Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

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   Brain sites involved in endogenous analgesia

   Luke A. Henderson, L. Crawford, James W. M. Kang et al. · 2026 · Pain · Not summarized yet

   Brain sites involved in endogenous analgesia describes neural circuits that modulate nociceptive input, rather than how pain signals encode inflammatory immune events.

   Abstract

   Abstract Pain modulation is a fundamental survival mechanism that prioritises, shapes, and suppresses nociceptive inputs to optimise behaviour. Although acute pain signals potential or actual tissue damage, sustained pain can impair essential behaviours, necessitating modulatory circuits that dynamically regulate nociception according to context and motivational state. These systems are deeply conserved, embedded within primitive spinal and brainstem structures, and capable of powerful modulation independent of cortical input, although higher regions such as the prefrontal cortex can influence their function. Decades of work have sought to identify these core modulatory circuits to advance b…

2. Close Broader context Cited by this paper Not relevant

   A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model

   Y. Arima, D. Kamimura, Toru Atsumi et al. · 2015 · eLife · cited 26 times · Not summarized yet

   A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis shows pain can alter immune disease, but studies spinal immune-cell recruitment and disease relapse.

   Abstract

   Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a loc…

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   Intracranial electrophysiology reveals distinct neural representations of nociception and salience in the human brain

   S. Joshi, Mensure Polat, Sofia Pantis et al. · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet

   Intracranial electrophysiology reveals distinct neural representations of nociception and salience examines human brain representations of nociception, without addressing inflammatory memory.

4. Close Review Not relevant

   Incision-triggered neuroimmune remodeling of nociceptor ion channels: from postoperative inflammation to pain chronification

   Xin-Ye Song, Miao Feng, Jia-Chen Hao et al. · 2026 · Frontiers in Immunology · Not summarized yet

   Incision-triggered neuroimmune remodeling of nociceptor ion channels reviews how surgical inflammation changes nociceptors and may promote chronic pain.

   Abstract

   Chronic postsurgical pain (CPSP) arises after a known tissue insult, yet no intervention reliably prevents its development. This Review examines whether incision-triggered inflammation remodels nociceptor voltage-gated ion channels in ways that sustain peripheral input and favor pain chronification. We integrate human genetic and clinical evidence, incision-specific perturbation studies, functional work in non-surgical models, and expression-level associations distinguishing mechanistic strength from directness to CPSP. We focus on NaV1.7, NaV1.8, NaV1.9, and CaV3.2 within a broader network that includes peripheral transducing channels whose gating, trafficking, and abundance can be altered …

5. Close Review Cited by this paper Not relevant

   Emerging targets in neuroinflammation-driven chronic pain

   R. Ji, Zhen-Zhong Xu, Yong-Jing Gao · 2014 · Nature reviews. Drug discovery · cited 1,044 times · Not summarized yet

   Emerging targets in neuroinflammation-driven chronic pain reviews immune and glial mechanisms that contribute to chronic pain.

   Abstract

   Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This Review focuses on emerging targets — such as chemokines, proteases and the WNT pathway — that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells…

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   Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice

   H. Kim, Y. