Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain

Javed, Hayate; Johnson, Aishwarya Mary; Challagandla, Anil Kumar; Emerald, Bright Starling; Shehab, Safa

doi:10.3390/cells11244049

Cited by 4 publications

(6 citation statements)

References 64 publications

(125 reference statements)

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“…A significant decrease in the mRNA level of Trpv1, Nav1.9, Kv4.3, and Cav2.2 was observed in the RTX-treated L4 DRG compared to vehicle-treated L4 and right control R4 DRGs, but no changes were found in the Kv1.1, Piezo2, and Kir4.1 (A). Similarly, the protein expression level of Trpv1, Nav1.9, Kv4.3,and Cav2. following intraplantar injection (Javed et al, 2022). These observations were not witnessed after the perineural application of RTX.…”

Section: Comparison With Other Studiesmentioning

confidence: 76%

“…In a different approach to evaluate the effects of local RTX application, we recently investigated the impact of intraplantar injection of RTX, rather than perineural application, on developing and preventing nerve injury-induced neuropathic pain in rats ( Javed et al, 2022 ). The study’s main findings revealed that intraplantar injection of RTX also alleviated and prevented nerve injury-induced thermal and mechanical hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are several advantages to utilizing perineural application over intraplantar injection, particularly when attempting to translate this therapeutic approach for treating and preventing neuropathic pain in humans. First, rats showed paw flicking and guarding shortly after recovery from general anesthesia and exhibited foot edema following intraplantar injection ( Javed et al, 2022 ). These observations were not witnessed after the perineural application of RTX.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the findings of how to treat neuropathic pain in animals using local applications of capsaicin and RTX ( Jancsó et al, 2007 ; Neubert et al, 2008 ; Sapio et al, 2018 ; Javed et al, 2020 , 2022 ; Iadarola et al, 2021 ), it is now imperative to test whether the procedures developed in animals can be translated from the laboratory to the clinic to treat neuropathic pain in human patients, for whom currently available treatments are ineffective. Figure 12 summarizes our proposals on how to treat neuropathic pain following partial or complete peripheral nerve injury in patients due to trauma, post-surgery, vertebral disc herniation, nerve entrapment, ischemia, and postherpetic lesion.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was extracted from left L4 DRGs from RTX and vehicle-treated rats as well as right control L4 DRGs. The qRT-PCR analysis was performed as we published previously ( Emerald et al, 2011 ; Javed et al, 2020 , 2022 ). Briefly, total RNA was extracted using TRIzol™ Reagent (Thermo Fisher Scientific) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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Unveiling the mechanisms of neuropathic pain suppression: perineural resiniferatoxin targets Trpv1 and beyond

Shehab,

Javed,

Johnson

et al. 2023

Front. Neuroanat.

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Neuropathic pain arises from damage or disorders affecting the somatosensory system. In rats, L5 nerve injury induces thermal and mechanical hypersensitivity/hyperalgesia. Recently, we demonstrated that applying resiniferatoxin (RTX) directly on uninjured L3 and L4 nerves alleviated thermal and mechanical hypersensitivity resulting from L5 nerve injury. Herein, using immunohistochemistry, Western blot, and qRT-PCR techniques, we reveal that perineural application of RTX (0.002%) on the L4 nerve substantially downregulated the expression of its receptor (Trpv1) and three different voltage-gated ion channels (Nav1.9, Kv4.3, and Cav2.2). These channels are found primarily in small-sized neurons and show significant colocalization with Trpv1 in the dorsal root ganglion (DRG). However, RTX treatment did not affect the expression of Kv1.1, Piezo2 (found in large-sized neurons without colocalization with Trpv1), and Kir4.1 (localized in satellite cells) in the ipsilateral DRGs. Furthermore, RTX application on L3 and L4 nerves reduced the activation of c-fos in the spinal neurons induced by heat stimulation. Subsequently, we investigated whether applying RTX to the L3 and L4 nerves 3 weeks before the L5 nerve injury could prevent the onset of neuropathic pain. Both 0.002 and 0.004% concentrations of RTX produced significant analgesic effects, while complete prevention of thermal and mechanical hypersensitivity required a concentration of 0.008%. Importantly, this preventive effect on neuropathic manifestations was not associated with nerve degeneration, as microscopic examination revealed no morphological changes. Overall, this study underscores the mechanisms and the significance of perineural RTX treatment applied to adjacent uninjured nerves in entirely preventing nerve injury-induced neuropathic pain in humans and animals.

