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date: 20 March 2019

The Transition from Acute to Chronic Pain

Abstract and Keywords

Chronic pain is not merely a prolonged form of acute pain but rather results from plastic changes that occur along sensory transduction pathways from the peripheral to the central nervous system. Recent studies have revealed that “hyperalgesic priming,” the plastic changes of nociceptors, is essential for the transition from acute to chronic pain. Once challenged, nociceptors may elicit a signal switch to favor pain chronicity in response to future noxious stimuli. This chapter summarizes the recent progress in research into hyperalgesic priming in different chronic pain models and highlight how the plastic changes of the signal switch varies in different nociceptors. Also discussed is the involvement of proton-sensing receptors in pain chronicity associated with rheumatoid arthritis and fibromyalgia.

Keywords: ASIC3, fibromyalgia, hyperalgesic priming, IB4, pain chronicity, proton-sensing GPCR, rheumatoid arthritis


Chronic pain associated with injury or diseases (arthritis, cancer, diabetes, fibromyalgia [FM], etc.) is characterized by its long-term nature and abnormal sensitivity to thermal and mechanical stimuli in the form of hyperalgesia or allodynia. Chronic pain is not merely a prolonged form of acute pain but rather results from plastic changes that occur along sensory transduction pathways, including the peripheral afferent nerve fibers that are activated by the original injury (peripheral sensitization), the spinal cord where the sensory signal is amplified (central sensitization), and the brain where the signal is interpreted. Emerging lines of evidence suggest neuronal plasticity as a key mechanism for the chronicity of pain. Neuronal plasticity not only occurs at the central level to regulate the chronicity and the spread of pain but also appears at the peripheral level to trigger development of chronic pain and the transition from the acute pain to chronic pain. In the past several decades, much effort has been devoted to elucidate how plastic changes are established to convert acute pain to chronic pain and reveal how neurons work in concert with other nonneuronal cells (such as immune cells, glial cells, bacterial cells, etc.) to contribute to chronic pain modulation. In this review, we summarize the studies of molecular mechanisms involved in pain chronicity in different animal models of chronic pain.

Hyperalgesic Priming Models

Levine and colleagues established the “hyperalgesic priming” model in the rat, which provides a simple system to explore how peripheral sensitization contributes to development of chronic pain. Transient hyperalgesia was first evoked by an intraplantar injection of carrageenan in rat. The second stimulus (such as prostaglandin E2 [PGE2], serotonin [5-HT], A2 adenosine receptor agonist CGS21680) is given to the same site 5 days later after the resolution of the first hyperalgesia. Interestingly, long-lasting hyperalgesia for at least 3 weeks was triggered by the second stimulus, which originally caused short-term hyperalgesia (a few hours) (Aley, Messing, Mochly-Rosen, & Levine, 2000). Later, Levine’s and other groups used various first or second stimuli to successfully reproduce the priming model (Table 1) and dissect molecular mechanisms of hyperalgesic priming. The priming model focuses neuroplastic changes on the peripheral nervous system (PNS) and the central nervous system (CNS) and distinguishes development of the chronic pain in different stages: the initiation state (acute phase), the primed state, and the maintenance state (chronic phase).

Table 1. Factors Involved in Different Types of Hyperalgesic Priming in Nociceptors

Priming Induction


Signal Switch

Pain Model


Injected Site



β2 Adrenergic receptor; TNFα receptor



PGE2-induced pain


Hind paw

Aley et al. (2000) and Parada et al. (2003)




PGE2-induced pain

Hind paw

Joseph, Bogen, Alessandri-Haber, and Levine (2007)





PGE2-induced pain

Hind paw

Eijkelkamp et al. (2010) and Wang et al. (2013)



PGE2-induced pain

Gastrocnemius muscle

Dina, Levine, and Green (2008)

Carrageenan, PKCε agonist



PGE2-induced pain

Hind paw

Bogen et al. (2012)

PKCε agonist



PGE2-induced pain

Hind paw

Aley et al. (2000)

PKCε agonist,

Activated αCaMKII




PGE2-induced pain

Hind paw

Ferrari et al. (2010)





PGE2-induced pain


Hind paw

Joseph and Levine (2010)

NGF & IL-6, IL-6

Protein translation

NGF&IL-6, IL-6-induced pain

Melemedjian et al. (2013)

NGF, IL-6, TNFα, MCP-1


Hind paw, spinal cord

Ferrari, Araldi et al. (2015) and Ferrari, Bogen et al. (2015)


IL-6 receptor

Spinal PKMζ

PGE2-induced pain

Hind paw

Asiedu et al. (2011)

Sound stress



PGE2-induced pain

Hind paw

Dina et al. (2009) and Khasar et al. (2008)


mu-Opioid receptor



PGE2-induced pain


Hind paw

Araldi et al. (2015)


A1 receptor


PGE2-induced pain

Hind paw

Araldi et al. (2016)



Spinal PKMζ

PGE2-induced pain

Hind paw

Melemedjian et al. (2013)



Enhanced TTX-S and TTX-R VGSC

Acid-induced pain


Gastrocnemius muscle

W. N. Chen et al. (2014)





Acid-induced pain

Hind paw

Dai et al. (2017) and W. Y. Huang et al, (2015)


Spinal PKC, ERK

Acid-induced pain

Hind paw

W. H. Chen et al. (2018)


PGE2 receptor



PGE2-induced pain

Hind paw

St-Jacques & Ma (2014)





Hind paw

W. Y. Huang et al. (2015)






Hind paw

Dai et al. (2017) and Huang et al. (2015)

Peripheral Mechanisms: Protein Kinase Cε–Dependent Hyperalgesic Priming

The short-term hyperalgesia induced by PGE2 is regulated by activation of protein kinase A (PKA), and the hyperalgesic effect is attenuated by PKA inhibitors (Aley & Levine, 1999). In primed animals, the acute phase (<4 hr) of hyperalgesia induced by PGE2 is still mediated by PKA. However, in the chronic phase (>4 hr) of PGE2 hyperalgesia, only peripheral inhibition of protein kinase Cε (PKCε) by a peptide inhibitor or antisense oligodeoxynucleotides is able to attenuate prolonged hyperalgesia (Aley et al., 2000; Parada, Yeh, Reichling, & Levine, 2003), suggesting that PKCε is essential in maintaining chronic hyperalgesia. PKCε-dependent prolonged hyperalgesia is restricted to isolectin B4-positive [IB4(+)] neurons due to a failure to establish hyperalgesic priming in the IB4-lesioned animals (Joseph & Levine, 2010). The switch from PKA to PKCε dependency apparently indicates the transition from the acute to the chronic phase of hyperalgesia. This phenomenon not only appears in the priming models, but also is observed in subchronic hyperalgesia induced by a single administration of Complete Freund’s Adjuvant (CFA) or carrageenan (W. Y. Huang, Dai, Chang, & Sun, 2015).

The switch from PKA to PKCε dependence is likely due to a switch of Gs to Gi/o protein coupling because PKCε-dependent prolonged hyperalgesia is inhibited by the Gi/o protein inhibitor pertussis toxin (PTX) (Dina, Khasar, Gear, & Levine, 2009; Joseph & Levine, 2010; Khasar et al., 2008). Similarly, blocking PKA or adenylyl cyclase (AC) only inhibits the acute phase (<4 hr) of hyperalgesia induced by a single injection of CFA, while blockers for Gi/o protein, phospholipase Cβ (PLCβ), or PKCε inhibit the chronic phase (>4 hr) (Huang, Dai, Chang, & Sun, 2015).

Despite the importance of PKCε, it is still not sufficient to explain such a long-lasting hyperalgesia by a simple switch in G protein coupling. It may be associated with gene expression changes and the formation of the pain memory in primary afferent nociceptors. These neuroplastic changes possibly occur at transcriptional and translational levels with distinct mechanisms and are established within 72 hr. At the transcriptional level, the cyclic adenosine monophosphate (cAMP) response element binding proteins (CREBs) are activated in the cell bodies of nociceptors after peripheral stimuli, to express CREB-dependent genes for hyperalgesic priming. Although the precise signaling molecules for activation of CREB remain unclear, it was demonstrated that an intrathecal block of cAMP in dorsal root ganglia (DRG) inhibited priming induction, and intraganglionic injection of cAMP analogues induced priming (Ferrari, Araldi, & Levine, 2015; Ferrari, Bogen, Reichling, & Levine, 2015). It seems that a local increase of the cAMP level in DRG is essential. However, we cannot exclude the possibility that peripherally activated PKA itself or PKA-dependent molecules act as a signal to activate CREB. A study of intraplantar injections of a PGE2 analogue demonstrated that PKA is also required for establishing the priming state (St.-Jacques & Ma, 2014).

