Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Oct 1.
Published in final edited form as: Curr Opin Physiol. 2019 Jun 18;11:67–74. doi: 10.1016/j.cophys.2019.06.006

Chronic non-inflammatory muscle pain: central and peripheral mediators

Joseph Lesnak a, Kathleen A Sluka a,*
PMCID: PMC6988739  NIHMSID: NIHMS1534824  PMID: 31998857

Abstract

Conditions with chronic widespread non-inflammatory muscle pain, such as fibromyalgia, have complex etiologies with numerous proposed mechanisms for their pathophysiology of underlying chronic pain. Advancements in neuroimaging have allowed for the study of brain function and connectivity in humans with these conditions, while development of animal models have allowed for the study of both peripheral and central factors that lead to chronic pain. This article reviews the current literature surrounding the pathophysiology of chronic widespread non-inflammatory muscle pain focusing on both peripheral and central nervous system, as well as immune system, contributions to the development and maintenance of pain. A better understanding of the mechanisms underlying these conditions can allow for improvements in patient education, treatment and outcomes.

Keywords: Chronic pain, muscle pain, hyperalgesia, neurobiology, central sensitization

1.0. Introduction

Chronic pain is a significant health problem affecting over 100 million Americans—more than diabetes, cancer, and heart disease combined, with musculoskeletal pain affecting between 13–47% of the population(1). Pain that persists beyond tissue healing time and without overt damage to peripheral tissues is common and difficult to treat. Clinically, localized pain is less common with only 20% of those surveyed reporting pain in one area(2). Participation in social, physical, and daily activities progressively decrease in relation to the number of pain areas(2). Women have a greater incidence of musculoskeletal pain(3), are more likely to have five or more areas of pain (23%) compared with men (11%)(2), and infusion of acidic buffer into muscle results in more referred pain in women (80%) compared with men (40%)(4). Chronic pain can be defined as pain that persists past normal tissue healing time, in the absence of nociceptive input, or that is out of proportion to the injury. Animal models to mimic this type of chronic pain have been developed which allow researchers to investigate potential mechanisms of chronic widespread pain. This review will focus on mechanisms underlying chronic widespread muscle pain.

1.1. Models of Non-Inflammatory widespread pain

Induction of long-lasting, widespread hyperalgesia occurs in response to multiple stressors or insults to the animal(5–15). These insults can include multiple muscle insults such as inflammation, acute fatiguing exercise, and decreases in local pH; or can include stress, obesity, and sedentary activity levels combined with muscle insult. The most common models involve repeated insults to somatic tissue, including muscle, and have been referred to as hyperalgesic priming. Hyperalgesic priming uses an initial priming stimulus, followed by a second inducing stimulus to result in a longer-lasting and enhanced hyperalgesia (Figure 1A). The priming stimulus has varied and includes inflammatory stimuli such as carrageenan, interleukin-6 (IL-6), or prostaglandins, and non-inflammatory stimuli such as acidic saline and/or fatiguing stimuli(5–7, 9, 10, 16). After the hyperalgesia resolves from the priming stimulus, a second stimulus is given, which results in in a longer-lasting hyperalgesia with minimal to no tissue damage. For example, two injections of pH 4.0 saline into the gastrocnemius muscle, given 2–5 days apart, results in widespread, long-lasting hyperalgesia (weeks); a single injection of pH 4.0 saline has only short-term effects (hours)(5)(Figure 1B). Similarly, injection of PGE2 after carrageenan-induced muscle inflammation has resolved results in long-lasting hyperalgesia (weeks); a single injection of PGE2 has only short-term effects (hours)(9). In parallel studies, in animals exposed to stressful conditions, an injection of PGE2 results in long-lasting hyperalgesia (weeks)(17, 18). Fatiguing exercise induced by whole-body fatigue or by local electrical stimulation of a single muscle combined with a subthreshold muscle insult also results in widespread and long-lasting hyperalgesia (weeks); fatigue or the muscle insult alone has no effect(6, 7, 16, 19, 20). Interestingly, the hyperalgesia that develops after fatigue combined with muscle insult is greater in female mice compared with male mice, is more widespread in female mice compared with males, is easier to induce in female mice, and is longer lasting in female mice(6, 7). Thus, there are several animal models that can result in a long-lasting, widespread and exaggerated hyperalgesia.

Figure 1.

Figure 1.

