Language：English   Publisher：Proceedings of the National Academy of Sciences of the United States of America  

When exposed to noxious cutaneous stimuli, animals exhibit nocifensive behaviors, including rapid defensive reflexes that limit tissue damage and subsequent coping behaviors—most commonly licking of the affected area—that alleviate pain. Despite its ubiquity, the neural mechanism underlying pain relief through licking remains poorly understood. Here, we demonstrate that Npy2r-Cre⁺ primary sensory neurons in the dorsal root ganglion (DRG), a population of Aβ fibers that includes touch-sensitive, rapidly adapting low-threshold mechanoreceptors, are critical for this process. Mice lacking Npy2r-Cre⁺ neurons exhibited a significant prolongation of coping behavior duration, but not bout frequency, following intraplantar injection of capsaicin or formalin. Conversely, optogenetic activation of Npy2r-Cre⁺ neurons produced attenuating effects on irritant-induced pain. Electrophysiological analyses revealed that Npy2r-Cre⁺ neurons form functional synaptic connections with neurons in the substantia gelatinosa of the spinal dorsal horn (SDH) and that their activation suppressed C fiber-evoked excitation of neurons in lamina I of the SDH, a region implicated in nociceptive transmission to the brain. Together, these findings identify Npy2r-Cre⁺ DRG neurons as a key neural substrate for gating nociceptive transmission in the SDH and mediating pain relief through coping behaviors.

DOI： 10.1073/pnas.2601766123

Web of Science

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PubMed

Language：English   Publisher：Cells  

Highlights: What are the main findings? Descending neuronal signaling from the primary somatosensory (S1) cortex to the spinal dorsal horn (SDH) directly contributes to Aβ fiber-derived neuropathic allodynia in male rats. Superficial SDH neurons receiving direct projections from S1 cortical neurons integrate excitatory inputs from Aβ fibers and inhibitory inputs from SDH interneurons; loss of this inhibition unmasks their excitatory influence on spinal circuits, leading to allodynia. What are the implications of the main findings? This study demonstrates that an aberrant brain–spinal cord circuit involving the S1→SDH pathway underlies the pathological conversion of innocuous touch into pain. Targeting this corticospinal pathway may represent a promising therapeutic strategy for neuropathic allodynia. Mechanical allodynia is the predominant symptom of neuropathic pain following peripheral nerve injury (PNI) and is characterized by pain evoked by innocuous sensory signals transmitted through low-threshold mechanoreceptive primary afferents, including Aβ fibers. However, the underlying neural mechanisms remain insufficiently understood. Previous studies have suggested that the pathological conversion of tactile input into nociceptive signals involves maladaptive alterations in neural circuits and function within the spinal dorsal horn (SDH). Somatosensory processing and transmission in the SDH are regulated not only by local neuronal circuits but also by descending inputs from the brainstem and higher cortical regions. In this study, we show that chemogenetic silencing of descending neurons projecting directly from the primary somatosensory (S1) cortex to the SDH (S1^→SDH neurons) suppresses both PNI-induced allodynia-like behavior and c-FOS expression in the superficial SDH observed in male rats where touch-sensing Aβ fibers were optogenetically activated. S1^→SDH neurons were excitatory and preferentially targeted excitatory SDH neurons (^S1→SDH neurons) broadly distributed across laminae I–V. ^S1→SDH neurons in the superficial laminae also received excitatory inputs from both Aβ fibers and inhibitory inputs from neuropeptide Y promoter active SDH neurons (NpyP⁺ neurons). Furthermore, loss of inhibition from NpyP⁺ neurons induced Aβ fiber-derived allodynia, which was attenuated by suppressing descending signaling from S1^→SDH neurons to the SDH. Moreover, silencing ^S1→SDH neurons alleviated neuropathic allodynia. These findings identify a new corticospinal mechanism that contributes to Aβ fiber-mediated neuropathic allodynia and highlight the S1→SDH pathway as a potential therapeutic target.

DOI： 10.3390/cells14231870

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PubMed

Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Allodynia, pain caused by innocuous stimuli, is a hallmark symptom of neuropathic pain. Since this symptom is resistant to existing analgesics, it is important to elucidate its underlying mechanism that provides a clue for developing novel therapies. Pain information in the spinal dorsal horn (SDH) is strongly controlled by top-down signals from the brain. While the brainstem is a well-known region of this control, but little is known about the role of other regions. In this study, we comprehensively explored the brain regions with neurons that directly project to the SDH using a whole-brain imaging system. Among many brain regions identified, we examined the role of some regions in neuropathic allodynia and found that activation and inhibition of the rostral ventromedial medulla (RVM)-SDH and primary somatosensory cortex (S1)-SDH neural pathways, respectively, attenuated behavioral response related to allodynia after nerve injury. Furthermore, inhibition of the S1-SDH pathway also reduced the number of c-FOS-positive neurons in the superficial lamina in SDH in response to optogenetic stimulation of primary afferent Aβ fibers. These data indicate the importance of these top-down signaling pathways in neuropathic allodynia and propose that these pathways may be therapeutic targets for neuropathic pain.</p>

DOI： 10.1254/jpssuppl.97.0_1-b-p-103

CiNii Research

Language：English   Publisher：Neuroscience Research  

Mechanical allodynia (pain caused by innocuous mechanical stimulation) is a hallmark symptom of neuropathic pain occurring following peripheral nerve injury (PNI). Using a transgenic mouse line, in which myelinated primary afferents, including Aβ fibers, express channelrhodopsin-2, we found that illumination of the plantar skin of mice following PNI produced an Aβ fiber-mediated pain-like withdrawal behavior and increased c-FOS⁺ neurons in the superficial spinal dorsal horn (SDH). These two responses were attenuated by chemogenetic silencing of primary sensory cortex (S1) neurons projecting directly to the SDH. These findings indicate that spinally projecting cortical S1 neurons contribute to Aβ fiber-derived neuropathic allodynia.

DOI： 10.1016/j.neures.2022.05.001

Web of Science

Scopus

PubMed

Language：English  

Language：English