At the translational level, several mechanisms are involved in the regulation of translation initiation (Khoutorsky & Price, 2018):

  1. 1. Polyadenylation of messenger RNA (mRNA): A long mRNA poly(A) tail stimulates the translation of mRNA by promoting a mRNA cap-to-tail closed loop through interaction between poly(A)-binding proteins (PABPs), eukaryotic translation initiation factor 4G (eIF4G), and eukaryotic translation initiation factor 4E (eIF4E). Regulation of mRNA polyadenylation involves an RNA-binding protein, cytoplasmic polyadenylation element binding protein (CPEB), which binds to the 3′ untranslated region (UTR) of mRNA and is phosphorylated to enhance the efficiency of polyadenylation-induced translation (Richter, 2007). Peripheral inhibition of protein translation by anisomycin prevents the carrageenan-induced priming (Bogen, Alessandri-Haber, Chu, Gear, & Levine, 2012). Given that CPEB is primarily expressed in IB4(+) DRG neurons (Bogen et al., 2012) and contains at least one potential PKCε phosphorylation site (Bogen et al., 2012; Numazaki, Tominaga, Toyooka, & Tominaga, 2002), it supports the view that CPEB is a potential substrate for PKCε. Indeed, suppression of CPEB expression in primary afferent prevents the enhanced and prolonged hyperalgesia induced by PGE2 in primed animals (Bogen et al., 2012). Thus, PKCε-dependent activation of CPEB acts at the peripheral terminals of IB4(+) nociceptors for ongoing protein translation, which maintains the neuroplastic changes in the priming state.

  2. 2. The eIF4F complex formation: The eIF4F complex comprises eIF4A, which is a RNA helicase; eIF4G, which links eIF4E and PABP to form the cap-to-tail loop; and eIF4E, which specifically binds to the 5′ cap of mRNA. eIF4F complex formation is regulated by the mammalian target of rapamycin complex 1 (mTORC1), the extracellular signal-regulated kinase (ERK), and p38 signaling pathways. mTORC1 phosphorylates 4E-binding protein (4E-BP) to dissociate 4E-BP from eIF4E, facilitating the eIF4F formation. Both ERK and p38 can phosphorylate mitogen-activated protein kinase–interacting kinase 1 (MNK1) to regulate eIF4E activity. Blocking protein translation, mTORC1, or ERK signaling inhibits hyperalgesia induced by nerve growth factor (NGF) or interleukin 6 (IL-6) (Melemedjian et al., 2010). mTOR inhibitors reduce NGF-mediated phosphorylation of 4E-BP, and MNK1 inhibitors block IL-6-mediated eIF4E phosphorylation. Thus, NGF or IL-6 triggers mTORC1 or ERK signaling pathways, respectively, to regulate axonal protein translation, contributing to neuronal plasticity. Mice lacking the MNK gene or the phosphorylation site for MNK on eIF4E confirm the involvement of eIF4E in hyperalgesic priming (Moy et al., 2017).

  3. 3. eIF2α phosphorylation: eIF2α-GTP (guanosine triphosphate) carries the initiator Met-tRNA to the small ribosome to form the preinitiation complex. Phosphorylation of eIF2α reduces its affinity to GTP, inhibiting general translation initiation. Although eIF2α phosphorylation reduces general protein synthesis, it facilitates ribosomal bypass to the translation of mRNA with 5′ upstream open reading frames (uORFs), such as activating transcription factor 4 (ATF4) mRNA translation (Vattem & Wek, 2004). Interestingly, the increase in eIF2α phosphorylation promotes CFA-induced thermal but not mechanical hyperalgesia, implying that ribosomal bypass translation is involved in thermal hyperalgesia (Khoutorsky et al., 2016).

The downstream calcium signaling molecule α calmodulin–dependent protein kinase II (αCaMKII) seems also to be involved in hyperalgesic priming. Hyperalgesic priming induced by activation of αCaMKII is calcium and ryanodine receptor dependent (Ferrari, Bogen, & Levine, 2013). PKCε agonist-induced priming can also be inhibited by a αCaMKII inhibitor or antisense oligonucleotides (Ferrari et al., 2013), suggesting that αCaMKII could be a downstream target of PKCε.

During the primed state, PGE2-induced prolonged hyperalgesia is cAMP dependent, but the downstream pathway now bypasses PKA to activate PKCε. It was suggested that the cAMP-activated guanine exchange factor (Epac) responds to cAMP to activate PKCε in IB4(+) neurons (Hucho, Dina, & Levine, 2005). Epac1 levels are increased in IB4(+) neurons in primed mice, and blocking Epac1 attenuates prolonged hyperalgesia induced by PGE2 or CFA (Wang et al., 2013). In contrast, the level of G protein–coupled receptor kinase 2 (GRK2) is decreased in IB4(+) neurons during priming, and overexpression of GRK2 attenuated prolonged hyperalgesia induced by PGE2 or CFA (Wang et al., 2013). Decreased GRK2 level induces biased cAMP signaling, switching PKA activation to Epac activation, leading to PKCε-dependent hyperalgesia (Eijkelkamp et al., 2010).

Peripheral Mechanisms: PKCε-Independent Hyperalgesic Priming

Hyperalgesic priming occurs in both IB4(+) and IB4(-) nociceptors (Ferrari, Bogen, & Levine, 2010). Nevertheless, PKCε-dependent hyperalgesic priming only occurs in IB4(+) nociceptors, not in IB4(-) nociceptors (Joseph & Levine, 2010), and it seems to appear only in male rats, not in female rats (Joseph, Parada, & Levine, 2003). Repeated exposure to μ-opioid receptor (MOR) agonists induces hyperalgesic priming, but such priming is independent of PKCε, Gαi protein, and protein translation. In contrast, it depends on PKA activation, Gβγ protein, and Src and occurs in IB4(-) neurons in both male and female rats (Araldi, Ferrari, & Levine, 2015). A single injection of A1 adenosine receptor agonist N-cyclepentyladenosine (CPA) also induces PKA-dependent hyperalgesic priming, but it is independent of Gβγ protein (Araldi, Ferrari, & Levine, 2016). Whether Gβγ signaling is involved in PKCε-independent hyperalgesic priming remains to be elucidated.

Central Mechanisms

Accumulating evidence suggests that the prolonged stimulus from peripheral nociceptors cause the neuroplastic changes in the CNS, especially in the dorsal horn of the spinal cord, contributing to establishment of hyperalgesic priming. With both noxious stimulation and peripheral inflammation, the major excitatory neurotransmitter, glutamate, is released from sensory afferents within the dorsal horn of the spinal cord, which acts on the postsynaptic ionotropic glutamate receptors (AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] or NMDA [N-methyl-d-aspartate] receptors) and the G protein–coupled metabotropic receptors (mGluRs) (D’Mello & Dickenson, 2008). If the peripheral stimulus is acute and short, glutamate release only acts on AMPA receptors and causes rapid excitatory neurotransmission in the CNS. Normally, the NMDA receptor is blocked by Mg2+. Thus, transient input cannot act on the NMDA receptor.

However, when the stimulus in peripheral tissues becomes continuous and strong, it can activate several protein kinase cascades, such as αCaMKII, PKA, and PKC, which play a role in the phosphorylation of AMPA receptors (Huganir & Nicoll, 2013). The phosphorylation may potentiate the activity of AMPA receptors and increase their trafficking to the plasma membrane (Esterban et al., 2003). With the repeated activation of AMPA, depolarization of the neurons drives Mg2+ out of the NMDA receptor, facilitating Ca2+ influx through the receptors, leading to activation of second messengers.

Noxious stimuli also trigger release of substance P, which activates the NK1 receptor to enhance single NMDA receptor opening (Lieberman & Mody, 1998). This phenomenon is known as windup, a form of long-term potentiation (LTP) that was originally studied in the brain and correlated with learning and memory. Studies in the superficial spinal dorsal horn revealed that LTP is also induced at C-fiber synapses and contributes to primary hyperalgesia (Sandkühler, 2007). The initial LTP generation requires kinase activities, while protein synthesis is essential for the maintenance of LTP (Abraham & Williams, 2008).

Several molecules and signaling cascades are thought to be involved in the establishment and maintenance of LTP. Primary sensory neurons release endogenous brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn following the short-term patterned electrical stimulation (Balkowiec & Katz, 2000). BDNF binding to tyrosine receptor kinase type B (trkB) regulates the synthesis and phosphorylation of atypical PKC isoform PKMζ (protein kinase M Zeta), maintaining LTP (Lu, Christian, & Lu, 2008; Sacktor, 2012). Intrathecal injection of PKMζ inhibitor ZIP (Zeta-Inhibitory Peptide) or TrkB antagonist ANA-12 (N2-(2-{[(2-oxoazepan-3-yl)amino]carbonyl}phenyl)benzo[b]thiophene-2-carboxamide) prevents the expression of subsequent PGE2-induced allodynia at the primed state (Asiedu et al., 2011; Cazorla et al., 2011; Melemedjian et al., 2013). Intrathecal injection of αCaMKII inhibitor in mice blocks LTP and prevents priming (Nicoll & Roche, 2013). Inhibition of the PKC/ERK signaling pathway in the spinal cord before the first acid injection reduces the LTP enhancement and prevents the second acid injection–induced primed hyperalgesia (W. H. Chen, Chang, Chen, Cheng, & Chen, 2018).

However, it remains puzzling why the initial hyperalgesia resolves if initial LTP is consolidated to late LTP. The study of spinal μ-opioid receptors (MORs) raises the possibility that endogenous analgesic mechanisms serve an inhibitory role in the initial hyperalgesia. During an initial stimulus, the endogenous opioid peptides are released in the dorsal horn, which acts on the MORs to trigger inhibitory signaling, preventing the persistent hyperalgesia. Intrathecal injection of MOR-selective antagonists prolongs the initial hyperalgesia is induced by CFA (Corder et al., 2013). However, repeated intradermal injection of the MOR agonist DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) induces PKCε-independent priming, which markedly prolongs PGE2-induced hyperalgesia (Araldi et al., 2015). It seems that peripheral MORs may have a distinct role from spinal MORs in hyperalgesic priming.

Acidosis-Induced Hyperalgesic Priming and Proton-Sensing Receptors

Studies using hyperalgesic priming models suggest priming is mediated by distinct pathways in different nociceptor populations (Figure 1). In IB4(+) neurons, hyperalgesic priming is (a) delayed in induction (3 days); (b) PKCε and Gi/o protein dependent; and (c) dependent on gene expression and terminal protein translation; and (d) happens in males only. In IB4(-) neurons, hyperalgesic priming is (a) rapidly induced (4 hr); (b) PKA and Src dependent; and (c) independent of terminal protein translation; and (4) happens in both females and males. In IB4(+) neurons, there is a switch time for G protein and kinase dependence, which occurs around 4 hr. However, in IB4(-) neurons, there is no switch for kinase dependency, so it is hard to distinguish the switch time. Because Src inhibition also works at 4 hr after the second stimulus, it seems likely that the transition from acute to chronic pain in the priming models occurs after 4 hr. Studies using dual acid injection and single challenge of inflammatory agents provide more insights into these two distinct features of hyperalgesic priming.

The Transition from Acute to Chronic PainClick to view larger

Figure 1. Hyperalgesic priming models in IB4(+) and IB4(-) nociceptors. An acute or inflammatory insult establishes the primed state that turns acute hyperalgesia into chronic hyperalgesia. The plastic changes occurring in the primed state involved distinct modulations of kinase signaling cascades in IB4(+) and IB4(-) nociceptors. At IB4(-) nociceptors, hyperalgesic priming was rapidly induced (4 hr), PKA and Src dependent, and independent of terminal protein translation. At IB4(+) neurons, hyperalgesic priming was induced with a delay (3 days), PKCε and Gi/o protein dependent, and dependent on CaMKII, gene expression, and terminal protein translation (via CPEB). Epac could be a switch factor from cAMP signaling to PKCε signaling.

When mice are first injected with acid (pH 4.0) in gastrocnemius muscle, a transient hyperalgesia is induced (<24 hr). After the second acid (pH 4.0) injection, mice developed a long-lasting referral and bilateral hyperalgesia (lasting more than 32 days) (W. N. Chen et al., 2014; Sluka, Kalra, & Moore, 2001). Such priming is rapidly induced (1 day), PKCε independent, and IB4(-) neuron specific. Deletion of acid-sensing ion channel 3 (ASIC3) completely inhibits dual acid-induced hyperalgesia, while deletion of transient receptor potential vanilloid receptor subtype 1 (TRPV1) only inhibits the chronic phase of hyperalgesia (W. N. Chen et al., 2014). It seems that ASIC3 is essential for initiating hyperalgesia and establishing hyperalgesic priming in muscle nociceptors, while TRPV1 is important for the maintenance of hyperalgesic priming.

Nevertheless, when mice were intraplantarly injected with acid (pH 5.0), a short-term referral hyperalgesia was induced, lasting for 3 days. Decreasing the injected pH to 4.0 caused a 5-day hyperalgesia (W. Y. Huang et al., 2015). After a second acid (pH 5.0) injection, the induced hyperalgesia became longer, to 8 days, but no contralateral hyperalgesia developed (Dai et al., 2017). Hyperalgesia induced by intraplantar acid administration is similar to that induced by a single injection of CFA or carrageenan. Both are dependent on PKA in the initial phase (<4 hr), but this switches to PKCε in the later phase (>4 hr) (W. Y. Huang et al., 2015). Prolonged hyperalgesia is also dependent on Gαi/o, Gβγ, and PLCβ protein because PTX, galleon, and U73122 inhibits prolonged hyperalgesia (W. Y. Huang et al., 2015). Deletion of T-cell death-associated gene 8 (TDAG8) gene or suppression of TDAG8 expression in DRG inhibits the initial phase of hyperalgesia and shortens prolonged hyperalgesia in both the CFA and dual acid model (Dai et al., 2017). Therefore, TDAG8 is a major candidate for the initiation of hyperalgesia and establishment of hyperalgesic priming in cutaneous nociceptors.

Given that TDAG8 mediates the Gs-cAMP-PKA pathway, it is likely that TDAG8 responds to acidosis signals to trigger the switch from PKA to PKCε through Epac. Alternatively, another proton-sensing receptor, ovarian cancer G protein–coupled receptor 1 (OGR1), mediating Gq or Gi/o-PLCβ-PKC pathways (Y. H. Huang, Su, Chang, & Sun, 2016) could be a potential candidate to regulate prolonged hyperalgesia. However, how TDAG8-mediated signaling regulates kinase or G protein switches remains unclear.

In the CNS, the initial hyperalgesia can be resolved probably through opioid receptor–mediated signaling. In the PNS, the proton-sensing receptor, G2 accumulation (G2A), seems to play a similar role to antagonize TDAG8-mediated signaling. G2A gene expression is increased at 90 min after CFA injection, and its expression is further enhanced by PKA inhibitor, suggesting that G2A is downregulated by PKA signaling (W. Y. Huang et al., 2015). Overexpression of G2A reduces acute pain induced by CFA injection through inhibition of cAMP production (Su et al., 2018), suggesting that G2A could antagonize TDAG8-mediated PKA signaling to resolve the initial hyperalgesia and prevent persistent hyperalgesia. It is likely that TDAG8 expression is increased after acid stimulation and TDAG8 responds to acidosis signals to active cAMP-PKA signaling, triggering pain and hyperalgesia.

Once G2A is expressed and antagonizes TDAG8-mediated PKA signaling, acute pain results. In chronic pain, TDAG8 responds to an acidosis signal to switch to biased cAMP-Epac signaling. Such biased signaling may inhibit G2A function and increase OGR1 function to facilitate establishment of prolonged hyperalgesia. OGR1 mediates Gq or Gi/o-PLCβ-PKC pathway to maintain hyperalgesia (Figure 2). OGR1 can form a heteromer with the G2A to enhance Gi-calcium signaling, compared to OGR1 alone (Y. H. Huang et al., 2016). Alternatively, TDAG8-mediated biased signaling may facilitate formation of OGR1/G2A heteromers to enhance OGR1 function and sequestrate G2A function.

The Transition from Acute to Chronic PainClick to view larger

Figure 2. A putative model of the transition from acute to chronic pain with regulation of proton-sensing receptors. (a) In a dual acid-injection model, acid (pH 5.0) was injected twice, 5 days apart. The first acid injection induced 3-day hyperalgesia, while the second acid injection caused 8-day hyperalgesia. (b) In the acute phase, TDAG8 responded to acid and activated the Gs-cAMP-PKA pathway to trigger acute hyperalgesia. G2A expression was induced later to antagonize TDAG8-mediated signaling, inhibiting pain. In the chronic phase, TDAG8-mediated signaling (probably through Epac) not only inhibited G2A expression, but also promoted OGR1 expression to facilitate the signaling switch. OGR1 could activate Gq or Gi/o protein to activate PKCε and Ca2+ signaling, which may regulate the channel expression and activity, leading to prolonged hyperalgesia.

Single intraplantar administration with acid, carrageenan, or CFA showed a different duration of hyperalgesia, from 3, 16, and 28 days, respectively (W. Y. Huang et al., 2015). All three models have a switch for G protein and kinase dependency, but the switch time varies from 2 to 4 hr and is dependent on PKA activity. Longer PKA activity has a delayed switch time and more prolonged hyperalgesia.

Regulation by Nonneuronal Cells in the Transition from Acute to Chronic Pain

Hyperalgesic priming models focus on signal transduction and the plastic mechanisms in neurons. However, emerging evidence suggests other nonneuronal cells also participate in the regulation of the transition from acute to chronic pain in nerve injury or inflammatory models.

In the CNS, two types of glial cells, microglia and astrocytes, become activated following tissue damage or inflammation. There is growing evidence that microglia and astrocytes contribute to pain processing (McMahon & Malcangio, 2009; Milligan & Watkins, 2009). In paw incision or L5 nerve transection, microglia appear early; astrocytes follow with some delay (Romero-Sandoval, Chai, Nutile-McMenemy, & Deleo, 2008). Similar results were demonstrated in the model of collagen antibody–induced arthritis (CAIA) (Bas et al., 2012). It seems that microglia are related to early induction of pain, but astrocytes contribute to the maintenance of chronic pain. However, the K/BxN serum-transfer arthritis model demonstrated that astrocytes are involved in the early phase, but microglia act on both early and late phases of chronic pain (Christianson et al., 2010), suggesting that microglia not only participate in the induction of pain but also act on the maintenance of chronic pain.

Spinal microglia express and release a lysosomal enzyme, cathepsin S (CatS) that liberates the pronociceptive domain of neuronal fractalkine (FKN, also CX3CL1) to induce activation of microglia, contributing to hyperalgesia. Delayed spinal delivery (14 days), but not acute administration (3 days), of CatS inhibitor reverses hyperalgesia induced by nerve injury (Clark et al., 2007). Of relevance, prolonged intrathecal delivery of CatS inhibitor or anti-FKN attenuates mechanical hyperalgesia in collagen-induced arthritis (CIA) mice (Clark, Grist, Al-Kashi, Perretti, & Malcangio, 2012). Deletion of the CatS gene or intraperitoneal injection of CatS inhibitor reverses the late phase of hyperalgesia through inhibiting the spinal infiltration of CD4+ T cells, which release interferon γ (IFN-γ) to reactivate microglia (Zhang, Wu, Hayashi, Okada, & Nakanishi, 2014).

Nevertheless, early ablation of microglia and monocytes reverses hyperalgesia induced by spinal nerve transection (SNT) (Peng et al., 2016), suggesting a microglial involvement in the induction of pain. Interestingly, only male mice were sensitive to microglial inhibitor reversal of hyperalgesia induced by nerve injury or CFA injection (Sorge et al., 2015). Female mice were insensitive to microglial inhibition but switched to a microglial-dependent pathway in the absence of adaptive immune cells (Sorge et al., 2015). Moreover, adult pain responses in rats could be primed by early life pain experience during the first postnatal week (Beggs, Currie, Salter, Fitzgerald, & Walker, 2012). The neonatal priming effect induced by either paw incision or electrical stimulation on peripheral nerves is maintained centrally in the spinal cord and involves enhanced microglial reactivity.

In the PNS, satellite glial cells (SGCs) tightly surround neurons in the DRG, participating in pain. The number of SGCs was increased and reached the peak at Day 7 after nerve injury and remained there for at least 56 days in an L5 spinal nerve ligation (SNL) model. Prolonged delivery of a glial metabolism inhibitor over 7 days attenuated mechanical hyperalgesia at Day 7 (Liu et al., 2012). This indicates SGC involvement in the early phase of chronic pain. The monoarthritis model demonstrated that SGCs peak at Day 7 and contribute to the early phase of the disease (Nascimento, Castro-Lopes, & Moreira Neto, 2014), while the osteoarthritis model suggested SGC participation in the later phase (6 weeks) (Adães et al., 2017).

Pain Chronicity in Rheumatic Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation, leading to cartilage damage and ultimately total joint destruction (Firestein, 2003). Patients with RA often have a symmetrical pattern of affected joints, with morning stiffness, joint swelling, and tenderness. Pain associated with RA can occur spontaneously or can be evoked by gentle stimulation of the joint when it is moved within its normal working range (Cheng & Penninger, 2004). Pain and tenderness are present not only in joints directly affected but also in surrounding tissues. Referred pain syndromes may also occur. RA pain is historically attributed to peripheral inflammation in the involved joints. Inflammatory pain symptoms can be partially relieved by nonsteroidal anti-inflammatory drugs (NSAIDs), biological or nonbiological disease-modifying antirheumatic drugs (DMARDs), but many patients continue to suffer from moderate pain (Wolfe & Michaud, 2007). More than 10% of patients with RA with inflammatory disease remission (disease activity score in 28 joints [DAS28] < 2.6) have clinically significant pain (pain numeric rating score ≥ 4) (Lee et al., 2011). There is a weak correlation between the intensity of pain and degree of peripheral inflammation (Courvoisier et al., 2008; Studenic, Radner, Smolen, & Aletaha, 2012).

In early RA, functional impairment is believed to be mostly due to an inflammatory process, but in established RA, disability may be due to joint damage (Guillemin, Briançon, & Pourel, 1992). The causes of RA-associated pain could also be different in early and late disease stages. The acute phase of pain could be associated with acute joint inflammation, but the chronic phase of pain could be linked to inflammatory components of neuron–immune interactions (Ji, Chamessian, & Zhang, 2016; Pinho-Ribeiro, Verri, & Chiu, 2017) and noninflammatory components as central pain regulatory mechanisms. The occurrence of pain in conjunction with other centrally mediated symptoms (insomnia, fatigue, memory problems, mood and sleep disturbances) is frequently observed in patients developing centralized pain (Goesling et al., 2013).

It is known that 25% of patients with RA have a comorbid FM; this rate is higher than the prevalence of FM in the general population (2%) (Atzeni et al., 2011). RA patients with comorbid FM have higher disease activity and greater pain (Atzeni et al., 2011; Lee, 2013). Accordingly, DAS28, widely used in practice and clinical trials, may be insufficient to evaluate the real inflammatory activity in patients with RA associated with chronic pain syndromes. Pain is indeed associated with disease activity (McWilliams et al., 2012); the disease activity, however, is not necessarily correlated with inflammatory components in established RA. Current treatments focusing on suppression of inflammation may produce an inadequate response in relieving chronic pain in many patients with RA, especially in patients with RA with other comorbidities.

Given the clinical complexity of RA pain, it is not surprising that it is hard for animal models to reproduce the clinical features of RA pain; some controversy has been reported about data from different arthritis animal models. Accumulating evidence suggests that local mucosal inflammation causes cytokine or autoantibody production and circulation, triggering joint inflammation (Demoruelle, Deane, & Holers, 2014). Proliferation of synoviocytes and infiltration of leukocytes release inflammatory mediators, activating joint fibers for acute pain processing. Activation of joint fibers further activates immune cells and glial cells and increase cytokines, causing more persistent inflammation and pain (Ji et al., 2016; Nieto et al., 2016; Pinho-Ribeiro et al., 2017). In joints, synoviocytes respond to cytokines to release acidic components, lowering pH in synovial fluid (Parak et al., 2000). High hydrogen ion concentration (acidosis) in synovial fluid is associated with disease activity in patients with RA (Farr, Garvey, Bold, Kendall, & Bacon, 1985). Proton-sensing G protein–coupled receptors (GPCRs) in synoviocytes were reportedly linked to the increase in intracellular calcium (Christensen, Kochukov, McNearney, Taglialatela, & Westlund, 2005), which could have a contribution in the downstream inflammatory and cellular proliferative processes of synoviocytes.

Genome-wide association studies (GWASs) demonstrated TDAG8 involvement in the pathogenesis of spondyloarthritis (Cortes et al., 2013) and high TDAG8 expression in pathogenic Th17 cells (Al-Mossawi et al., 2017). Silencing TDAG8 reduces pathogenic cytokine production, potentially attenuating pathogenic T cells (Al-Mossawi et al., 2017). TDAG8-deficient mice reduced the number of Th17 cells and secretion of IL-17A (Gaublomme et al., 2015). Arthritis animal models using repeated intra-articular injection of CFA provided further supporting evidence that TDAG8 deficiency reduced RA disease severity and associated pain (Hsieh, Kung, Huang, Lin, & Sun, 2017), although the model using anticollagen antibody/lipopolysaccharide had opposite results, that TDAG8 deficiency increased RA disease severity (Onozawa, Komai, & Oda, 2011).

In the dual acid or single injection of CFA model, suppression or deletion of TDAG8 inhibited induction of hyperalgesia and shortened chronic hyperalgesia (Dai et al., 2017). However, in an arthritis animal model using repeated intra-articular injection of CFA, knockdown of the TDAG8 gene in peripheral nerves only attenuated the early phase of RA pain, while knockout of the TDAG8 gene attenuated not only the early phase, but also the late phase of pain (Hsieh et al., 2017). These data raise the possibility that peripheral afferents could contribute to the acute and the chronic phases in localized pain (dual acid– or CFA-induced pain).

However, in RA pain, peripheral afferents play a major role in the induction of pain, but a minor role in the maintenance of chronic pain. Some other cells, such as central nerve, immune, or glial cells, could also participate in the chronic phase. The K/BxN serum transfer arthritis model demonstrated that astrocytes are involved in the early phase, but microglia act on early and late phases of chronic pain (Christianson et al., 2010), suggesting microglia importance in the maintenance of chronic pain. TDAG8 is expressed not only in neurons (C. W. Huang et al., 2007) but also in macrophages, T cells, neutrophils, and microglia (Jin et al., 2014; Mogi et al., 2009; Onozawa et al., 2012). It may explain why TDAG8 deficiency affects the chronic phase of RA pain.

TDAG8 mediates hyperalgesic priming in the dual acid or the CFA model. Although the priming effect appears not significant in RA pain, it cannot exclude the role of TDAG8 in the transition from acute to chronic RA pain. In RA pain, such a transition occurs approximately at 3–4 weeks, compared to 4 hr in dual acid– or CFA-induced pain. It is unclear how TDAG8 may mediate such a transition. It may use a similar mechanism as found in the dual acid or CFA model. TDAG8 in peripheral afferents in joints responds to acidosis signals to establish peripheral neuroplastic changes, inducing central neuroplastic changes. Sensitization of peripheral afferents may further activate immune cells and glial cells to work in concert to maintain the chronic phase. ASIC3- or TRPV1-deficient mice showed reduced RA hyperalgesia in the late phase (Hsieh et al., 2017). TDAG8 can potentiate TRPV1 function in the CFA-induced inflammatory model and acid-induced itch model (Y. J. Chen, Huang, Lin, Chang, & Sun, 2009; S. H. Lin et al., 2017). Therefore, ASIC3 and TRPV1 are two potential downstream effectors for TDAG8-mediated signaling.

Pain Chronicity in Fibromyalgia

Fibromyalgia is one of the most mysterious diseases, affecting 1–5% of the population (Jones et al., 2015). FM is characterized by chronic pain, which is widespread in the musculoskeletal system and associated with allodynia and hyperalgesia and often accompanied by comorbid conditions of migraine, chronic fatigue, sleep disturbance, depression, and so on (Hung & Chen, 2015; Sluka & Clauw, 2016). The processes involved in the development and maintenance of chronic widespread muscle pain in FM are still unclear. Factors that influence the process of pain chronicity may include (a) the time course of afferent stimulation of peripheral nociceptors in (sub)acute phases; and (b) relatively minor noxious stimulation in established sensitization of central pain pathways (Nijs & van Houdenhove, 2009). Clinically, migraine and visceral pain might trigger the development of FM by augmenting the level of central sensitization (Giamberardino et al., 2015; Constantini, Affaitai, Wesselmann, Czakanski, & Giamberardino, 2017). In addition, stages of chronicity in FM are highly associated with pain catastrophizing, a thinking process that accompanies the experience of unremitting pain (Rodero et al., 2010). However, because the etiology of FM remains obscure, we can only probe the underlying mechanisms that regulate the pain chronicity for chronic widespread muscle pain, instead of FM.

In rodents, chronic widespread muscle pain (or FM-like pain) can be induced by dual acid (pH 4.0 saline) injections to the gastrocnemius muscle (Sluka et al., 2001, 2003). In this model, a single acid injection to one side of the gastrocnemius muscle elicits transient hyperalgesia and nociceptor priming; a second acid injection to the same site induces long-lasting hyperalgesia (Sun & Chen, 2016). Although the noxious acid stimulation is only at one side of the gastrocnemius muscle, animals not only express bilateral muscle hyperalgesia but also develop referral and mirror image hyperalgesia in both hind paws, which mimics the chronic widespread pain symptoms in patients with FM.

As mentioned, ASIC3 and TRPV1 are essential for the acid-induced hyperalgesic priming in IB4(-) muscle nociceptors. Different from other nociceptors, enhanced activity of voltage-gated sodium channels (VGSCs), but not PKCε, was involved in acid-induced hyperalgesic priming in muscle nociceptors (W. N. Chen et al., 2014). Moreover, the stimulation modality would have profound effects on two modes of hyperalgesic priming: the duration of the priming and the establishment of the priming, which determines how long the chronic pain (hyperalgesia) can last (Fong et al., 2015). The duration of priming is determined by the activation of ASIC3 and enhanced activity of TTX-sensitive VGSCs. In contrast, the establishment of priming is determined by activation of both ASIC3 and TRPV1 and enhanced activity of TTX-resistant VGSCs. Interestingly, the acid-induced hyperalgesic priming is balanced between the activation of ASIC3-TRPV1 and a non-ASIC3, non-TRPV1 proton-sensing receptor (or called the acid sensor X, AS-X), which triggers the release of substance P and thus opens the Kv7 channel to inhibit acid-induced neuron depolarization (Figure 3) (W. N. Chen & Chen, 2014; C. C. J. Lin et al., 2012). Of note, substance P is a well-known pain neurotransmitter released by nociceptors to activate neurokinin 1 (NK1) receptor, a GPCR, and thus induce neurogenic inflammation in the periphery and facilitate central sensitization in the spinal cord dorsal horn (Hokfelt, Pernow, & Wahren, 2001). However, substance P is antinociceptive in muscle nociceptors; intramuscular injection of substance P induces neither muscle pain nor neurogenic inflammation of muscle tissue (C. C. J. Lin et al., 2012; Mense, 1993). When both ASIC3 and TRPV1 are inhibited, intramuscular acid (pH 4.0) injection would trigger neither transient hyperalgesia nor hyperalgesic priming. Instead, activation of AS-X mediates an antinociceptive effect lasting for 2 days (W. N. Chen & Chen, 2014). In such a case, muscle nociceptors are blunt to further acid challenges. In contrast, either by genetic deletion of substance P or pharmacological blockade of NK1 receptor, a single acid injection could trigger long-lasting, chronic, widespread pain in mice lacking substance P signaling (C. C. J. Lin et al., 2012).

The Transition from Acute to Chronic PainClick to view larger

Figure 3. Factors that modulate the hyperalgesic priming in IB4(-) muscle nociceptors in a mouse model of fibromyalgia. In the Sluka acid-induced, chronic, widespread muscle pain model, two intramuscular injections of acid saline (pH 4.0), 5 days apart, induced chronic mechanical hyperalgesia that lasted for more than 4 weeks. The first acid injection induced a hyperalgesic priming lasting for 1 to 5 days on IB4-negative muscle nociceptors. Activation of ASIC3 in muscle nociceptors enhanced the activity of TTX-sensitive (TTX-S) sodium channels and determined the duration of the priming, whereas activation of ASIC3 or TRPV1 enhanced the activation of TTX-resistant (TTX-R) sodium channels and determined the establishment of priming. Meanwhile, activation of the non-ASIC3, non-TRPV1, proton-sensing receptor (acid sensor X or AS-X) triggered the release of substance P, which acted on NK1R to open M-type potassium channels and thus inhibited the hyperalgesic priming.

The rodent models of acid-induced chronic widespread pain provide insights to dissect how nociceptive and antinociceptive signaling pathways are involved in nociceptor priming and pain chronicity. Conceptually, repeated acid challenges and imbalanced acid–substance P signaling might be the risk factors for the pain chronicity in the transition from acute musculoskeletal pain to chronic widespread pain and FM. Nevertheless, further studies of animal models and human genetics are needed to explore the causative factors of FM.


Taken together, repeated noxious stimuli seem to be the major risk factors contributing to the transition from acute to chronic pain. In most cases, a single noxious challenge of inflammation or tissue acidosis would prime specific nociceptors, by which the primed nociceptors trigger a signal switch to favor the chronic pain development in response to future noxious stimulation. The signal switch mechanism is operated in a modality-specific manner and is cell type specific. For instance, although tissue acidosis would activate all types of proton-sensing receptors, signal switch patterns are different between IB4(+) and IB4(-) nociceptors projecting to hind paws or muscle. Nevertheless, we are just at the beginning of our appreciation of the complexity of hyperalgesic priming. Future research into pain chronicity in different chronic pain models would warrant the development of better strategies to conquer the intractable pain associated with RA, FM, and neuropathic pain.


This work was supported by intramural funding of Academic Sinica and grants from the Ministry of Science and Technology, Taiwan (MOST105-2320-B-001-018-MY3, MOST107-2321-B-001-020, and MOST107-2319-B-001-002 for CCC; MOST106-2320-B-008-004-MY3 for WHS). We thank Miss Chia-Wen Wong for her wonderful work in scientific illustration.


Abraham, W. C., & Williams, J. M. (2008). LTP maintenance and its protein synthesis-dependence. Neurobiology of Learning and Memory, 89(3), 260–268.Find this resource:

Adães, S., Almeida, L., Potes, C. S., Ferreira, A. R., Castro-Lopes, J. M., Ferreira-Gomes, J., & Neto, F. L. (2017). Glial activation in the collagenase model of nociception associated with osteoarthritis. Molecular Pain, 13, 1–12.Find this resource:

Aley, K. O., & Levine, J. D. (1999). Role of protein kinase A in the maintenance of inflammatory pain. The Journal of Neuroscience, 19(16), 2181–2186.Find this resource:

Aley, K. O., Messing, R. O., Mochly-Rosen, D., & Levine, J. D. (2000). Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. The Journal of Neuroscience, 20(12), 4680–4685.Find this resource:

Al-Mossawi, M. H., Chen, L., Fang, H., Ridley, A., de Wit, J., Yager, N., … Bowness, P. (2017). Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nature Communications, 8(1), 1510.Find this resource:

Araldi, D., Ferrari, L. F., & Levine, J. D. (2015). Repeated mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain. The Journal of Neuroscience, 35(36), 12502–12517.Find this resource:

Araldi, D., Ferrari, L. F., & Levine, J. D. (2016). Adenosine-A1 receptor agonist induced hyperalgesic priming type II. Pain, 157(3), 698–709.Find this resource:

Asiedu, M. N., Tillu, D. V., Melemedjian, O. K., Shy, A., Sanoja, R., Bodell, B., … Price, T. J. (2011). Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. The Journal of Neuroscience, 31(18), 6646–6653.Find this resource:

Atzeni, F., Cazzola, M., Benucci, M., Di Franco, M., Salaffi, F., & Sarzi-Puttini, P. (2011). Chronic widespread pain in the spectrum of rheumatological diseases. Best Practice & Research Clinical Rheumatology, 25(2), 165–171.Find this resource:

Balkowiec, A., & Katz, D. M. (2000). Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. The Journal of Neuroscience, 20(19), 7417–7423.Find this resource:

Bas, D. B., Su, J., Sandor, K., Agalave, N. M., Lundberg, J., Codeluppi, S., … Svensson, C. I. (2012). Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis & Rheumatism, 64(12), 3886–3896.Find this resource:

Beggs, S., Currie, G., Salter, M. W., Fitzgerald, M., & Walker, S. M. (2012). Priming of adult pain responses by neonatal pain experience: Maintenance by central neuroimmune activity. Brain, 135(Pt. 2), 404–417.Find this resource:

Bogen, O., Alessandri-Haber, N., Chu, C., Gear, R. W., & Levine, J. D. (2012). Generation of a pain memory in the primary afferent nociceptor triggered by PKCε activation of CPEB. The Journal of Neuroscience, 32(6), 2018–2026.Find this resource:

Cazorla, M., Premont, J., Mann, A., Girard, N., Kellendonk, C., & Rognan, D. (2011). Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. The Journal of Clinical Investigation, 121(5), 1846–1857.Find this resource:

Chen, W. H., Chang, Y. T., Chen, Y. C., Cheng, S. J., & Chen, C. C. (2018). Spinal protein kinase C/extracellular signal-regulated kinase signal pathway mediates hyperalgesia priming. Pain, 159(5), 907–918.Find this resource:

Chen, W. N., & Chen, C. C. (2014). Acid mediates a prolonged antinociception via substance P signaling in acid-induced chronic widespread pain. Molecular Pain, 10, 30.Find this resource:

Chen, W. N., Lee, C. H., Lin, S. H., Wong, C. W., Sun, W. H., Wood, J. N., & Chen, C. C. (2014). Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Molecular Pain, 10, 40.Find this resource:

Chen, Y. J., Huang, C. W., Lin, C. S., Chang, W. H., & Sun, W. H. (2009). Expression and function of proton-sensing G protein-coupled receptors in inflammatory pain. Molecular Pain, 5, 39.Find this resource:

Cheng, H. Y., & Penninger, J. M. (2004). Dreaming about arthritic pain. Annals of the Rheumatic Diseases, 63(Suppl. 2), ii72–ii75.Find this resource:

Christensen, B. N., Kochukov, M., McNearney, T. A., Taglialatela, G., & Westlund, K. N. (2005). Proton-sensing G protein-coupled receptor mobilizes calcium in human synovial cells. American Journal of Physiology Cell Physiology, 289(3), C601–C608.Find this resource:

Christianson, C. A., Corr, M., Firestein, G. S., Mobargha, A., Yaksh, T. L., & Svensson, C. I. (2010). Characterization of the acute and persistent pain state present in K/BxN serum transfer arthritis. Pain, 151(2), 394–403.Find this resource:

Clark, A. K., Grist, J., Al-Kashi, A., Perretti, M., & Malcangio, M. (2012). Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis & Rheumatism, 64(6), 2038–2047.Find this resource:

Clark, A. K., Yip, P. K., Grist, J., Gentry, C., Staniland, A. A., Marchand, F., … Malcangio, M. (2007). Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America, 104(25), 10655–10660.Find this resource:

Constantini, R., Affaitai, G., Wesselmann, U., Czakanski, P., & Giamberardino, M. A. (2017). Visceral pain as a triggering factor for fibromyalgia symptoms in comorbid patients. Pain 158(10), 1925–1937.Find this resource:

Corder, G., Doolen, S., Donahue, R. R., Winter, M. K., Jutras, B. L., He, Y., … Taylor, B. K. (2013). Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science, 341(6152), 1394–1399.Find this resource:

Cortes, A., Hadler, J., Pointon, J. P., Robinson, P. C., Karaderi, T., Leo, P., … Brown, M. A. (2013). Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature Genetics, 45(7), 730–738.Find this resource:

Courvoisier, N., Dougados, M., Cantagrel, A., Goupille, P., Meyer, O., Sibilia, J., … Combe, B. (2008). Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: A prospective study. Arthritis Research & Therapy, 10(5), 1186.Find this resource:

