Demise of nociceptive Schwann cells causes nerve retraction and pain hyperalgesia

Rinwa, Puneet; Calvo-Enrique, Laura; Zhang, Mingdong; Nyengaard, Jens Randel; Karlsson, Páll; Ernfors, Patrik

doi:10.1097/j.pain.0000000000002169

Cited by 56 publications

(59 citation statements)

References 47 publications

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“…This irregular patterning of nociceptor terminals is also likely to change their functional connectivity with specialized cutaneous mechanosensitive glial cells at the sub-epidermal border, which are proposed to transmit nociceptive signals 49 . Consistently, ablation of these specialized Schwann cells was recently reported to cause the retraction of epidermal nerve fibres and induce allodynia 50 . Our ultrastructural morphological observations on atypical Meissner connectivity during reinnervation also raise the idea that remodelling of Meissner corpuscles anatomically links light touch to nociceptor activation in neuropathic pain, essentially ‘converting’ nociceptors to low-threshold afferents.…”

Section: Nociceptors Mediate Reinnervation Painmentioning

confidence: 55%

Neuropathic pain caused by miswiring and abnormal end organ targeting

Gangadharan

Zheng

Taberner

et al. 2022

Nature

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Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1–3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents—which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4–7—did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

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Section: Nociceptors Mediate Reinnervation Painmentioning

confidence: 55%

Neuropathic pain caused by miswiring and abnormal end organ targeting

Gangadharan

Zheng

Taberner

et al. 2022

Nature

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“…7,22 In recent studies, specialized nociceptive Schwann cells were characterized that form a meshlike network with nerve fibers at the dermis-epidermis border accompanying nerve fibers into the epidermis in the murine model 11 and also in human skin when assessed using electron microscopy. 12 Interestingly, selective depletion of intraepidermal nerve fibers resulted in a reduction of Schwann cell counts in murine skin, whereas ablation of Schwann cells led to nerve fiber retraction. 12 In line with these findings, we found lower numbers of Schwann cells in skin samples of SFN patients with reduced distal IENFD, but our study design did not allow conclusions about causality.…”

Section: Schwann Cell Counts Are Not Associated With Clinical Pain Ch...mentioning

confidence: 99%

“…12 Interestingly, selective depletion of intraepidermal nerve fibers resulted in a reduction of Schwann cell counts in murine skin, whereas ablation of Schwann cells led to nerve fiber retraction. 12 In line with these findings, we found lower numbers of Schwann cells in skin samples of SFN patients with reduced distal IENFD, but our study design did not allow conclusions about causality. Also, using fluorescent microscopy, we did not observe epidermal Schwann cell branches, but found them to vanish at the basement membrane.…”

Section: Schwann Cell Counts Are Not Associated With Clinical Pain Ch...mentioning

confidence: 99%

Subepidermal Schwann cell counts correlate with skin innervation – an exploratory study

et al. 2022

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Introduction/Aims: Schwann cell clusters have been described at the murine dermisepidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype.Methods: Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined. Results: Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics. Discussion: Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.

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“…Consistent with this idea many studies have shown that cultured sensory neurons, whether mechanoreceptors or nociceptors, are mechanosensitive in that mechanical stimuli activate fast inward currents in these cells [7][8][9][10] . This paradigm, placing the nociceptive neuron at the center of pain control, was recently challenged by the finding that specialized nociceptive Schwann cells expressing the transcription factor Sox10 are tightly associated with sensory endings and can initiate pain 11,12 . Sox10 + Schwann cells are also found associated with mechanoreceptor endings in skin end-organs needed for touch sensation 7,13,14 .…”

mentioning

confidence: 99%

Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception

Ojeda-Alonso

Calvo-Enrique

Paricio-Montesinos

et al. 2022

Preprint

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That sensory neurons alone transduce mechanical stimuli was challenged by the discovery of nociceptive Schwann cells that can initiate pain. Consistent with the existence of inherently mechanosensitive sensory Schwann cells, we found that mechanosensory function of almost all nociceptors, including those signaling fast pain were critically dependent on sensory Schwann cells. Furthermore, in polymodal nociceptors, sensory Schwann cells signal mechanical, but not cold or heat pain. Terminal Schwann cells also surround mechanoreceptor nerve-endings forming Meissners corpuscles that signal vibrotactile touch, raising the possibility that touch sensation is also dependent on such cells. Using optogenetics we show that Meissner`s corpuscle Schwann cells are necessary for the detection and perception of vibrotactile stimuli. Our results show that sensory Schwann cells within diverse glio-neural mechanosensory end-organs are sensors for mechanical pain as well as touch perception. These results place specialized sensory Schwann cells at the center of somatic sensation to all types of mechanical stimuli.

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Demise of nociceptive Schwann cells causes nerve retraction and pain hyperalgesia

Abstract: The role of nociceptive Schwann cells for chronic pain is not known. We find that their demise is sufficient to cause neuropathy and neuropathic pain.

Cited by 56 publications

References 47 publications

Neuropathic pain caused by miswiring and abnormal end organ targeting

Neuropathic pain caused by miswiring and abnormal end organ targeting

Subepidermal Schwann cell counts correlate with skin innervation – an exploratory study

Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception

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