TRPV1 activation alters the function of Aδ and C fiber sensory neurons that innervate bone

Morgan, Michael; Nencini, Sara; Thai, Jenny; Ivanusic, Jason J.

doi:10.1016/j.bone.2019.03.040

Cited by 35 publications

(37 citation statements)

References 87 publications

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“…We have previously shown that activation of TRPV1 (another acid sensing ion channel) sensitizes Aδ and C fiber bone afferent neurons to mechanical stimulation 49. Of note, approximately half of the ASIC3 expressing bone afferent neurons we observed in the present study also express TRPV1.…”

Section: Discussionsupporting

confidence: 64%

ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Aδ and C fiber sensory neurons that innervate bone

et al. 2020

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The Acid Sensing Ion Channel 3 (ASIC3) is a non-selective cation channel that is activated by acidification, and is known to have a role in regulating inflammatory pain. It has pro-algesic roles in a range of conditions that present with bone pain, but the mechanism for this has not yet been demonstrated. We aimed to determine if ASIC3 is expressed in Aδ and/or C fiber bone afferent neurons, and to explore its role in the activation and sensitization of bone afferent neurons after acute inflammation. A combination of retrograde tracing and immunohistochemistry was used to determine expression of ASIC3 in the soma of bone afferent neurons. A novel, in vivo, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons in the presence of carrageenan-induced inflammation, with and without the selective ASIC3 inhibitor APET×2. A substantial proportion of bone afferent neurons express ASIC3, including unmyelinated (neurofilament poor) and small diameter myelinated (neurofilament rich) neurons that are likely to be C and Aδ nerve fibers respectively. Electrophysiological recordings revealed that application of APET×2 to the marrow cavity inhibited carrageenan-induced spontaneous activity of C and Aδ fiber bone afferent neurons. APET×2 also inhibited carrageenan-induced sensitization of Aδ and C fiber bone afferent neurons to mechanical stimulation, but had no effect on the sensitivity of bone afferent neurons in the absence of inflammation. This evidence supports a role for ASIC3 in the pathogenesis of pain associated with inflammation of the bone.

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Section: Discussionsupporting

confidence: 64%

ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Aδ and C fiber sensory neurons that innervate bone

et al. 2020

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“…The day after the third intrathecal injection of Piezo2 ODNs, rats were anesthetized with urethane (50% w/v, 1.5 g/kg; i.p. ), and electrophysiological experiments were made using our recently developed in vivo, bone nerve preparation Nencini et al, , 2018Nencini et al, , 2019Morgan et al, 2019). A fine branch of the tibial nerve that innervates the marrow cavity of the rat tibia was dissected and placed over a platinum hook electrode for electrophysiological recordings.…”

Section: Electrophysiological Recordings Using An In Vivo Bone-nerve Preparationmentioning

confidence: 99%

“…We have recently developed a novel in vivo electrophysiological bone-nerve preparation that allows us to record, for the first time, the activity of different populations of bone afferent neurons in response to noxious mechanical stimulation Nencini et al, , 2018Nencini et al, , 2019Morgan et al, 2019;Morgan et al, 2020). In the present study, we use this approach to determine how Piezo2 knockdown affects the ability of bone afferent neurons to respond to noxious mechanical stimulation applied to the bone.…”

Section: Introductionmentioning

confidence: 99%

Piezo2 Knockdown Inhibits Noxious Mechanical Stimulation and NGF-Induced Sensitization in A-Delta Bone Afferent Neurons

et al. 2021

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Piezo2 is a mechanically gated ion-channel that has a well-defined role in innocuous mechanical sensitivity, but recently has also been suggested to play a role in mechanically induced pain. Here we have explored a role for Piezo2 in mechanically evoked bone nociception in Sprague Dawley rats. We have used an in vivo electrophysiological bone-nerve preparation to record the activity of single Aδ bone afferent neurons in response to noxious mechanical stimulation, after Piezo2 knockdown in the dorsal root ganglia with intrathecal injections of Piezo2 antisense oligodeoxynucleotides, or in control animals that received mismatch oligodeoxynucleotides. There were no differences in the number of Aδ bone afferent neurons responding to the mechanical stimulus, or their threshold for mechanical activation, in Piezo2 knockdown animals compared to mismatch control animals. However, bone afferent neurons in Piezo2 knockdown animals had reduced discharge frequencies and took longer to recover from stimulus-evoked fatigue than those in mismatch control animals. Piezo2 knockdown also prevented nerve growth factor (NGF)-induced sensitization of bone afferent neurons, and retrograde labeled bone afferent neurons that expressed Piezo2 co-expressed TrkA, the high affinity receptor for NGF. Our findings demonstrate that Piezo2 contributes to the response of bone afferent neurons to noxious mechanical stimulation, and plays a role in processes that sensitize them to mechanical stimulation.

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“…Pain is associated with most bony pathologies and it puts a significant burden (both in terms of quality of life and cost) on individuals, society, and the health care system all over the world. Small diameter myelinated and unmyelinated sensory neurons innervate both the periosteum and the marrow cavity (Furusawa, ; Ishida, Tanaka, Sekiguchi, Sugiyama, & Kawamata, ; Ivanusic, ; Ivanusic, Mahns, Sahai, & Rowe, ; Mach et al, ; Seike, ), and there is a rapidly growing body of evidence demonstrating that they are responsive to noxious chemical and/or mechanical stimuli (Ivanusic, Mahns, Sahai, Vickery, & Rowe, ; Morgan, Nencini, Thai, & Ivanusic, ; Nencini & Ivanusic, ; Nencini et al, ; Nencini et al, ; Nencini, Thai, & Ivanusic, ). Most previous work in the context of bone pain has focused on studying myelinated (Aδ‐fiber) nociceptors, and/or peptidergic unmyelinated (C‐fiber) nociceptors, because these have been the easiest to identify immunohistochemically (Castaneda‐Corral et al, ; Chartier et al, ; Imai et al, ; Mach et al, ).…”

Section: Discussionmentioning

confidence: 99%

Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing

Thai

Kyloh

Travis

et al. 2020

J of Comparative Neurology

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While sensory and sympathetic neurons are known to innervate bone, previous studies have found it difficult to unequivocally identify and characterize only those that are of sensory origin. In this study, we have utilized an in vivo anterograde tracing technique to selectively label spinal afferent (sensory) nerve endings that innervate the periosteum and marrow cavity of murine long bones. Unilateral injections of dextran-biotin (anterograde tracer; 20% in saline, 50-100 nl) were made into L3-L5 dorsal root ganglia. After a 10-day recovery period to allow sufficient time for selective anterograde transport of the tracer to nerve terminal endings in bone, the periosteum (whole-mount) and underlying bone were collected, processed to reveal anterograde labeling, and immuno-labeled with antibodies directed against protein gene product (pan-neuronal marker; PGP9.5), tyrosine hydroxylase (sympathetic neuron marker; TH), calcitonin gene-related protein (peptidergic nociceptor marker; CGRP), and/or neurofilament 200 (myelinated axon marker; NF200).Anterograde-labeled nerve endings were dispersed throughout the periosteum and marrow cavity and could be identified in close apposition to blood vessels and at sites distant from them. The periosteum and the marrow cavity were each innervated by myelinated (NF200+) sensory neurons, and unmyelinated (NF200-) sensory neurons that were either peptidergic (CGRP+) or nonpeptidergic (CGRP-). Spinal afferent nerve endings did not express TH, and lacked the cylindrical morphology around blood vessels characteristic of sympathetic innervation. This approach to selective labeling of sensory nerve terminal endings will help to better identify how different sub-populations of sensory neurons, and their peripheral nerve terminal endings, interact with bone.

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TRPV1 activation alters the function of Aδ and C fiber sensory neurons that innervate bone

Cited by 35 publications

References 87 publications

ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Aδ and C fiber sensory neurons that innervate bone

ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Aδ and C fiber sensory neurons that innervate bone

Piezo2 Knockdown Inhibits Noxious Mechanical Stimulation and NGF-Induced Sensitization in A-Delta Bone Afferent Neurons

Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing

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