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. Author manuscript; available in PMC: 2018 Dec 1.
Published in final edited form as: Pain. 2017 Dec;158(12):2285–2289. doi: 10.1097/j.pain.0000000000001055

Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia

Jun-Ho La 1, Jin Mo Chung 1
PMCID: PMC5680132  NIHMSID: NIHMS902892  PMID: 28885453

Mechanical allodynia is a debilitating pain from innocuous mechanical stimuli such as touch. To unravel its mechanism, one approach has been to focus on the fact that different afferent types mediate mechanical allodynia from stimuli ‘moving’ across the skin (e.g., brushing) and from stimuli ‘fixed’ on a certain spot (e.g., gentle pressure or weak punctate stimulation); the former type of allodynia being designated ‘dynamic’ and the latter, ‘static’ [23; 39] (these terms, however, differentiate mechanical allodynia by ‘stimulation mode’, not by afferent type). Thus, since the stimulation mode differs between dynamic and static mechanical allodynia, different afferent inputs are presumably generated and then differentially processed in the spinal cord. In this regard, recent literature suggests that inhibitory processing of afferent inputs by glycine- and γ-aminobutyric acid (GABA) transmission differs between dynamic and static mechanical allodynia, respectively [36; 41]. In addition to the dynamic/static stimulation mode, factors such as the size/depth of stimulated area (e.g., large pressure probe vs. von Frey filament) and the stimulation velocity/duration can influence mechanical allodynia because of spatial/temporal summation, counteraction between afferents [2; 34], and afferents’ adaptation properties.

Since the nature of afferent inputs and the spinal inhibitory processing seem to differ in the 2 types of mechanical allodynia, this review summarizes what we know of these issues in various pathologic and experimental pain conditions. In this review, as a caveat, we do not deal with ‘mechanical hyperalgesia’, a pain from a mechanical stimulus that normally provokes pain.

1. Peripheral afferents mediating dynamic and static mechanical allodynia

Most Aβ-fibers are low-threshold mechanoreceptors, while the majority of mechanosensitive Aδ/C-fibers are high-threshold, leading to the generalization that Aβ-fibers are touch sensors, whereas mechanosensitive Aδ/C-fibers are mechanical nociceptors. Although there are Aδ/C low-threshold mechanoreceptors functioning as light touch sensors in the hairy skin, their exact role in mechanical allodynia in humans remains unclear [29; 38].

As mechanical allodynia is evoked by low-intensity stimulation, it must be initiated by excitation of touch sensors or sensitized mechanical nociceptors that become responsive to low-intensity stimulation (for nociceptor sensitization, see [17]). Literature shows that blocking A-fiber conduction abolishes dynamic mechanical allodynia [22; 23; 39; 52]; in two studies, the abolition coincided with touch sensory loss, suggesting Aβ-fibers as the symptom-mediating afferents. In contrast, static mechanical allodynia appears to be mediated by various afferent types in different pathologic or experimental conditions (Table 1).

Table 1.

Afferent types mediating dynamic and static mechanical allodynia in various pain conditions

Pain condition Species Stimulation Afferent type Identification approach Ref
peripheral neuropathy mouse punctate A Piezo2 knockdown 10
A QX-314 with flagellin 56(a)
rat punctate TRPV1(+) capsaicin-induced desensitization 13(b)
TRPV1(+) QX-314 with capsaicin 4
human pressure C compression nerve block 39
brushing A compression nerve block 39
inflammation mouse punctate TRPA1(+) TRPA1 antagonist (2–3 days post-CFA) 28
TRPA1(+) QX-314 with cinnamaldehyde (2–3 days post-CFA) 28
TRPA1(+) TRPA1 knockout (2 days–2 weeks post-CFA) 15(c)
A Piezo2 knockdown (≥4 days post-CFA) 49(d)
rat pressure TRPV1(+) TRPV1 antagonist 16
punctate TRPV1(+) QX-314 with capsaicin 4
1° zone human pressure C compression nerve block 22, 23
brushing A compression nerve block 22, 23
2° zone punctate A compression nerve block 59
brushing A compression nerve block 22, 52
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QX-314: lidocaine N-ethyl bromide, TRPV1: Transient Receptor Potential Channel V1, TRPA1: Transient Receptor Potential Channel A1.