Open in a new tab

(A) Illustration of hyperalgesic priming. A single priming stimulus produces a short-lived hyperalgesic response that resolves (green). A second inducing stimulus, given within a critical window, will then produce a longer-lasting and more robust hyperalgesia (orange). For comparison the initial priming response is overlayed on the enhanced response. Copyright by Dr. Kathleen Sluka. (B) Intraomuscular injection of pH 4.0 produces a short duration decrease in withdrawal threshold to mechanical stimulation of the paw. A second injection 5 days later produces a greater and longer lasting decrease in withdrawal threshold. Reproduced with permission from(5). (C) Injection of NGF into human masseter (MA) muscle caused a decrease in masseter muscle pressure pain thresholds (PPT) at day 1 and day 7 following injection. This effect was localized to the masseter muscle since no decrease in PPT at the masseter muscle was seen following injection of NGF into the temporalis (TA) muscle. Muscle contraction produces pain over the tibialis anterior muscle after NGF injection that results in a greater area of pain after several days. Reproduced with permission from(33, 34). (D) Model of peripheral mediators implicated in the development of pain. Fatigue metabolites (H+, ATP) and nerve growth factor (NGF) secreted from muscles activate nociceptors by binding to their receptors. Fatigue metabolites also activate macrophages to increase the production of inflammatory cytokines which work to activate nociceptors. Copyright by Dr. Kathleen Sluka.

2.0. Peripheral drivers of chronic pain

2.1. Nociceptors

Nociceptors are sensory receptors that relay mechanical, thermal, or chemical signals of damaging or potentially damaging stimuli to the central nervous system. Nociceptors are located throughout the body and have peripheral terminals in tissues such as skin, muscle, joint, and visceral organs. Nociceptors have the potential to undergo plastic changes in response to repeated stimuli resulting in sensitization allowing the organism to avoid damaging stimuli(21, 22). However, in the case of chronic pain, this plasticity can outlast the tissue damage or threat, and thus not serve a protective purpose(23–26). We will discuss mediators and systems that can sensitize nociceptors and produce long-lasting, widespread hyperalgesia including fatigue metabolites, neurotrophins, and cells and factors associated with the immune system.

2.2. Fatigue metabolites

Fatigue Metabolites are released from contracting muscle and can activate receptors located on immune cells or nociceptors to sensitize primary afferent fibres. These metabolites include adenosine triphosphate (ATP), lactate, or decreases in pH which can activate purinergic receptors or Acid Sensing Ion Channels (ASICs), respectively. Combined intramuscular injection of protons, lactate, and ATP reduces muscle withdrawal threshold in rats while lactate or ATP alone did not reduce the withdrawal threshold(27). Group III and IV muscle nociceptors are activated by fatigue metabolites mixtures of protons, lactate, and ATP(28). In DRG neurons, combinations of these fatigue-metabolites synergize to enhance intracellular calcium release and currents(29, 30). In both muscle nociceptors and DRG neurons two subgroups were found to respond to differing metabolites, low and high(29). In human subjects, intramuscular injection of the combined metabolites produces a synergistic response in a dose-dependent manner with low-dose metabolites producing a fatigue-sensation and high dose metabolites producing a pain-sensation(31). Thus, decreases in pH, lactate and ATP produce a synergistic activation of nociceptors to produce hyperalgesia(27, 31).

Decreases in pH and lactate activate ASICs and both ASIC3 and ASIC1 are involved in development of chronic widespread pain. In a hyperalgesic priming model using two injections of pH 4.0 saline, mechanical hyperalgesia does not develop in ASIC3 knockout mice or if a non-selective ASIC antagonist is given prior to the second injection; however, ASIC1 knockout mice still develop hyperalgesia similar to wild-type mice(32–34). Repeated acid injection produces a bilateral spread of receptive fields of dorsal horn neurons that does not occur in ASIC3 knockout mice(32). Similarly, using muscle fatiguing stimuli combined with a subthreshold acidic saline injection (2, pH 5.0 saline injections), genetic or pharmacological blockade of ASIC3 prevents development of hyperalgesia(33, 35). Interestingly, in this fatigue-induced pain model, pharmacological blockade of ASIC1 prevents development of hyperalgesia and alters the kinetics of heteromeric ASICs(36). Thus, both ASIC1 and ASIC3 mediate the effects of hyperalgesic priming by acid and fatiguing stimuli.

Adenosine Triphosphate (ATP) is a metabolite that is implicated in the development of the muscle hyperalgesia. ATP binds to purinergic receptors (P2X and P2Y), activates group III and IV muscle nociceptors, and produce hyperalgesia(37–40). ATP-mediated mechanical hyperalgesia is facilitated through activation of P2X while ATP-mediated thermal hyperalgesia is induced through the activation of P2Y and TRPV1(41–43), showing that ATP is involved in development of multiple pain mechanisms.

2.3. Nerve Growth Factor

The neurotrophin, nerve growth factor (NGF), has been extensively studied for its role in muscle pain. NGF is synthesized by skeletal muscle(2), is increased in individuals with chronic migraine headaches and fibromyalgia (FM)(44, 45), and injection of NGF into human subjects reduces pain thresholds to mechanical stimuli both pressure and muscle contraction, but does not produce spontaneous pain(46, 47)(Figure 1C). Recordings from human C-fibers show intramuscular injection of NGF produces longlasting sensitization in female mice (48). Similarly, in animals NGF activates approximately 60% of Group IV muscle nociceptors(49), and sensitizes nociceptors to heat and mechanical stimuli(50, 51). Mechanical hyperalgesia is induced by NGF injection into rat muscle(48), and this hyperalgesia is prevented by blockade of the tropomyosin related kinase A (TrkA)(48) or p75 neurotrophin receptor(52). Peripheral injection of NGF activates the majority of dorsal horn neurons, recorded intracellularly, as evidenced by excitatory post-synaptic potentials (EPSPs), and results in increased responsiveness to noxious and innocuous mechanical stimuli (49). Thus, animal studies parallel findings in humans.