Dai, S. P., Huang, Y. H., Chang, C. J., Huang, Y. F., Hsieh, W. S., Tabata, Y., … Sun, W. H. (2017). TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice. Scientific Reports, 7, 41415.Find this resource:

Demoruelle, M. K., Deane, K. D., & Holers, V. M. (2014). When and where does inflammation begin in rheumatoid arthritis? Current Opinion in Rheumatology, 26(1), 64–71.Find this resource:

Dina, O. A., Khasar, S. G., Gear, R. W., & Levine, J. D. (2009). Activation of Gi induces mechanical hyperalgesia poststress or inflammation. Neuroscience, 160(2), 501–507.Find this resource:

Dina, O. A., Levine, J. D., & Green, P. G. (2008). Muscle inflammation induces a protein kinase Cepsilon-dependent chronic-latent muscle pain. Journal of Pain, 9(5), 457–462.Find this resource:

D’Mello, R., & Dickenson, A. H. (2008). Spinal cord mechanisms of pain. British Journal of Anaesthesia, 101(1), 8–16.Find this resource:

Eijkelkamp, N., Wang, H., Garza-Carbajal, A., Willemen, H. L., Zwartkruis, F. J., Wood, J. N., … Kavelaars, A. (2010). Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK. The Journal of Neuroscience, 30(38), 12806–12815.Find this resource:

Esterban, J. A., Shi, S. H., Wilson, C., Nuriya, M., Huganir, R. L., & Malinow, R. (2003). PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neuroscience, 6(2), 136–143.Find this resource:

Farr, M., Garvey, K., Bold, A. M., Kendall, M. J., & Bacon, P. A. (1985). Significance of the hydrogen ion centration in synovial fluid in rheumatoid arthritis. Clinical and Experimental Rheumatology, 3(2), 99–104.Find this resource:

Ferrari, L. F., Araldi, D., & Levine, J. D. (2015). Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming. The Journal of Neuroscience, 35(15), 6107–6116.Find this resource:

Ferrari, L. F., Bogen, O., & Levine, J. D. (2010). Nociceptor subpopulations involved in hyperalgesic priming. Neuroscience, 165(3), 896–901.Find this resource:

Ferrari, L. F., Bogen, O., & Levine, J. D. (2013). Role of nociceptor αCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. The Journal of Neuroscience, 33(27), 11002–11011.Find this resource:

Ferrari, L. F., Bogen, O., Reichling, D. B., & Levine, J. D. (2015). Accounting for the delay in the transition from acute to chronic pain: Axonal and nuclear mechanisms. The Journal of Neuroscience, 35(2), 495–507.Find this resource:

Firestein, G. S. (2003). Evolving concepts of rheumatoid arthritis. Nature, 423(6937), 356–361.Find this resource:

Fong, S. W., Chen, W. N., & Chen, C. C. (2015). Is acid painful or not? Itch & Pain, 2, e721.Find this resource:

Gaublomme, J. T., Yosef, N., Lee, Y., Gertner, R. S., Yang, L. V., Wu, C., … Regev, A. (2015). Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell, 163(6),1400–1412.Find this resource:

Giamberardino, M. A., Affaitai, G., Martelletti, P., Tana, C., Negro, A., Lapenna, D., … Costantini, R. (2015). Impact of migraine on fibromyalgia symptoms. The Journal of Headache and Pain, 17, 28.Find this resource:

Goesling, J., Clauw, D. J., & Hassett, A. L. (2013). Pain and depression: An integrative review of neurobiological and psychological factors. Current Psychiatry Reports, 15(12), 421.Find this resource:

Guillemin, F., Briançon, S., & Pourel, J. (1992). Functional disability in rheumatoid arthritis: Two different models in early and established disease. Journal of Rheumatology, 19(3), 366–369.Find this resource:

Hokfelt, T., Pernow, B., & Wahren, J. (2001). Substance P: A pioneer amongst neuropeptides. Journal of Internal Medicine, 249(1), 27–40.Find this resource:

Hsieh, W. S., Kung, C. C., Huang, S. L., Lin, S. C., & Sun, W. H. (2017). TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis. Scientific Reports, 7, 8870.Find this resource:

Huang, C. W., Tzeng, J. N., Chen, Y. J., Tsai, W. F., Chen, C. C., & Sun, W. H. (2007). Nociceptors of dorsal root ganglion express proton-sensing G protein-coupled receptors. Molecular and Cellular Neuroscience, 36(2), 195–210.Find this resource:

Huang, W. Y., Dai, S. P., Chang, Y. C., & Sun, W. H. (2015). Acidosis mediates the switching of Gs-PKA and Gi-PKCε dependence in prolonged hyperalgesia induced by inflammation. PLoS One, 10, e0125022.Find this resource:

Huang, Y. H., Su, Y. S., Chang, C. J., & Sun, W. H. (2016). Heteromerization of OGR1 and G2A enhance proton signaling. Journal of Receptors and Signal Transduction, 36(6), 633–644.Find this resource:

Hucho, T. B., Dina, O. A., & Levine, J. D. (2005). Epac mediates a cAMP-to-PKC signaling in inflammatory pain: An isolectin B4(+) neuron-specific mechanism. The Journal of Neuroscience, 25(26), 6119–6126.Find this resource:

Huganir, R. L., & Nicoll, R. A. (2013). AMPARs and synaptic plasticity: The last 25 years. Neuron, 80(3), 704–717.Find this resource:

Hung, C. H., & Chen, C. C. (2015). Current challenges of research into fibromyalgia: From clinical studies to animal models. Fibromyalgia: Open Access, 1(1), e103.Find this resource:

Ji, R. R., Chamessian, A., & Zhang, Y. Q. (2016). Pain regulation by non-neuronal cells and inflammation. Science, 354(6312), 572–577.Find this resource:

Jin, Y., Sato, K., Tobo, A., Mogi, C., Tobo, M., Murata, N., … Okajima, F. (2014). Inhibition of interleukin-1β production by extracellular acidification through the TDAG8/cAMP pathway in mouse microglia. Journal of Neurochemistry, 129(4), 683–695.Find this resource:

Jones, G. T., Atzeni, F., Beasley, M., Flub, E., Sarzi-Puttini, P., & Macfarlane, G. J. (2015). The prevalence of fibromyalgia in the general population: A comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. Arthritis & Rheumatology, 67(2), 568–575.Find this resource:

Joseph, E. K., Bogen, O., Alessandri-Haber, N., & Levine, J. D. (2007). PLC-beta 3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia. Pain, 132(1), 67–73.Find this resource:

Joseph, E. K., & Levine, J. D. (2010). Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience, 169(1), 431–435.Find this resource:

Joseph, E. K., Parada, C. A., & Levine, J. D. (2003). Hyperalgesic priming in the rat demonstrates marked sexual dimorphism. Pain, 105(1), 143–150.Find this resource:

Khasar, S. G., Burkham, J., Dina, O. A., Brown, A. S., Bogen, O., Alessandri-Haber, N., … Levine, J. D. (2008). Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain. The Journal of Neuroscience, 28(22), 5721–5730.Find this resource:

Khoutorsky, A., & Price, T. J. (2018). Translational control mechanisms in persistent pain. Trends in Neurosciences, 41(2), 100–114.Find this resource:

Khoutorsky, A., Sorge, R. E., Prager-Khoutorsky, M., Pawlowski, S. A., Longo, G., Jafarnejad, S. M., Tahmasebi, S., … Sonenberg, N. (2016). eIF2α phosphorylation controls thermal nociception. Proceedings of the National Academy of Sciences of the United States of America, 113(42), 11949–11954.Find this resource:

Lee, Y. C. (2013). Effect and treatment of chronic pain in inflammatory arthritis. Current Rheumatology Reports, 15(1), 300.Find this resource:

Lee, Y. C., Cui, J., Lu, B., Frits, M. L., Iannaccone, C. K., Shadick, N. A., … Solomon, D. H. (2011). Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: A longitudinal observational study. Arthritis Research and Therapy, 13(3), R83.Find this resource:

Lieberman, D. M., & Mody, I. (1998). Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. Journal of Neurophysiology, 80(1), 113–119.Find this resource:

Lin, C. C. J., Chen, W. N., Chen, C. J., Lin, Y. W., Zimmer, A., & Chen, C. C. (2012). An antinociception role for substance P in acid-induced chronic muscle pain. Proceedings of the National Academy of Sciences of the United States of America, 109(2), E76–E83.Find this resource:

Lin, S. H., Steinhoff, M., Ikoma, A., Chang, Y. C., Cheng, Y. R., Chandra Kopparaju, R., … Chen, C. C. (2017). Involvement of TRPV1 and TDAG8 in pruriception associated with noxious acidosis. Journal of Investigative Dermatology, 137(1), 170–178.Find this resource:

Liu, F. Y., Sun, Y. N., Wang, F. T., Li, Q., Su, L., Zhao, Z. F., … Wan, Y. (2012). Activation of satellite glial cells in lumbar dorsal root ganglia contributes to neuropathic pain after spinal nerve ligation. Brain Research, 1427, 65–77.Find this resource:

Lu, Y., Christian, K., & Lu, B. (2008). BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiology of Learning and Memory, 89(3), 312–323.Find this resource:

McMahon, S. B., & Malcangio, M. (2009). Current challenges in glia-pain biology. Neuron, 64(1), 46–54.Find this resource:

McWilliams, D. F., Zhang, W., Mansell, J. S., Kiely, P. D., Young, A., & Walsh, D. A. (2012). Predictors of change in bodily pain in early rheumatoid arthritis: An inception cohort study. Arthritis Care & Research (Hoboken), 64(10), 1505–1513.Find this resource:

Melemedjian, O. K., Asiedu, M. N., Tillu, D. V., Peebles, K. A., Yan, J., Ertz, N., … Price, T. J. (2010). IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. The Journal of Neuroscience, 30(45), 15113–15123.Find this resource:

Melemedjian, O. K., Tillu, D. V., Asiedu, M. N., Mandell, E. K., Moy, J. K., Blute, V. M., … Price, T. J. (2013). BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Molecular Pain, 9, 12.Find this resource:

Mense, S. (1993). Nociception from skeletal muscle in relation to clinical muscle pain. Pain, 54(3), 241–289.Find this resource:

Milligan, E. D., & Watkins, L. R. (2009). Pathological and protective roles of glia in chronic pain. Nature Review Neuroscience, 10(1), 23–36.Find this resource:

Mogi, C., Tobo, M., Tomura, H., Murata, N., He, X. D., Sato, K., … Okajima, F. (2009). Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. Journal of Immunology, 182(5), 3243–3251.Find this resource:

Moy, J. K., Khoutorsky, A., Asiedu, M. N., Black, B. J., Kuhn, J. L., Barragán-Iglesias, P., … & Price, T. J. (2017). The MNK-eIF4E signaling axis contributes to injury-induced nociceptive plasticity and the development of chronic pain. The Journal of Neuroscience, 37(31), 7481–7499.Find this resource:

Nascimento, D. S., Castro-Lopes, J. M., & Moreira Neto, F. L. (2014). Satellite glial cells surrounding primary afferent neurons are activated and proliferate during monoarthritis in rats: Is there a role for ATF3? PLoS One, 9, e108152.Find this resource:

Nicoll, R. A., & Roche, K. W. (2013). Long-term potentiation: Peeling the onion. Neuropharmacology, 74, 18–22.Find this resource:

Nieto, F. R., Clark, A. K., Grist, J., Hathway, G. J., Chapman, V., & Malcangio, M. (2016). Neuron-immune mechanisms contribute to pain in early stages of arthritis. Journal of Neuroinflammation, 13(1), 96.Find this resource:

Nijs, J., & van Houdenhove, B. (2009). From acute musculoskeletal pain to chronic widespread pain and fibromyalgia: Application of pain neurophysiology in manual therapy practice. Manual Therapy, 14(1), 3–12.Find this resource:

Numazaki, M., Tominaga, T., Toyooka, H., & Tominaga, M. (2002). Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. Journal of Biological Chemistry, 277(16), 13375–13378.Find this resource:

Onozawa, Y., Fujita, Y., Kuwabara, H., Nagasaki, M., Komai, T., & Oda, T. (2012). Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro. European Journal of Pharmacology, 683(3), 325–331.Find this resource:

Onozawa, Y., Komai, T., & Oda, T. (2011). Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. European Journal of Pharmacology, 654(3), 315–319.Find this resource:

Parada, C. A., Yeh, J. J., Reichling, D. B., & Levine, J. D. (2003). Transient attenuation of protein kinase Cepsilon can terminate a chronic hyperalgesic state in the rat. Neuroscience, 120(1), 219–226.Find this resource:

Parak, W. J., Dannohl, S., George, M., Schuler, M. K., Schaumburger, J., Gaub, H. E., … Aicher, W. K. (2000). Metabolic activation stimulates acid production in synovial fibroblasts. Journal of Rheumatology, 27(10), 2312–2322.Find this resource:

Peng, J., Gu, N., Zhou, L. B., Eyo, U., Murugan, M., Gan, W. B., & Wu, L. J. (2016). Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nature Communications, 7, 12029.Find this resource:

Pinho-Ribeiro, F. A., Verri, W. A., Jr., & Chiu, I. M. (2017). Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends in Immunology, 38(1), 5–19.Find this resource:

Richter, J. D. (2007). CPEB: A life in translation. Trends in Biochemical Sciences, 32(6), 279–285.Find this resource:

Rodero, B., Casanueva, B., Garcia-Campayo, J., Roca, M., Magallon, R., & del Hoyo, Y. L. (2010). Stages of chronicity in fibromyalgia and pain catastrophizing: A cross-sectional study. BMC Musculoskeletal Disorders, 11, 251.Find this resource:

Romero-Sandoval, A., Chai, N., Nutile-McMenemy, N., & Deleo, J. A. (2008). A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain Research, 1219, 116–126.Find this resource:

Sacktor, T. C. (2012). Memory maintenance by PKMζ—an evolutionary perspective. Molecular Brain, 5, 31.Find this resource:

Sandkühler, J. (2007). Understanding LTP in pain pathways. Molecular Pain, 3, 9.Find this resource:

Sluka, K. A., & Clauw, D. J. (2016). Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience, 338, 114–129.Find this resource:

Sluka, K. A., Kalra, A., & Moore, S. A. (2001). Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve, 24(1), 37–46.Find this resource:

Sluka, K. A., Price, M. P., Breese, N. M., Stucky, C. L., Wemmie, J., & Welsh, M. J. (2003). Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain, 106(3), 229–239.Find this resource:

Sorge, R. E., Mapplebeck, J. C., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., … Mogil, J. S. (2015). Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nature Neuroscience, 18(8), 1081–1083.Find this resource:

St.-Jacques, B., & Ma, W. (2014). Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors. Experimental Neurology, 261, 354–366.Find this resource:

Studenic, P., Radner, H., Smolen, J. S., & Aletaha, D. (2012). Discrepancies between patients and physicians in their perceptions of rheumatoid arthritis disease activity. Arthritis & Rheumatology, 64(9), 2814–2823.Find this resource:

Su, Y. S., Huang, Y. F., Wong, J., Lee, C. W., Hsieh, W. S., & Sun, W. H. (2018). G2A as a threshold regulator of inflammatory hyperalgesia modulates chronic hyperalgesia. Journal of Molecular Neuroscience, 64(1), 39–50.Find this resource:

Sun, W. H., & Chen, C. C. (2016). Roles of proton-sensing receptors in the transition from acute to chronic pain. Journal of Dental Research, 95(2), 135–142.Find this resource:

Vattem, K. M., & Wek, R. C. (2004). Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America, 101(31), 11269–11274.Find this resource:

Wang, H., Heijnen, C. J., van Velthoven, C. T., Willemen, H. L., Ishikawa, Y., Zhang, X., … Kavelaars, A. (2013). Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain. The Journal of Clinical Investigation, 123(12), 5023–5034.Find this resource:

Wolfe, F., & Michaud, K. (2007). Assessment of pain in rheumatoid arthritis: Minimal clinically significant difference, predictors, and the effect of anti-tumor necrosis factor therapy. Journal of Rheumatology, 34(8), 1674–1683.Find this resource:

Zhang, X., Wu, Z., Hayashi, Y., Okada, R., & Nakanishi, H. (2014). Peripheral role of cathepsin S in Th1 cell-dependent transition of nerve injury-induced acute pain to a chronic pain state. The Journal of Neuroscience, 34(8), 3013–3022.Find this resource: