Table 1 Main findings of different animal models of fibromyalgia according to central and peripheral factors

Repeated muscle insult

Acid saline induced pain

No peripheral damage [5]

Widespread (visceral, cutaneous and muscle) and long-lasting mechanical hyperalgesia [5, 6]; decreased voluntary physical activity [7]

Reversal of mechanical hyperalgesia by neurotrophin-3 [8]

Muscle hyperalgesia is similarly developed if the first acid injection is performed in different muscles, such as right lateral gastrocnemius, right medial gastrocnemius or left lateral gastrocnemius, keeping the second injection at the same site for all [9]

ASIC3-/- mice do not develop hyperalgesia [10]

ASIC3-/- mice do not develop hyperalgesia or central neuron sensitization, localization of ASIC3 in muscle afferents [10]

Substance P mediates NK1 receptor pathway to block acid activation in muscle nociceptors [11]

Shift of the cardiac autonomic balance towards a sympathetic predominance and reduction in baroreceptor reflex sensitivity [12]

Aerobic exercise with treadmill running reduces cutaneous and muscle hyperalgesia and increases neurotrophin-3 levels in muscle [13]

Increased ERK activity in the amygdala, and increased post-synaptic excitatory transmission from parabrachial nucleus in amygdala [14]

T-type calcium channels mediate hyperalgesia supraspinally, increases in ERK in paraventricular thalamus that depend on activation of T-type calcium channels [15]

Local anesthetic in the RVM during the second injection prevents the development of muscle hyperalgesia and reverses existing hyperalgesia [16]

Increased release of glutamate and aspartate and decreased glycine in the RVM during the second injection [17]

Reversal of both cutaneous and muscle hyperalgesia through microinjection of NMDA receptor antagonists into the RVM, and only cutaneous hyperalgesia into the NGC [18]

Increased expression of NR1 subunit of NMDA receptor in the RVM produces muscle hyperalgesia; downregulation of NR1 subunit in RVM prevents development of muscle hyperalgesia [19]

Reversal and prevention of hyperalgesia by blockade of spinal NMDA and non-NMDA glutamate receptors [20]

Increased number of spinothalamic neurons expressing p-NR1 in lamina X of the spinal cord [21]

Increased number of spinothalamic neurons expressing p-NR1 in lamina X of the spinal cord [21]

Increased spinal glutamate and aspartate concentrations in the spinal cord in a calcium-dependent manner [22]

Phosphorylation of CREB through activation of the spinal cAMP pathway in a time-dependent manner [23]

Muscle stimulation produces Fos expression ipsilaterally in all regions of the dorsal horn; paw stimulation produces ipsilateral Fos expression in the superficial spinal laminae, and bilaterally in deep laminae [24]

Reversal of mechanical hyperalgesia by μ and δ opioid receptor agonist (but not κ), glutamate receptor antagonist, pregabalin, reuptake inhibitors, K⁺ channel opener, Na⁺ channel blocker, but not cyclooxygenase-2 inhibitor and benzodiazepine; co-administration of tramadol and milnancipran is more effective in reducing muscle hyperalgesia than tramadol alone [20, 25–28]

Low intensity exercise reduces mechanical hyperalgesia, which is attenuated by opioid receptor agonist [29]; regular exercises prevent the development of muscle pain and exercise-induced chronic muscle pain through the decrease of phosphorylation of the NR1 in the RVM [30]

Hyperalgesic priming

Development of chronic muscle hyperalgesia (2 weeks) after acute muscle inflammation [31]

Priming hyperalgesia (cutaneous) involves activation of a cAMP/PKCϵ in nociceptors [31, 32]

IL-6 in muscle primes response to subsequent PGE2, and antisense to IL-6 or gp130 prevents hyperalgesic priming [33]

Spinal pretreatment with oligodeoxynucleotide antisense to PKCϵ reduces muscle hyperalgesia [31]

Cutaneous inflammation primes the hyperalgesic response to a subsequent injection of PGE2, 5-HT, or A2 agonist; PKCϵ inhibitor prevents priming effect [34]

αCaMKII produces hyperalgesic priming; inhibition of αCaMKII prevents activation of PKCϵ-induced priming; activation of αCaMKII produces priming that is not prevented by pretreatment with PKCϵ antisense [35]

Inhibitors of enzymes implicated in the metabolism of cyclic nucleotides to adenosine; A1 adenosine receptors block late phase of PGE2-induced muscle hyperalgesia [36]

Pretreatment with a selective neurotoxin (IB4-saporin) prevents GDNF-induced hyperalgesia; NGF and PsiepsilonRACK produce muscle hyperalgesia [37]

Hyperalgesic priming is reversed through the inhibition of translation in the peripheral terminal of the nociceptor [38]

Fatigue enhanced muscle pain

No inflammation or damage to muscle with whole-body or single-muscle fatigue tasks; no change in muscle lactate, pCO₂, pO₂, creatinine kinase, or phosphate after whole-body muscle fatigue [39, 40]

Whole-body fatigue enhances hyperalgesia to muscle insult [40, 41]; single muscle fatigue enhances hyperalgesia to muscle insult [39]

Reduced muscle force after whole-body fatigue or single-muscle fatigue task [39, 40]

Enhancement of paw and muscle hypersensitivity in both male and female mice [39, 41]

Female mice show greater enhancement of hyperalgesia that is prevented by ovariectomy (whole body fatigue); greater time-window, greater spatial window for induction of hyperalgesia, and longer lasting hyperalgesia not affected by ovariectomy (single-muscle fatigue) [39, 41]

Blockade of RVM NMDA receptors during fatigue prevents development of hyperalgesia [42]

c-Fos expression in nucleus raphe pallidus, obscurus, and magnus; increased p-NR1 in RVM with whole-body fatigue but not single-muscle fatigue [30, 39, 42]

Prevention of hyperalgesia and enhanced p-NR1 in RVM by regular physical activity [30]

Biogenic amine depletion

Reduction of levels of biogenic amines in central nervous system [43]

Increased time of immobility as a measure of depression [43]

Enhanced sensitivity to muscle and cold stimuli after reserpine; no pathology in peripheral nerves or brain [44]

Depletion of biogenic amines with reserpine leads to development of muscle hyperalgesia that is reversed by pregabalin, duloxetine, and pramipexol, but not diclofenac; 5HT2C receptor agonists reverse muscle hyperalgesia induced by reserpine; NSAIDs have no effect [43, 45]

Stress

Cold stress

Bilateral muscle and paw mechanical hyperalgesia, thermal hyperalgesia [46, 47]

Increased plasma corticosterone concentration; no change in anxiety or depression-like behaviors [46]

Decreased serotonin and its metabolites in brain and spinal cord after repeated cold stress [48]

Decreased morphine analgesia; increased U50,488 analgesia; decreased DAMGO analgesia when given supraspinally; diazepam prevented the decreased DAMGO analgesia [49]

Post-translational changes in proteins supraspinally after stress [50]

Blockade of substance P and calcitonin gene-related peptide, NMDA receptors in spinal cord reduces cold-stress hyperalgesia [51–53]

Hyperalgesia reversed by gabapentin and antidepressants [46, 54]

Sound stress

Increase in hyperalgesia after local injections of PGE2, epinephrine, or LPS [55, 56]

Widespread hyperalgesia of paw, viscera and jaw muscle [57]

Increased plasma levels of epinephrine and increased activity of catecholamine synthetizing enzymes in adrenal medulla for >28 days [55, 58]

Increased anxiety [57]

IL-6 downregulation on primary afferents prevents hyperalgesia dependent on glucocorticoids and catecholamines [56]

Subchronic swimming stress

Thermal hyperalgesia, decreased grip force, enhanced response to inflammatory irritants [59–61]

Enhanced c-fos expression in response to formalin spinally [60]

Basal and evoked release of GABA is decreased, and glutamate is increased, in spinal cord [62, 63]

Reversal of hyperalgesia by reuptake inhibitors, serotonin precursor tryptophan, and diazepam [59, 61, 62]