NGF can alter neurotransmitter expression on nociceptors to make them more excitable. For example, there is increased expression of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptors in dorsal root ganglia (DRG) neurons innervating muscle after injection of NGF that is longer-lasting in females(53). However, blockade of NMDA receptors in muscle reverses hyperalgesia in male, but not female mice(53), suggesting NR2B changes are not involved in the hyperalgesia in females. Indeed, females show increases in the neuropeptide Substance P expression in NR2B positive muscle DRG that does not occur in males(53). Thus, NGF has been shown to be involved the development of hyperalgesia which is sexually dimorphic in animal models.

2.5. Immune system

Resident macrophages are located in most tissues including muscle and play a role in protecting against disease(54, 55) and recent studies show a role for macrophages in chronic muscle pain models. In the acid-induced and fatigue-induced priming models there are increases in the number of macrophages in the injected muscle, depletion of macrophages in muscle prevents development of hyperalgesia, and blockade of the immune cell receptor toll-like 4 (TLR4) during a priming injection prevents development of hyperalgesia after the second injection(35, 56). Macrophages produce their effects through release of cytokines. In sedentary animals, the M1 macrophage phenotype releases inflammatory cytokines that can subsequently activate and sensitize nociceptors(57, 58). The inflammatory cytokines, IL-1β and IL-6, sensitize group IV muscle nociceptors(59, 60), induce mechanical hyperalgesia(61), increase the number of macrophages in muscle(56, 61), and prime the animal to subsequent stimuli like acid or prostaglandin(9, 56). In contrast, the M2 macrophage phenotype secretes anti-inflammatory cytokines such as IL-10 which prevents development of hyperalgesia(62). Physically active animals show an increase in the proportion of M2 macrophages in the muscles and the acid-induced priming model does not develop; this analgesia is prevented by blockade of IL-10(62). Thus, peripheral macrophages within the muscle are involved in the generation of chronic muscle pain through inflammatory cytokines (Figure 1D).

3.0. Central drivers of chronic muscle pain

Multiple central pathways have been discovered to play a role in the generation and maintenance of chronic widespread pain(63–66). In humans, imaging studies have extensively examined cortical sites and connectivity, while in animals, studies have examined multiple sites, neurotransmitter systems, and intracellular pathways involved in the generation of widespread pain(65, 67–69).

3.1. Imaging

Advancements in neuroimaging have led to a better understanding of brain mechanisms involved in chronic pain. Functional magnetic resonance imaging (fMRI) shows that individuals with FM have greater brain activity in pain processing regions in response to peripherally applied noxious stimuli when compared to healthy controls(70–72). More recent studies show increased connectivity between the default mode network (DMN), a network of the brain active during resting state, and the insula in individual’s with FM that is associated with ongoing pain(73) (Figure 2A). Simultaneously, there is decreased activation of the rostral anterior cingulate cortex (ACC), periaqueductal grey (PAG), rostral ventromedial medulla (RVM), and thalamus during pain states in individuals with FM, all of which are key locations in the descending pain modulatory system(74–77). Further, there is decreased grey matter volume in multiple cortical areas including ACC, PAG, amygdala, insula, prefrontal cortex, cingulate, striatum, and parahippocampal gyri(77–80), with the decreases in grey matter in the PAG associated with decreased efficiency of descending pain modulation(77). Thus, imaging studies show changes in multiple systems that are consistent with enhanced central excitability and reduced central inhibition in individuals with chronic widespread pain.

Figure 2.

Figure 2.

Open in a new tab

(A) Higher degree of intrinsic connectivity is seen between the default mode network (DMN) and the insula in people with fibromyalgia (FM). Intrinsic DMN connectivity to the right (R) anterior and middle insula was correlated greater spontaneous pain intensity on a visual analog scale (VAS) at the time of the fMRI. Red circles represent individuals with FM. Reproduced with permission(73). (B) Increased activity in the anterior and posterior middle cingulate cortex (MCC) measured by standardized uptake value ratio (SUVR) was found for individuals with FM reporting higher levels of fatigue on the American College of Rheumatology (ACR) fibromyalgia diagnostic criteria. There were no other significant associations between SUVR at these cortical sites and any other clinical variable. Reproduced with permission from(83). (C) Blockade of the serotonin transporter by 20 nmol of fluoxetine injected in the rostral ventromedial medulla (RVM) 24 hours after the second acid injection resulted in a reversal of hyperalgesia measured by muscle withdrawal thresholds in the acid hyperalgesic priming model. Reproduced from(103). Immunohistochemical staining of SERT in the nucleus raphe obscurus (NRO), nucleus raphe pallidus (NRP) and nucleus raphe magnus (NRM) in naïve and WT mice 24 hours after induction of activity-induced hyperalgesia priming model. There was an increase in the SERT immunoreactivity in the NRO, NRM and NRP of the RVM in WT mice following induction of the model. Reproduced with permission from(104). (D) Blockade of ERK with the MEK inhibitor during the priming injection prevented development of hyperalgesia after the second injection. Photomicrographs show immunohistochemical staining for phosphorylated extracellular signal-related kinases (pERK) in the dorsal horn of the spinal cord 2 hours after the acid priming injection. The bar graphs show a significant increase in the number of cells labeled with p-ERK after the first priming injection compared to pH 7.2 injection. Reproduced with permission from(107).

Central nervous system glial activation in pain processing is well-established in animal models of pain(81). Although not studied extensively in animal models of chronic non-inflammatory muscle pain, recent imaging studies show increased glial activity in individuals with FM. In individuals with chronic pain, FM and low back pain, positron emission tomography (PET) using a glial activation marker, translocator protein (TPSO), show enhanced activity in the cingulate cortices; this activity correlates with fatigue(82, 83). Interestingly, FM subjects with a genetic polymorphism for TSPO conferring high binding affinity report high pain intensity; this effect was modulated by the serotonin transporter gene(83, 84) (Figure 2B).

3.2. Glutamate/NMDA

Glutamate is an excitatory amino acid which binds to N-methyl-D-aspartate (NMDA) receptor and is crucial in the development of muscle pain. In human subjects with FM, proton magnetic resonance spectroscopy shows increased levels of glutamate are found in the right amygdala(85), posterior insula(86), posterior gyrus(87), and posterior cingulate cortex(88). The levels of glutamate correlated with FM-symptoms including pressure pain thresholds, function, and pain catastrophizing(86–88).

In the acid-hyperalgesic priming model, the second injection increases release of the excitatory neurotransmitter glutamate in the spinal cord dorsal horn and brainstem rostral ventromedial medulla (RVM)(89, 90), key areas involved in nociception. In the RVM and spinal cord, blockade of NMDA receptors both prevents and reverses development of acid-induced priming hyperalgesia(89, 91–93). The NR1 subunit of the NMDA receptor is required for NMDA receptor expression at the synapse, and when phosphorylated increases trafficking to the synapse and increases NMDA currents(94, 95). In the acid-induced and fatigue-induced model, there is increased phosphorylation of the NR1 subunit (p-NR1) in spinothalamic tract cells in the spinal cord, and increased p-NR1 in the RVM(96, 97). Further, over-expression of NR1 in RVM neurons produces mechanical hyperalgesia, while downregulation of NR1 in the RVM prevents acid-induced priming hyperalgesia(93). Thus, glutamate and NMDA receptors play a significant role in development and maintenance of chronic muscle pain in the cortex, brainstem, and spinal cord.

3.3. Serotonin

Serotonin (5-HT) has a complex role in pain processing showing both pro-nociceptive and anti-nociceptive effects depending on the location and receptor subtype it is acting on. Reuptake inhibitors are associated with reductions in pain in individuals with FM(98), and reduce hyperalgesia in animal models of muscle pain(99), suggesting a role for serotonin in maintaining the hyperalgesia. In the RVM, increases in serotonin are analgesic(100, 101) while depletion of serotonin, using reserpine, produces widespread hyperalgesia(99, 102). Endogenous activity of 5HT is mediated through serotonin transporter (SERT) which controls the reuptake of 5HT. In both the acid-induced and fatigue-induced hyperalgesic priming models there is enhanced expression of SERT while pharmacological blockade of SERT in the RVM reverses hyperalgesia(103, 104) (Figure 2C). In human subjects with FM there is a higher proportion of individuals with a SERT polymorphism that confers lower serotonin tone(105). Thus, the serotonin system, and in particular SERT, may play a critical role in development of widespread hyperalgesia.

3.4. Intracellular messengers

In the acid-induced hyperalgesic priming model, there are increases in phosphorylation of the transcription factor extracellular signal related kinase (pERK) in the central nociceptive pathways: spinal cord, amygdala and the paraventricular thalamic nucleus anterior in response to the first(106–109) and second injection(108). Blockade of ERK in the spinal cord (it), but not peripherally (im) or supraspinally (icv), prior to the first injection prevents, while blockade of ERK in the amygdala reverses, the hyperalgesia. Similarly, blockade of protein kinase C in the spinal cord, which phosphorylates ERK, also prevents hyperalgesia(107). The priming acid injection enhanced long-term potentiation in the spinal cord; this was prevented by pharmacological blockade of ERK(107). In the amygdala, an area involved in the affective dimension of pain, there is increased synaptic transmission between the parabrachial nucleus and the central amygdaloid nucleus after second acid injection that is prevented by pharmacological blockade of ERK (Figure 2D). Together these data suggest that the transcription factor ERK play a role in the generation and maintenance of chronic widespread hyperalgesia at multiple sites involved in nociceptive transmission.

