Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain

MacDonald, Donald Iain; Luiz, Ana Paula; Iseppon, Federico; Millet, Queensta; Emery, Edward C.; Wood, John N.

doi:10.1093/brain/awab086

Cited by 35 publications

(70 citation statements)

References 58 publications

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“…Here our work elucidates the role of KOR action via TRPA1 channels potentiating calcium signaling which might underlie the cold hypersensitivity, conversely Snyder et al elucidated the role of peripheral KOR activation in mitigation of chemical pain (Snyder et al, 2018). These findings together with recent data showing that cold sensing neurons mediate mechanical stimuli (MacDonald et al, 2021) suggest that these cold sensing neurons likely play a dual role in modulating noxious cold hypersensitivity and chemical pain. Exploration of the downstream signaling pathway mediating the calcium homeostasis via the KOR is warranted in order to understand the canonical/non-canonical pathway meditating KORinduced noxious cold hypersensitivity.…”

Section: Discussionsupporting

confidence: 59%

“…To understand how activation of KOR mediates noxious cold hypersensitivity, we investigated TRPA1 and TRPM8 channels, both well known for their role in cold sensitivity (MacDonald et al, 2021;McKemy et al, 2002b;Palkar et al, 2015;Patapoutian et al, 2009). Interestingly, there has been targeted research exploring MOR, but not KOR, and TRP channel interactions (Shapovalov et al, 2013;Williams et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate how peripheral KOR mediates cold hypersensitivity we explored TRP channels, known to be necessary for temperature sensation. Specifically, the TRPA1 and TRPM8 channels have been most widely associated with cold sensitivity (MacDonald et al, 2021;McKemy et al, 2002b;Patapoutian et al, 2009). To determine whether KOR were expressed in TRPA1-and/or TRPM8expressing cells in DRG, we performed in situ hybridization against the mRNA for KOR (oprk1), TRPA1 (trpa1), and TRPM8 (trpm8) in male (Fig 3A-F) and female (Fig 3G-L).…”

Section: Kor Colocalizes With Trpa1 and Trpm8 Transcripts And Potentiates Ca 2+ Mobilization Via Trpa1 In Drgmentioning

confidence: 99%

“…While less in known about cold pain, significantly more is known about cold sensation, particularly how it is regulated by transient receptor potential (TRP) channels, TRPA1 and TRPM8 in DRG (Bautista et al, 2006a;Dhaka et al, 2008;McKemy et al, 2002a;Patapoutian et al, 2009;Pogorzala et al, 2013;Story et al, 2003) . Most recently, it was shown that blocking Kv1 potassium channels on large-diameter neurons in the periphery potentiated cold hypersensitivity in chronic pain states (MacDonald et al, 2021). Similarly loss of Nav1.9 sodium channel (Nav1.9 -/mice) known to predominantly express in DRG significantly attenuated chemotherapy-induced cold allodynia (Lolignier et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Madasu

Thang

Chilukuri

et al. 2020

Preprint

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Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Kor Colocalizes With Trpa1 and Trpm8 Transcripts And Potentiates Ca 2+ Mobilization Via Trpa1 In Drgmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Madasu

Thang

Chilukuri

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Primary sensory neuron excitability in vitro shown here provides a potential mechanism relevant to the block of chronic pain in the mouse model. The role of large-diameter neurons such as those implicated in cold sensing and Aβ nerve fibers are important in chronic pain behaviors including spontaneous pain and tactile allodynia [33][34][35]. The findings here imply the P2X4R scFv95 has potential to block phenotypic switching from acute to chronic pain.…”

Section: Discussionmentioning

confidence: 71%

Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

Westlund

Montera

Goins

et al. 2021

IJMS

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Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

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Trigeminal neurons control immune-bone cell interaction and metabolism in apical periodontitis

Austah

Lillis

Akopian

et al. 2022

Cell. Mol. Life Sci.

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Apical periodontitis (AP) is an inflammatory disease occurring following tooth infection with distinct osteolytic activity. Despite increasing evidence that sensory neurons participate in regulation of non-neuronal cells, their role in the development of AP is largely unknown. We hypothesized that trigeminal ganglia (TG) Nav1.8+ nociceptors regulate bone metabolism changes in response to AP. A selective ablation of nociceptive neurons in Nav1.8Cre/Diphtheria toxin A (DTA)Lox mouse line was used to evaluate the development and progression of AP using murine model of infection-induced AP. Ablation of Nav1.8+ nociceptors had earlier progression of AP with larger osteolytic lesions. Immunohistochemical and RNAscope analyses demonstrated greater number of macrophages, T-cells, osteoclast and osteoblast precursors and an increased RANKL:OPG ratio at earlier time points among Nav1.8Cre/ DTALox mice. There was an increased expression of IL-1α and IL-6 within lesions of nociceptor-ablated mice. Further, co-culture experiments demonstrated that TG neurons promoted osteoblast mineralization and inhibited osteoclastic function. The findings suggest that TG Nav1.8+ neurons contribute to modulation of the AP development by delaying the influx of immune cells, promoting osteoblastic differentiation, and decreasing osteoclastic activities. This newly uncovered mechanism could become a therapeutic strategy for the treatment of AP and minimize the persistence of osteolytic lesions in refractory cases. Graphical abstract

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Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain

Cited by 35 publications

References 58 publications

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

Trigeminal neurons control immune-bone cell interaction and metabolism in apical periodontitis

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