(a)

QX-314 with capsaicin had only a mild effect in this model;

(b)

In comparison, neonatal capsaicin-induced ablation of TRPV1(+)-afferents did not prevent neuropathic static mechanical allodynia [48]; (

(c)

These young (3–6 month-old) TRPA1 knockout mice later developed static mechanical allodynia unlike their aged (≥18 moths) counterpart;

(d)

This approach was ineffective at 1 day post-CFA as in [47].

1.1. Afferents mediating static mechanical allodynia in peripheral neuropathy

Piezo2 is a mechanosensitive ion channel that confers low-threshold mechanosensitivity to A-fibers. The loss of Piezo2 causes significant defects in touch sensation without affecting normal mechanical nociceptive behaviors evoked by pressure/punctate stimulation [47]. When mechanical allodynia to punctate stimulation developed in mice after peripheral nerve injury, downregulating Piezo2 expression alleviated the allodynia, suggesting that low-threshold A-fibers mediate the allodynia [10]. Similarly, neuropathic mechanical allodynia to punctate stimulation was temporarily relieved by delivering the lidocaine derivative QX-314 selectively into A-fibers in mice [56]; and the allodynia was only mildly attenuated when the anesthetic was delivered into a subpopulation of Aδ/C-nociceptors expressing Transient Receptor Potential channel V1 (TRPV1).

By contrast, blocking A-fiber conduction did not abolish pressure-evoked mechanical allodynia in 15 of 18 neuropathic pain patients, suggesting that C-fibers mediate the allodynia in these patients [39]. Also in rats exhibiting mechanical allodynia to punctate stimulation after nerve injury, the allodynia was alleviated when TRPV1-expressing nociceptors were ‘desensitized’ by multiple doses of intraplantar capsaicin or ‘silenced’ by QX-314 [4; 13].

Concerning what seems to be an inconsistent role of TRPV1-expressing nociceptors in mediating neuropathic static mechanical allodynia, we should consider species differences in mechanosensory function of TRPV1-expressing cutaneous afferents. These afferents have little or no mechanosensory function in normal mice [6; 26; 37], unlike rats and humans [3; 33]. Therefore, in mice, we may expect no significant contribution of TRPV1-expressing nociceptors to static mechanical allodynia unless they acquire such mechanosensitivity, or other mechanosensitive afferents start expressing TRPV1 in pathological conditions. Such abnormal function/expression of TRPV1 after nerve injury [12; 32; 54; 55] would confound the afferent type identification based on afferents’ reactivity to TRPV1 agonists/antagonists. Interestingly, ‘neonatal ablation’ of TRPV1-expressing nociceptors in rats did not prevent static mechanical allodynia after nerve injury in adulthood [48]. It would be interesting to examine whether abnormal expression of TRPV1 by nerve injury would contribute to the allodynia in this rat model.

1.2. Afferents mediating static mechanical allodynia in inflammation

When inflammatory mechanical allodynia to pressure/punctate stimulation developed after complete Freund’s adjuvant (CFA) injection, a TRPV1 antagonist, or silencing of TRPV1-expressing nociceptors by QX-314, significantly alleviated the allodynia in rats [4; 16]. However, as expected based on the difference between rats and mice in TRPV1-expressing cutaneous nociceptors, inflammatory static mechanical allodynia in mice was not affected when TRPV1 itself or TRPV1-expressing afferents were inhibited [5; 6; 28; 37]. Instead, in CFA-injected mice, targeting TRPA1-expressing nociceptors before or 2–3 days after the inflammation prevented or alleviated the allodynia [15; 28]. These results may seem to contradict the findings that inhibiting A-fibers in mice by Piezo2 downregulation (initiated 1 day post-CFA) significantly alleviated the inflammatory static mechanical allodynia ≥4 days post-CFA [49]. However, Piezo2 downregulation initiated 3 days before CFA injection did not prevent static mechanical allodynia 1 day post-CFA [47; 49]. Collectively, it appears that TRPA1-expressing afferents mediate mouse inflammatory static mechanical allodynia early after the inflammation develops (≤3 days post-CFA), whereas A-fibers do so later (≥4 days post-CFA).