4.0. Conclusion

Chronic widespread muscle pain in mediated through both peripheral and central factors. Peripherally, fatigue metabolites, neurotrophins, intracellular messengers, and the immune system can sensitize nociceptors leading to hyperalgesia. In the central nervous system, changes in neurotransmitters and intracellular pathways can lead to hyperalgesia, and imaging studies have identified specific cortical site alterations associated with chronic pain. These changes in both the periphery and the central nervous system can lead to the development of chronic widespread muscle pain.

Highlights:

  • Animal models have been developed to study widespread chronic muscle pain

  • Both central and peripheral factors mediate chronic muscle pain

  • Neuroimaging has discovered cortical changes in individuals with chronic pain

Acknowledgments

Funding: National Institutes of Health AR061371, UM1 AR063381 and UM1 AR063381-S1. The funding sources had no involvement in the conduct of the research or preparation of the manuscript and decision to submit for publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Declarations of interest: None

References

  • 1.Gaskin DJ, Richard P, The economic costs of pain in the United States. J Pain 13, 715–724 (2012). [DOI] [PubMed] [Google Scholar]
  • 2.Kamaleri Y, Natvig B, Ihlebaek CM, Bruusgaard D, Localized or widespread musculoskeletal pain: does it matter? Pain 138, 41–46 (2008). [DOI] [PubMed] [Google Scholar]
  • 3.Berkley KJ, Zalcman SS, Simon VR, Sex and gender differences in pain and inflammation: a rapidly maturing field. Am. J Physiol Regul. Integr. Comp Physiol 291, R241–R244 (2006). [DOI] [PubMed] [Google Scholar]
  • 4.Frey Law LA et al. , Acidic buffer induced muscle pain evokes referred pain and mechanical hyperalgesia in humans. Pain 140, 254–264 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Sluka KA, Kalra A, Moore SA, Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle & Nerve 24, 37–46 (2001). [DOI] [PubMed] [Google Scholar]
  • 6.Sluka KA, Rasmussen LA, Fatiguing exercise enhances hyperalgesia to muscle inflammation. Pain 148, 188–197 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gregory NS, Gibson-Corley K, Frey-Law L, Sluka KA, Fatigue-enhanced hyperalgesia in response to muscle insult: Induction and development occur in a sex-dependent manner. Pain 154, 2668–2676 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Khasar SG, Dina OA, Green PG, Levine JD, Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines. J. Pain 10, 1073–1077 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Dina OA, Green PG, Levine JD, Role of interleukin-6 in chronic muscle hyperalgesic priming. Neuroscience 152, 521–525 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dina OA, Levine JD, Green PG, Muscle inflammation induces a protein kinase Cepsilon-dependent chronic-latent muscle pain. J Pain 9, 457–462 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.de Melo Aquino B et al. , P2X3 receptors contribute to muscle pain induced by static contraction by a mechanism dependent on neutrophil migration. Purinergic Signal, (2019). [DOI] [PMC free article] [PubMed]
  • 12.Yoshida S et al. , Involvement of neutrophils and interleukin-18 in nociception in a mouse model of muscle pain. Mol. Pain 14, 1744806918757286 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Borghi SM et al. , Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice. PLoS One 11, e0162267 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Larson AA, Nunez MG, Kissel CL, Kovacs KJ, Intrathecal urocortin I in the spinal cord as a murine model of stress hormone-induced musculoskeletal and tactile hyperalgesia. Eur. J. Neurosci 42, 2772–2782 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Sutton BC, Opp MR, Sleep fragmentation exacerbates mechanical hypersensitivity and alters subsequent sleep-wake behavior in a mouse model of musculoskeletal sensitization. Sleep 37, 515–524 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Sluka KA, Danielson J, Rasmussen L, Dasilva LF, Exercise-Induced Pain Requires NMDA Receptor Activation in the Medullary Raphe Nuclei. Med Sci Sports Exerc 44, 420–427 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Dina OA, Levine JD, Green PG, Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress. Eur. J Pain 15, 796–800 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Green PG, Chen X, Alvarez P, Ferrari LF, Levine JD, Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat. Pain 152, 2549–2556 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Yokoyama T, Lisi TL, Moore SA, Sluka KA, Muscle Fatigue Increases the Probability of Developing Hyperalgesia in Mice. J Pain 8, 692–699 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Sluka KA, O’Donnell JM, Danielson J, Rasmussen LA, Regular physical activity prevents development of chronic pain and activation of central neurons. J. Appl. Physiol 114, 725–733 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Mense S, in Muscle Pain: Understanding the Mechanisms, Mense S, Gerwin RD, Eds. (Springer, Heidelberg, 2010), pp. 49–104. [Google Scholar]