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Section: Comparison With Other Studiesmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Unveiling the mechanisms of neuropathic pain suppression: perineural resiniferatoxin targets Trpv1 and beyond

Shehab,

Javed,

Johnson

et al. 2023

Front. Neuroanat.

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Changes of Trigeminal Ganglion Neurons Innervating the Temporomandibular Joint in Chronic Pain Rat Model

Liu,

Jiang,

et al. 2024

International Journal of Dentistry

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Background: Phenotype alterations of nociceptive neurons have been shown to be a key step in the pathogenesis of many pain‐related diseases. However, it is unclear if the characteristic changes of temporomandibular joint (TMJ) primary afferent neurons are related to the pathogenesis of temporomandibular joint osteoarthritis (TMJOA) chronic pain. This study aimed to determine the morphological and neurochemical changes in trigeminal ganglion (TG) neurons innervating the TMJ in TMJOA chronic pain rats.Materials and Methods: Monosodium iodoacetate (MIA)‐induced TMJOA chronic pain rat model was established (n = 6), and saline was injected in rats of the control group (n = 6). TMJ primary afferent neurons were labeled with retrograde tracing (Dil). The spatial distribution and the expression of calcitonin gene‐related peptide (CGRP), isolectin B4 (IB4), and neurofilament 200 (NF200) of TMJ primary afferent neurons in TG were investigated using immunofluorescence. Intracellular calcium signaling was recorded by calcium imaging (n = 20).Results: TMJ primary afferent neurons were located only in the V3 region of the TG from both saline‐ and MIA‐injected rats. The number of TG neurons innervating the TMJ was increased in MIA‐injected rats. Elevated number and intracellular calcium concentration of small‐ and medium‐sized instead of large‐sized Dil+ TG neurons were found in MIA‐injected rats. The upregulated expression of CGRP and IB4, but not NF200, in TG neurons innervating the rat TMJs was accompanied by TMJOA chronic pain.Conclusion: This study suggests that sensitization of small‐ to medium‐sized Dil+ TG neurons and CGRP‐ and IB4‐positive Dil+ TG neurons might contribute to the development of TMJOA chronic pain in rats. This will provide valuable information for more efficient control of TMJOA chronic pain.

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TRPV1+ neurons alter Staphylococcus aureus skin infection outcomes by affecting macrophage polarization and neutrophil recruitment

Huang,

Chen,

Cai

et al. 2023

BMC Immunol

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Background The interaction between the nervous system and the immune system can affect the outcome of a bacterial infection. Staphylococcus aureus skin infection is a common infectious disease, and elucidating the relationship between the nervous system and immune system may help to improve treatment strategies. Results In this study, we found that the local release of calcitonin gene-related peptide (CGRP) increased during S. aureus skin infection, and S. aureus could promote the release of CGRP from transient receptor potential cation channel subfamily V member 1 (TRPV1+) neurons in vitro. The existence of TRPV1+ neurons inhibited the recruitment of neutrophils to the infected region and regulated the polarization of macrophages toward M2 while inhibiting polarization toward M1. This reduces the level of inflammation in the infected area, which aggravates the local infection. Furthermore, this study demonstrates that TRPV1 may be a target for the treatment of S. aureus skin infections and that botulinum neurotoxin A (BoNT/A) and BIBN4096 may reverse the inhibited inflammatory effect of CGRP, making them potential therapeutics for the treatment of skin infection in S. aureus. Conclusions In S. aureus skin infection, TRPV1+ neurons inhibit neutrophil recruitment and regulate macrophage polarization by releasing CGRP. BoNT/A and BIBN4096 may be potential therapeutic agents for S. aureus skin infection.

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Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain

Cited by 4 publications

References 64 publications

Unveiling the mechanisms of neuropathic pain suppression: perineural resiniferatoxin targets Trpv1 and beyond

Unveiling the mechanisms of neuropathic pain suppression: perineural resiniferatoxin targets Trpv1 and beyond

Changes of Trigeminal Ganglion Neurons Innervating the Temporomandibular Joint in Chronic Pain Rat Model

TRPV1+ neurons alter Staphylococcus aureus skin infection outcomes by affecting macrophage polarization and neutrophil recruitment

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