1.3. Afferents mediating static mechanical allodynia in primary and secondary zones of skin injury

Static mechanical allodynia develops inside (primary zone) and outside (secondary zone) injured skin areas. Blocking A-fiber conduction failed to abolish pressure-evoked mechanical allodynia in the primary zone injured by topical capsaicin or freezing, suggesting C-fibers are the symptom-mediating afferents [22; 23]. On the contrary, in the secondary zone of capsaicin-injected human skin area, static mechanical allodynia to punctate stimulation (at an intensity normally below the 50% pain threshold) was abolished by blocking A-fiber conduction [59].

The above findings suggest that dynamic mechanical allodynia is consistently mediated by touch sensors and static mechanical allodynia by either touch sensors or sensitized mechanical nociceptors, depending on pathological/experimental conditions. Concerning the role of sensitized mechanical nociceptors in static mechanical allodynia, no clear evidence of ‘decreased nociceptor mechanical thresholds’ has been obtained [1; 19; 28; 50] despite that static mechanical allodynia is characterized by a decreased pain threshold. Sensitized mechanical nociceptors rather show increased firing upon suprathreshold stimulation. It seems necessary to compare the mechanical thresholds for nociceptor excitation with those for pain perception/behaviors in static mechanical allodynia conditions. In one exemplary study using rats, normal mechanical thresholds for nociceptive behavior were significantly higher than those for nociceptor excitation (which supports the idea that suprathreshold nociceptor activity is necessary to evoke normal mechanical pain sensations in humans [18]). After incision injury, the behavioral thresholds dropped to within the threshold range of mechanical nociceptors [44]. Therefore, it could be that nociceptor sensitization to suprathreshold stimulation is manifested as static mechanical allodynia in some conditions or simple nociceptor excitation at threshold intensity, which is normally insufficient to activate spinal nociceptive neural circuits, becomes able to do so because the circuits are sensitized to afferent inputs (for central sensitization, see [25]). In the following, we address the literature reporting spinal disinhibition as one of the key central sensitization mechanisms for mechanical allodynia.

2. Dysfunction of spinal inhibitory system in dynamic and static mechanical allodynia

Because nociceptors already have connections to nociceptive neural circuits in the spinal dorsal horn of naïve animals, nociceptors can easily evoke allodynia when they are sensitized and/or the spinal nociceptive circuits are sensitized to their inputs. However, since touch sensors are normally unable to activate nociceptive circuits, altered processing of their inputs must take place for their excitation to evoke allodynia.

The nociceptive circuits in the spinal cord are under strong inhibition, an important component of which are interneurons releasing the inhibitory neurotransmitters GABA and glycine. Many pathological pain conditions are associated with decreased spinal inhibition [58], and experimentally suppressing GABAergic/glycinergic inhibition makes excitation of spinal dorsal horn neurons to brush, pressure, and pinch stimulations greater than normal [42] and reveals novel A-fiber excitatory inputs to the spinal nociceptive circuits [53].

In the rodent spinal dorsal horn, glycine is mostly detected in GABAergic neurons, and fast inhibitory synaptic transmission in this area is often composed of both GABAergic (GABAA receptor-mediated) and glycinergic components [21; 45; 46; 51]. Accordingly, intrathecal injection of blockers of GABAA (bicuculline or picrotoxin) and glycine receptors (strychnine) produces mechanical allodynia [40; 57]. Recent studies show that the disinhibition of each system differentially affects spinal neuronal responses to Aβ-inputs and behaviors to dynamic and static mechanical stimulations.

In the rat spinal cord, Aβ-inputs excite inhibitory interneurons that in turn suppress the activation of protein kinase Cγ (PKCγ)-expressing excitatory interneurons by the same Aβ-inputs. This feed-forward inhibition was removed by strychnine but not by bicuculline [31]. In line with these findings, rats treated with intracisternal strychnine showed dynamic mechanical allodynia to air puffing on the face in a PKCγ antagonist-dependent manner [35]. Notably, these rats did not show static mechanical allodynia to punctate stimulation of the face. In contrast, rats treated with intracisternal bicuculline showed static but not dynamic mechanical allodynia [36]. Collectively, these studies suggest that glycinergic disinhibition in the rat medullary dorsal horn (spinal trigeminal nucleus) allows dynamic stimulation-generated Aβ-inputs to activate nociceptive circuits but does not abnormally process static stimulation-generated afferent inputs. On the other hand, suppression of GABAA receptor-mediated inhibition in the same region activates nociceptive circuits by the latter afferent inputs but not by the former. To better understand this differential processing of mechanosensory inputs by the two inhibitory systems at a circuit level, it will be necessary to identify the nature of afferent inputs mediating the bicuculline-induced static mechanical allodynia in the rat face.