  • 22.Queme LF, Ross JL, Jankowski MP, Peripheral Mechanisms of Ischemic Myalgia. Front Cell Neurosci 11, 419 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hucho T, Levine JD, Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55, 365–376 (2007). [DOI] [PubMed] [Google Scholar]
  • 24.Woolf CJ, Neuronal Plasticity: Increasing the Gain in Pain. Science 288, 1765–1768 (2000). [DOI] [PubMed] [Google Scholar]
  • 25.Woolf CJ, Ma Q, Nociceptors--noxious stimulus detectors. Neuron 55, 353–364 (2007). [DOI] [PubMed] [Google Scholar]
  • 26.Luo C, Kuner T, Kuner R, Synaptic plasticity in pathological pain. Trends Neurosci 37, 343–355 (2014). [DOI] [PubMed] [Google Scholar]
  • 27.Gregory NS, Whitley PE, Sluka KA, Effect of Intramuscular Protons, Lactate, and ATP on Muscle Hyperalgesia in Rats. PLoS. One 10, e0138576 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Jankowski MP, Rau KK, Ekmann KM, Anderson CE, Koerber HR, Comprehensive phenotyping of group III and IV muscle afferents in mouse. J Neurophysiol 109, 2374–2381 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Light AR et al. , Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1. J Neurophysiol 100, 1184–1201 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Birdsong WT et al. , Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68, 739–749 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Pollak KA et al. , Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects. Exp. Physiol 99, 368–380 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sluka KA et al. , Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106, 229–239 (2003). [DOI] [PubMed] [Google Scholar]
  • 33.Chen WN et al. , Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Mol. Pain 10, 40 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Sluka KA, Price MP, Wemmie JA, Welsh MJ, in Proceedings of the 10th World Congress on Pain, Dostrovsky JO, Carr DB, Koltzenburg M, Eds. (IASP Press, Seattle, 2003), chap. 7, pp. 71–79. [Google Scholar]
  • 35.Gregory NS, Brito R, Fusaro MCGO, Sluka KA, ASIC3 is required for development of fatigue-induced hyperalgesia. Molecular Neurobiology 53, 1020–1030 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gregory NS, Gautam M, Benson CJ, Sluka KA, Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics. Neuroscience 386, 166–174 (2018).**Study shows the ASIC1 antagonist psalmatoxin prevents activity-induced hyperalgesia and alters kinetics of ASIC1 heteromers particularly ASIC1/3
  • 37.Reinohl J, Hoheisel U, Unger T, Mense S, Adenosine triphosphate as a stimulant for nociceptive and non-nociceptive muscle group IV receptors in the rat. Neurosci Lett 338, 25–28 (2003). [DOI] [PubMed] [Google Scholar]
  • 38.Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R, Experimental muscle pain and tenderness following infusion of endogenous substances in humans. Eur. J Pain 7, 145–153 (2003). [DOI] [PubMed] [Google Scholar]
  • 39.Shinoda M, Ozaki N, Sugiura Y, Involvement of ATP and its receptors on nociception in rat model of masseter muscle pain. Pain 134, 148–157 (2008). [DOI] [PubMed] [Google Scholar]
  • 40.Hilliges M et al. , ATP responses in human C nociceptors. Pain 98, 59–68 (2002). [DOI] [PubMed] [Google Scholar]
  • 41.Walder RY et al. , ASIC1 and ASIC3 Play Different Roles in the Development of Hyperalgesia After Inflammatory Muscle Injury. J Pain 11, 210–218 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Sluka KA et al. , ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 129, 102–112 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Molliver DC et al. , Deletion of the murine ATP/UTP receptor P2Y2 alters mechanical and thermal response properties in polymodal cutaneous afferents. Neuroscience 332, 223–230 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Sarchielli P, Alberti A, Floridi A, Gallai V, Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients. Neurology 57, 132–134 (2001). [DOI] [PubMed] [Google Scholar]
  • 45.Sarchielli P et al. , Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J. Pain 8, 737–745 (2007). [DOI] [PubMed] [Google Scholar]
  • 46.Sorensen LB, Boudreau SA, Gazerani P, Graven-Nielsen T, Enlarged Areas of Pain and Pressure Hypersensitivityby Spatially Distributed Intramuscular Injections ofLow-Dose Nerve Growth Factor. J. Pain 20, 566–576 (2018).***Study shows multiple injections (5, 1mg) of NGF 4 cm apart produce a larger area of pain than a single injection (1, 5 mg) injection of NGF.
  • 47.Svensson P, Cairns BE, Wang K, Arendt-Nielsen L, Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain 104, 241–247 (2003). [DOI] [PubMed] [Google Scholar]
  • 48.Svensson P, Wang MW, Dong XD, Kumar U, Cairns BE, Human nerve growth factor sensitizes masseter muscle nociceptors in female rats. Pain 148, 473–480 (2010). [DOI] [PubMed] [Google Scholar]
  • 49.Hoheisel U, Unger T, Mense S, Sensitization of rat dorsal horn neurons by NGF-induced subthreshold potentials and low-frequency activation. A study employing intracellular recordings in vivo. BRAIN RES 1169, 34–43 (2007). [DOI] [PubMed] [Google Scholar]
  • 50.Murase S et al. , Bradykinin and nerve growth factor play pivotal roles in muscular mechanical hyperalgesia after exercise (delayed-onset muscle soreness). J NEUROSCI 30, 3752–3761 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Rukwied R et al. , Nerve growth factor-evoked nociceptor sensitization in pig skin in vivo. J. Neurosci. Res 88, 2066–2072 (2010). [DOI] [PubMed] [Google Scholar]
  • 52.Khodorova A, Nicol GD, Strichartz G, The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw. Neuroscience 254, 312–323 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Wong H et al. , NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors. Neuroscience 269, 232–244 (2014). [DOI] [PubMed] [Google Scholar]
  • 54.Arnold L et al. , Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med 204, 1057–1069 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Lawrence T, Natoli G, Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol 11, 750–761 (2011). [DOI] [PubMed] [Google Scholar]
  • 56.Gong WY, Abdelhamid RE, Carvalho CS, Sluka KA, Resident macrophages in muscle contribute to development of hyperalgesia in a mouse model of non-inflammatory muscle pain. J Pain 17, 1081–1094 (2016).**Study shows that removal of macrophages in muscle prevents hyperalgesia priming induced by priming with pH 4.0, IL-6 or LPS, blockade of the immune receptor TLR4 prevents hyperalgesic priming, and application of acidic saline to cultured macrophages induces release of inflammatory cytokines
  • 57.Schaible HG et al. , The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann. N. Y. Acad. Sci 1193, 60–69 (2010). [DOI] [PubMed] [Google Scholar]
  • 58.Richter F et al. , Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum 62, 3806–3814 (2010). [DOI] [PubMed] [Google Scholar]
  • 59.Hoheisel U, Unger T, Mense S, Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat. Pain 114, 168–176 (2005). [DOI] [PubMed] [Google Scholar]
  • 60.Binshtok AM et al. , Nociceptors are interleukin-1beta sensors. J NEUROSCI 28, 14062–14073 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Manjavachi MN, Motta EM, Marotta DM, Leite DF, Calixto JB, Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice. Pain 151, 345–355 (2010). [DOI] [PubMed] [Google Scholar]
  • 62.Leung A, Gregory NS, Allen LA, Sluka KA, Regular physical activity prevents chronic pain by alatering resident muscle macrophage phenotype and increasing IL-10 in mice. Pain 157, 79–79 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Sluka KA, Clauw DJ, Neurobiology of fibromyalgia and chronic widespread pain. Neurosci 338, 114–129 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Min MY et al. , ERK, synaptic plasticity and acid-induced muscle pain. Commun. Integr. Biol 4, 394–396 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.DeSantana JM, Sluka KA, Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Curr. Pain Headache Rep 12, 338–343 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Lee YC, Nassikas NJ, Clauw DJ, The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia. Arthritis Res Ther 13, 211 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Kuner R, Flor H, Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci 18, 113 (2017). [DOI] [PubMed] [Google Scholar]
  • 68.Bardin L, The complex role of serotonin and 5-HT receptors in chronic pain. Behav Pharmacol 22, 390–404 (2011). [DOI] [PubMed] [Google Scholar]
  • 69.Smallwood RF et al. , Structural brain anomalies and chronic pain: a quantitative meta-analysis of gray matter volume. J Pain 14, 663–675 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Gracely RH, Petzke F, Wolf JM, Clauw DJ, Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 46, 1333–1343 (2002). [DOI] [PubMed] [Google Scholar]
  • 71.Gracely RH et al. , Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 127, 835–843 (2004). [DOI] [PubMed] [Google Scholar]
  • 72.Staud R, Craggs JG, Perlstein WM, Robinson ME, Price DD, Brain activity associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls. Eur. J. Pain 12, 1078–1089 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Napadow V et al. , Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 62, 2545–2555 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Jensen KB et al. , Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. Pain 144, 95–100 (2009). [DOI] [PubMed] [Google Scholar]
  • 75.Kong JS et al. , Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis. Arthritis Rheum 62, 179–190 (2010). [DOI] [PubMed] [Google Scholar]
  • 76.Jensen KB et al. , Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol. Pain 8, 32 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Harper DE et al. , Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation. J. Pain 19, 635.e631–635.e615 (2018).**variation in functional connectivity of the PAG explains the variability in the CPM test
  • 78.Burgmer M et al. , Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia. Psychosom. Med 71, 566–573 (2009). [DOI] [PubMed] [Google Scholar]
  • 79.Kuchinad A et al. , Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J. Neurosci 27, 4004–4007 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Schmidt-Wilcke T et al. , Striatal grey matter increase in patients suffering from fibromyalgia--a voxel-based morphometry study. Pain 132 Suppl 1, S109–116 (2007). [DOI] [PubMed] [Google Scholar]
