; Takasu et al., 2011; Vannucci et al., 2013). In addition, gene therapy can be applied in a site-specific manner to avoid systemic adverse effects. Overall, the development of a drug delivery system to the neural system is required for clinical application of miRNA-related drugs. In addition to therapeutics, miRNAs are expected to be novel biomarkers for neurological disorders (Rao et al., 2013). Since the causes of chronic pain are often not clearly identified and subjective responses to analgesics vary among individual patients, biomarkers for chronic pain would seem to be significantly informative. miRNAs are released into the blood, cerebrospinal fluid and urine from a variety of cells, including neurons. Extracellular miRNAs are detected inside membrane-enclosed vesicles such as exosomes and outside vesicles in complexes with Argonaute2 or lipoproteins such as HDL. Although the mechanism underlying the selection of miRNAs for secretion is poorly understood, extracellular miRNAs may reflect the gene expression profiles of their secreting cells. In fact, miRNA expression changes are highly dependent on distinct chronic pain conditions, as already noted. Accordingly, many miRNAs were decreased in blood samples obtained from patients with complex regional pain syndrome compared with control subjects (Orlova et al., 2011). Nine miRNA expressions in cerebrospinal fluid collected from the lumbar region were decreased in patients with fibromyalgia (Bjersing et al., 2013). miR-150 and miR-342-3p were elevated in blood samples obtained from patients with irritable bowel syndrome (Fourie et al., 2014).

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7. Conclusions and future directions

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miRNA expressions are massively modulated in the overall somatosensory system from primary sensory neurons to higher central nervous system cells in chronic pain, and the therapeutic potential of miRNAs appears promising. However, only a few target genes have been demonstrated to mediate miRNA effects on pain. In addition, the mechanisms of the miRNA expression changes are largely unknown. Difficulties in experimental identification of transcription start sites or promoter regions partly hamper our understanding of the transcriptional modulation of miRNA expression, although expression screenings and bioinformatics analyses have revealed possible promoter regions to some extent. Furthermore, miRNAs were recently reported to mediate intercellular communication. Exosome-mediated transfer of miRNAs to neighboring cells affected protein translation in the recipient cells (Hu et al., 2012; Morel et al., 2013; Xin et al., 2012). Accordingly, miRNAs were suggested to be transmitted transsynaptically (Smythies and Edelstein, 2012). Recently, Park et al. (2014) showed that upon neuronal excitation, miR-let-7b is peripherally released from DRG neurons to excite nociceptor neurons. Intriguingly, the action of miR-let-7b was mediated by the binding of miRNA to toll-like receptor-7 on the nociceptor neurons and subsequent activation

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of TRPA1. Consistently, miR-let-7b inhibitor reduced formalininduced spontaneous pain. Thus, besides the well-known roles of miRNA in translational modulation, miRNAs could be released from DRG neurons and act on the peripheral and spinal neurons as well as microglia and astrocytes as a signal transmitter, contributing to sensitization of the nociceptive pathway. Therefore, we are only at an initial stage in our understanding of the pleiotropic roles of miRNAs in chronic pain; further elucidation will lead to the development of novel strategies for chronic pain medication.

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This work was supported by a Grant-in-Aid for Encouragement of Young Scientists (B) (22791457 to A.S.) from the Japan Society for the Promotion of Science and a grant (S0801035 to H.S.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Please cite this article in press as: Sakai, A., Suzuki, H. Emerging roles of microRNAs in chronic pain. Neurochem. Int. (2014), http://dx.doi.org/10.1016/ j.neuint.2014.05.010