In other body parts of rats and mice and in the mouse face, however, have been obtained results that speak against the differential role of glycinergic and GABAergic disinhibition in the development of dynamic and static mechanical allodynia (Table 2). For instance, either intrathecal strychnine or targeted silencing of spinal glycinergic neurons resulted in static mechanical allodynia to punctate stimulation in the rat and mouse hindpaw [14; 31]. In addition, intracisternal bicuculline produced dynamic mechanical allodynia in the mouse face [27] and intrathecal bicuculline similarly in the flank of both rats and mice [20; 40]. The combination of intrathecal bicuculline and strychnine was synergistic in producing dynamic mechanical allodynia in rats [30].

Table 2.

Effects of glycinergic vs. GABAergic (GABAA-mediated) disinhibition on mechanical nociceptive responses

Species Body part Stimulation type Glycinergic disinhibition GABAergic disinhibition Ref
rat face brush/air puff dynamic allodynia no nociceptive response 35, 36
punctate no nociceptive response static allodynia 36
flank brush dynamic allodynia dynamic allodynia 20
plantar punctate static allodynia - 31
mouse face brush - dynamic allodynia 27
flank brush dynamic allodynia dynamic allodynia 40
plantar brush - dynamic allodynia 27
punctate static allodynia - 14
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GABA, γ-aminobutyric acid

As possible explanations for the above discrepancy, it should be noted that GABAergic and glycinergic inhibitory systems are not mutually exclusive. Spinal dorsal horn inhibitory interneurons construct an interacting neural network, feeding GABAergic and glycinergic fast inhibitory inputs to themselves [24]. That similar blockage of GABAA receptor-mediated inhibition either in the rat spinal cord vs. medullary dorsal horn or in the rat vs. mouse medullary dorsal horn produces different results, warrants studies examining regional and species differences in the degree of GABAergic and glycinergic inhibitory interactions suppressing mechanosensory afferent inputs generated by these various stimulation modes.

Targeted manipulations of specific spinal dorsal horn neurons reveal critical roles of phenotypically diverse inhibitory interneurons in the feed-forward suppression of Aβ-input-evoked nociceptive circuit activation [8; 9; 43] where a population of spinal excitatory interneurons transiently expressing vesicular glutamate transporter 3 (VGLUT3) participate in dynamic but not static (punctate) mechanical allodynia, while somatostatin-expressing ones do in both [7]. It would be interesting to examine whether GABAergic and glycinergic inhibition differentially affect responses of these two excitatory neuronal populations to mechanosensory afferent inputs.

3. Concluding remarks

In general, dynamic mechanical allodynia is mediated by Aβ-fibers in pathological conditions, whereas static mechanical allodynia is mediated by various afferent types depending on the pain conditions. Spinal disinhibition allows abnormal processing of these afferent inputs to produce mechanical allodynia, and there seem to be regional/species differences in glycinergic and GABAergic inhibitory processing of afferent inputs generated by dynamic/static stimulation.

Since dynamic and static mechanical allodynia can differ in their peripheral and central neural substrates, their sensitivities to therapeutics could also differ. Indeed, for example, dynamic mechanical allodynia was significantly attenuated by μ-opioid agonists, whereas no consistent effect was seen on static mechanical allodynia, in neuropathic pain patients [11]. In contrast, morphine was effective only on static mechanical allodynia in animals [7; 13]. Therefore, with species differences being considered, investigating both types of mechanical allodynia is necessary to better understand the pathological mechanisms and ultimately develop mechanism-based, more efficacious treatments.

Acknowledgments

We thank Dr. Richard E. Coggeshall and Ms. Denise Broker for reviewing the manuscript.

This work was supported by a NIH grant R01 NS031680.

Footnotes

The authors have no conflict of interest to disclose.

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