  • 81.Milligan ED, Watkins LR, Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci 10, 23–36 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Loggia ML et al. , Evidence for brain glial activation in chronic pain patients. Brain 138, 604–615 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Albrecht DS et al. , Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation. Brain. Behav. Immun 75, 72–83 (2019).**Study shows activation of glia in human subjects with fibromyalgia using PET imaging of TSPO.
  • 84.Kosek E et al. , The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia. Brain. Behav. Immun 58, 218–227 (2016). [DOI] [PubMed] [Google Scholar]
  • 85.Valdes M et al. , Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study. Arthritis Rheum 62, 1829–1836 (2010). [DOI] [PubMed] [Google Scholar]
  • 86.Harris RE et al. , Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 60, 3146–3152 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Fayed N et al. , Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res. Ther 12, R134 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Fayed N et al. , Brain dysfunction in fibromyalgia and somatization disorder using proton magnetic resonance spectroscopy: a controlled study. Acta Psychiatr. Scand 126, 115–125 (2012). [DOI] [PubMed] [Google Scholar]
  • 89.Radhakrishnan R, Sluka KA, Increased glutamate and decreased glycine release in the rostral ventromedial medulla during induction of a pre-clinical model of chronic widespread muscle pain. Neurosci. Lett 457, 141–145 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Skyba DA, King EW, Sluka KA, Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. Pain 98, 69–78 (2002). [DOI] [PubMed] [Google Scholar]
  • 91.Tillu DV, Gebhart GF, Sluka KA, Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insult. Pain 136, 331–339 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Da Silva LF, Desantana JM, Sluka KA, Activation of NMDA receptors in the brainstem, rostral ventromedial medulla, and nucleus reticularis gigantocellularis mediates mechanical hyperalgesia produced by repeated intramuscular injections of acidic saline in rats. J. Pain 11, 378–387 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Da Silva LF, Walder RY, Davidson BL, Wilson SP, Sluka KA, Changes in expression of NMDA-NR1 receptor subunits in the rostral ventromedial medulla modulate pain behaviors. Pain 151, 155–161 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Chen BS, Roche KW, Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53, 362–368 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Ehlers MD, Tingley WG, Huganir RL, Regulated subcellular distribution of the NR1 subunit of the NMDA receptor. Science 269, 1734–1737 (1995). [DOI] [PubMed] [Google Scholar]
  • 96.Sluka KA, Danielson J, Rasmussen L, DaSilva LF, Exercise-induced pain requires NMDA receptor activation in the medullary raphe nuclei. Med. Sci. Sports Exerc 44, 420–427 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Bement MK, Sluka KA, Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model. Neurosci. Lett 418, 22–27 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Patetsos E, Horjales-Araujo E, Treating Chronic Pain with SSRIs: What Do We Know? Pain Res Manag 2016, 2020915 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Murai N et al. , Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats. Neuroscience 289, 262–269 (2015). [DOI] [PubMed] [Google Scholar]
  • 100.Llewelyn MB, Azami J, Roberts MH, The effect of modification of 5-hydroxytryptamine function in nucleus raphe magnus on nociceptive threshold. Brain Res 306, 165–170 (1984). [DOI] [PubMed] [Google Scholar]
  • 101.Llewelyn MB, Azami J, Roberts MHT, Effects of 5-hydroxytryptamine applied into the nucleus raphe magnus on nociceptive thresholds and neuronal firing rate. Brain Res 258, 59–68 (1983). [DOI] [PubMed] [Google Scholar]
  • 102.Taguchi T et al. , Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model. Pain 156, 415–427 (2015). [DOI] [PubMed] [Google Scholar]
  • 103.Brito RG, Rasmussen LA, Sluka KA, Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms. Pain reports 2, e618 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Lima LV, DeSantana JM, Rasmussen LA, Sluka KA, Short-duration physical activity prevents the development of activity-induced hyperalgesia through opioid and serotoninergic mechanisms. Pain 158, 1697–1710 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Offenbaecher M et al. , Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum 42, 2482–2488 (1999). [DOI] [PubMed] [Google Scholar]
  • 106.Chen WK et al. , Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J. Neurosci 30, 10360–10368 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Chen WH, Chang YT, Chen YC, Cheng SJ, Chen CC, Spinal PKC/ERK signal pathway mediates hyperalgesia priming. Pain , (2018).**This study shows that activation of the PKC/ERK signalling pathway is required for acid-saline hyperalgesic priming and LTP-enhancement by acid injection
  • 108.Cheng SJ et al. , Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice. J. Neurosci 31, 2258–2270 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Min MY et al. , ERK, synaptic plasticity and acid-induced muscle pain. Commun. Integr. Biol 4, 394–396 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES