Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain

Nelson, Tyler S.; Sinha, Ghanshyam P.; Santos, Diogo F. S.; Jukkola, Peter; Prasoon, Pranav; Winter, Michelle K.; McCarson, Kenneth E.; Smith, Bret N.; Taylor, Bradley K.

doi:10.1073/pnas.2204515119

Cited by 28 publications

(41 citation statements)

References 110 publications

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“…As expected, we observed no mCherry-labelled cells in the contra- or ipsilateral L4 or L5 DRG of these mice (data not shown). Spinal NPY signalling has been implicated in the suppression of neuropathic pain through inhibition of NPY Y1 receptor (Y1R)-expressing excitatory interneurons in the dorsal horn 29, 43, 44 . Therefore the suppression of neuropathic hypersensitivity that we observed during chemogenetic activation of NPY-INs could be due to GABAergic transmission, NPY signalling, or a combination of both.…”

Section: Resultsmentioning

confidence: 99%

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Boyle

Polgár

Gutièrrez‐Mecinas

et al. 2023

Preprint

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Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here we investigate the role of interneurons that continue to express NPY (NPY-INs) in adulthood. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

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Section: Resultsmentioning

confidence: 99%

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Boyle

Polgár

Gutièrrez‐Mecinas

et al. 2023

Preprint

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“…Since the optogenetic activation of NPY1R + JNC neurons trigger expiratory reflexes in mice (1) and NPY1R activation impacts pain and itching reflexes (34)(35)(36)(37)(38)(39)(40)(41)(42), we sought to test how it would impact airway nociceptor neuron function. Interestingly, we found that along with airway inflammation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…NPY1R is a Gi-coupled receptor (44) and its activation in DRG nociceptor neurons promotes either analgesia or noxious hypersensitivity (34)(35)(36)(37)(38)(39)(40)(41)(42). Given this discrepancy we set out to address how NPY-NPY1R modulates cultured JNC nociceptor neuron sensitivity.…”

Section: Resultsmentioning

confidence: 99%

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Cytokines reprogram airway sensory neurons in asthma

Crosson

Bhat

Wang

et al. 2023

Preprint

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Nociceptor neurons play a crucial role in maintaining the body's equilibrium by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. Using an ovalbumin mouse model of airway inflammation, we found that these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r, along with Il6. A screening of asthma-driving cytokines revealed that IL-13 drives part of this reprogramming, including Npy1r overexpression via the JAK/STAT6 pathway, while IL-1β induces IL-6 expression and release. Additionally, we observed that sympathetic neurons release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, characterized by the release of IL-6, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity.

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“…Peripheral sensitization is due to a sustained peripheral stimulation that makes primary sensory neurons undergo altered plasticity and become abnormally excitable [ 4 , 5 ]. Neurons undergo epigenetic changes to respond to harmful stimulation [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

Niu

Liu

et al. 2023

Brain Sciences

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Bone cancer pain (BCP) is excruciating for cancer patients, with limited clinical treatment options and significant side effects, due to the complex and unclear pathogenesis of bone cancer pain. Peripheral sensitization in dorsal root ganglion (DRG) neurons is a recognized cellular mechanism for bone cancer pain. The pathological mechanism of chronic pain is increasingly being affected by epigenetic mechanisms. In this study, we unbiasedly showed that the DNA hydroxymethylase ten-eleven translocation 1 (TET1) expression was significantly increased in the L4–6 DRG of BCP rats and ten-eleven translocation 2 (TET2) expression did not change significantly. Notably, TET1 inhibition by intrathecal injection of Bobcat339 (a TET1 inhibitor) effectively relieved mechanical hyperalgesia in BCP rats. Peripheral sensitization in chronic pain relies on the activation and overexpression of ion channels on neurons. Here, we demonstrated that TRPV4, one of the transient receptor potential ion channel family members, was significantly elevated in the L4–6 DRG of BCP rats. In addition, TRPV4 inhibition by intrathecal injection of HC067047 (a TRPV4 inhibitor) also significantly attenuated mechanical hyperalgesia in BCP rats. Interestingly, we found that TET1 inhibition downregulated TRPV4 expression in the L4–6 DRG of BCP rats. As a result, these findings suggested that TET1 may contribute to bone cancer pain by upregulating TRPV4 expression in the L4–6 DRG of BCP rats and that TET1 or TRPV4 may become therapeutic targets for bone cancer pain.

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Spinal neuropeptide Y Y1 receptor-expressing neurons are a pharmacotherapeutic target for the alleviation of neuropathic pain

Cited by 28 publications

References 110 publications

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Cytokines reprogram airway sensory neurons in asthma

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

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