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Microgliosis in the spinal dorsal horn early after peripheral nerve injury is associated with damage to primary afferent aβ-fibers
Shibata Y, Matsumoto Y, Kohno K, Nakashima Y, Tsuda M (2025) Microgliosis in the spinal dorsal horn early after peripheral nerve injury is associated with damage to primary afferent aβ-fibers. Cells 14(9):666. doi: 10.3390/cells14090666 PMID: 40358190
Objective: To investigate the spatial relationship between microgliosis and the projections of injured nerves by generating mice that had expressed tdTomato in the fourth lumbar dorsal root ganglion (L4-DRG) neurons via intra-L4-spinal nerve (SpN) injection of adeno-associated viral vectors.
Summary: After transection of the L4-SpN, authors found that microgliosis in the SDH selectively occurred in the innervation territories of the injured primary afferent fibers. However, denervating transient receptor potential vanilloid 1 (TRPV1)-expressing primary afferent fibers in theSDH through intrathecal injection of capsaicin did not trigger microgliosis, nor did it influence the microgliosis induced by L4-SpN injury. Conversely, pharmacological damage to myelinated DRG neurons, including Aβ-fibers, was sufficient to induce microgliosis. Furthermore, L4-SpN injury also induced microgliosis in the gracile nucleus, which primarily receives innervation from Aβ-fibers. These findings suggest that microgliosis in the SDH shortly after peripheral nerve injury is predominantly associated with damage to primary afferent Aβ-fibers.
Usage: WT mice were injected with saporin into the L4-SpN, administering 400 nL of saporin solution [saporin conjugated with cholera toxin B subunit (CTB-SAP), isolectin B4 (IB4-SAP),and unconjugated saporin (Ctrl-SAP)]
Related Products: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Involvement of the transient receptor channels in preclinical models of musculoskeletal pain
Kudsi SQ, Viero FT, Pereira LG, Trevisan G (2024) Involvement of the transient receptor channels in preclinical models of musculoskeletal pain. Curr Neuropharmacol 22(1):72-87. doi: 10.2174/1570159X21666230908094159 PMID: 37694792
Objective: To provide an updated view of the most studied preclinical models of muscle hyperalgesia and the role of transient receptor potential (TRP) in these models.
Summary: The participation of TRPV1, TRPA1, and TRPV4 in different models of musculoskeletal pain was evaluated using pharmacological and genetic tools. All the studies detected the antinociceptive effect of respective antagonists or reduced nociception in knockout mice. Hence, TRPV1, TRPV4, and TRPA1 blockers could potentially be utilized in the future for inducing analgesia in muscle hypersensitivity pathologies.
Usage: NK1-expressing neurons were ablated by SP-SAP (neurotoxin saporin conjugated to substance P) to Vc, and the ablation of NK1-expressing second-order neurons reduced the MGS and bite force nociceptive behaviors.
Related Products: SP-SAP (Cat. #IT-07)
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Contribution of small diameter non-peptidergic primary afferent neurons to central neuropathic pain in a new, more clinically relevant mouse model of multiple sclerosis
Nguyen KL, Lamerand SR, Deshpande RP, Taylor BK (2021) Contribution of small diameter non-peptidergic primary afferent neurons to central neuropathic pain in a new, more clinically relevant mouse model of multiple sclerosis. Neuroscience 2021 Abstracts P377/07. Society for Neuroscience, Virtual.
Summary: Over 50% of multiple sclerosis (MS) patients suffer from neuropathic pain (MSNP). Current treatments give inadequate relief due to incomplete understanding of underlying mechanisms. Recent electrophysiological recordings of primary afferent neurons (PAN) in the dorsal root ganglion (DRG) following experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, revealed increased afterhyperpolarization in small-diameter fibers. These data form the premise of our goal to understand the contribution of small-diameter (peptidergic or non-peptidergic) PANs to MSNP. Arguably the most common method to induce EAE is administration of myelin oligodendrocyte glycoprotein (MOG) to generate an autoimmune response targeting the myelin sheath. A MOG fragment is typically given with two adjuvants: complete Freund’s adjuvant (CFA) to boost immunogenicity and pertussis toxin (PTX) to breakdown the blood-brain barrier and facilitate CNS immune cell infiltration. However, PTX can disrupt G-protein coupled receptors, cause pain, and alter autoimmune response gene expression. In 10-week-old C57BL/6 mice, we conducted the first rigorous comparison of a classic PTX EAE model with the novel non-PTX (nPTX) EAE model. We found that both PTX and nPTX EAE mouse models showed the same degree of: 1) motor deficits; 2) plantar hindpaw mechanical and cold hypersensitivity (except cold hypersensitivity resolved more quickly after PTX EAE than nPTX EAE); and 3) lumbar spinal cord demyelination. Unlike most rodent models of MS including PTX EAE, the nPTX EAE group exhibited somatosensory cortex demyelination, a core feature of MS in human patients and cold hypersensitivity. We suggest nPTX EAE to be the most clinically relevant rodent model available to study not only MSNP, but MS in general. To evaluate the contribution of peptidergic and non-peptidergic neurons to MSNP, we induced nPTX EAE. After 12 days we administered capsaicin (10µg/mouse, i.t.) or IB4-saporin (1.5µg/mouse, i.t.) to primarily ablate peptidergic or nonpeptidergic C-fibers, respectively. Ablation efficacy was successfully confirmed with dramatic loss in DRG of TRPV1/CGRP immunoreactivity (peptidergic C-fibers) following capsaicin, and IB4 immunoreactivity (nonpeptidergic C-fibers) following IB4-saporin. IB4-saporin, but not capsaicin, partially reduced mechanical hypersensitivity and reversed cold hypersensitivity within 9 days. These data suggest nonpeptidergic but not peptidergic C-fibers contribute to MSNP. Our next studies will use genetic knockout, chemogenetic, and optogenetic strategies using MrgprdCreER mice to modulate the activity of nonpeptidergic C-fibers.
Related Products: IB4-SAP (Cat. #IT-10)
TRP channels in cancer pain
de Almeida AS, Bernardes LB, Trevisan G (2021) TRP channels in cancer pain. Eur J Pharmacol 904:174185. doi: 10.1016/j.ejphar.2021.174185 PMID: 34015320
Objective: To describe the role of TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) involved in cancer pain mechanisms.
Summary: Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
Usage: Ablation of IB4 (+) neurons.
Related Products: IB4-SAP (Cat. #IT-10)
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Nociceptors expressing TRPV1 and trigeminal nucleus neurons expressing NK1 mediate orthodontic pain
Wang S, Kim M, Ong K, Pae E-K, Chung M-K (2019) Nociceptors expressing TRPV1 and trigeminal nucleus neurons expressing NK1 mediate orthodontic pain. Neuroscience 2019 Abstracts 052.10. Society for Neuroscience, Chicago, IL.
Summary: Orthodontic force produces mechanical irritation and inflammation in periodontium, which inevitably accompanies pain. Despite its high prevalence, treatment of orthodontic pain is not effective. Determining detailed neural mechanisms involving peripheral and central nervous system should be critical to improve the management of orthodontic pain. Periodontal ligament is projected by peptidergic nociceptors, which is enriched with transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin. Trigeminal subnucleus caudalis (Vc), is critical for relaying orofacial nociceptive signal into brain. A group of second- order neurons in the superficial dorsal horn of Vc express neurokinin 1 receptor (NK1), a receptor for substance P, and receive inputs from peptidergic nociceptors. However, the contribution of these nociceptive neurons to orthodontic pain has not been determined. Orthodontic force of 10g produced reliable tooth movement in mice. Orthodontic pain was evaluated by measuring mouse grimace scale (MGS) and bite force (BF), which could represent spontaneous pain and chewing-evoked pain, respectively. Orthodontic force increased MGS and decreased BF, which peaked at 1d and returned near to sham level at 7d. Using targeted chemical ablation of specific subsets of neurons, we determined the contribution of TRPV1+ nociceptors and NK1+ Vc neurons to orthodontic pain behaviors in mice. Ablation of TRPV1+ nociceptors by injecting resiniferatoxin into trigeminal ganglia significantly attenuated orthodontic force assessed by MGS and BF. Chemical ablation of NK1+ Vc neurons by injecting saporin conjugated with substance P into Vc also significantly reduced the extent of changes in MGS and BF by orthodontic force. These results suggest that TRPV1+ trigeminal nociceptors and NK1+ Vc neurons constitute a major neural pathway for transmission of orthodontic pain, which is a fundamental neural mechanism of orthodontic pain transmission. The new mouse model of orthodontic pain will be useful for mechanistic study to develop novel approaches for painless orthodontics.
Related Products: SSP-SAP (Cat. #IT-11)
Neuropeptide Y release in the rat spinal cord measured with Y1 receptor internalization is increased after nerve injury.
Marvizon JC, Chen W, Fu W, Taylor BK (2019) Neuropeptide Y release in the rat spinal cord measured with Y1 receptor internalization is increased after nerve injury. Neuropharmacology 158:107732. doi: 10.1016/j.neuropharm.2019.107732
Summary: NPY is released from dorsal horn interneurons or primary afferent terminals by electrical stimulation and by activation of TRPV1, PKA or NMDA receptors in. Release evoked by noxious and tactile stimuli increases after peripheral nerve injury. Ablation of Y1-expressing dorsal horn neurons with NPY-saporin produced antinociception (Lemons and Wiley) and reduced mechanical and cold hypersensitivity in the spared nerve injury model (Nelson et al.), suggesting that they are pro-nociceptive neurons.
Related Products: NPY-SAP (Cat. #IT-28)
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TRPV1 expression level in isolectin B₄-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity.
Ono K, Ye Y, Viet C, Dang D, Schmidt B (2015) TRPV1 expression level in isolectin B₄-positive neurons contributes to mouse strain difference in cutaneous thermal nociceptive sensitivity. J Neurophysiol 113:3345-3355. doi: 10.1152/jn.00973.2014
Summary: In order to determine whether IB4-positive trigeminal sensory neurons affect pain sensitivity, the authors administered 2 μg of rIB4-SAP (Cat. #IT-10) to the right infraorbital foramen. Saporin (Cat. #PR-01) was used as a control.
Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors.
Devesa I, Ferrándiz-Huertas C, Mathivanan S, Wolf C, Luján R, Changeux J, Ferrer-Montiel A (2014) αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors. Proc Natl Acad Sci U S A 111:18345-18350. doi: 10.1073/pnas.1420252111
Summary: The sensitization of transient receptor potential vanilloid 1 (TRPV1) can lead to the development and maintenance of chronic pathological pain conditions. In this work the authors determined that TRPV1 receptors use membrane insertion mechanisms in order to potentiate neuronal excitability. In order to specifically link this activity to peptidergic neurons the authors treated rat primary dorsal root ganglion cultures with 10 mM rIB4-SAP (Cat. #IT-10) to deplete the non-peptidergic neurons.
Related Products: IB4-SAP (Cat. #IT-10)
IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma.
Ye Y, Bae S, Viet CT, Troob S, Bernabe D, Schmidt BL (2014) IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma. Behav Brain Funct 10(1):5. doi: 10.1186/1744-9081-10-5
Objective: To evaluate subtypes of sensory neurons involved in cancer pain and proliferation.
Summary: IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.
Usage: IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.
Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice.
Pinto LG, Souza GR, Lopes AHP, Talbot J, Cunha FQ, Cunha TM, Ferreira SH (2013) Role of nonpeptidergic subset of primary afferent neurons in inflammatory hypernociception in mice. Neuroscience 2013 Abstracts 256.15. Society for Neuroscience, San Diego, CA.
Summary: Sensory information is transmitted from the periphery to the spinal cord by distinct subsets of primary afferent neurons, including small diameter unmyelinated C-fibers, which plays an important role in detecting noxious stimuli. C-fiber nociceptors have been divided into two classes, the peptidergic and nonpeptidergic. While many of the differences between peptidergic and nonpeptidergic neurons are now appreciated, a possible functional difference between these two classes of C fibers in the genesis of acute nociception as well as inflammatory pain is still unclear. Thus, this study aims to clarify the role of nonpeptidergic C fibers in acute nociception induced by mechanical, thermal and chemical stimuli as well as in inflammatory hypernociception. In order to elucidate differences between these two classes of C fibers, a neurotoxin was used to selectively eliminate the nonpeptidergic C fibers: a saporin conjugated to isolectin B4 (IB4). Nociceptive threshold was evaluated through thermal (Hargreaves) and mechanical (filaments and electronic von Frey) tests in C57BL/6 mice. Nociception models were induced by intraplantar (i.pl.) injection of capsaicin and formalin (acute nociception) or by i.pl. administration of prostaglandin E2 (PGE2), epinephrine, endothelin, NGF, GDNF and carrageenan (inflammatory hypernociception). P2X3 and TRPV1 expression were analyzed by Western blot of dorsal root ganglion (DRG). The expression of IB4-labeled in spinal cord was determined by immunofluorescense using confocal microcopy. Firstly, it was observed that the intrathecal administration of IB4-saporin did not change baseline thermal and mechanical nociceptive threshold of the mice paw when compared to saline and saporin-control groups. The intrathecal administration of IB4-saporin reduced mechanical inflammatory hypernociception induced by carrageenan, epinephrine, endothelin, PGE2 or GDNF, but not NGF, in mice. Similarly, the treatment with IB4-saporin inhibited the nociception caused by intraplantar injection of the capsaicin. By contrast, the acute nociception induced by formalin did not change by administration of IB4-saporin. In addition, the expression of TRPV1 and P2X3 in DRG were reduced after treatment with IB4-saporin. Consistent with these findings, we found that IB4-saporin injection decreased the expression of IB4-labeled in spinal cord. These results suggest that absence the nonpeptidergic C fibers does not affect basal nociceptive threshold. However, these fibers are essential for the development of nociception in the paw of mice induced by inflammatory stimuli like PGE2, epinephrine, endothelin, carrageenan and capsaicin.
Related Products: IB4-SAP (Cat. #IT-10)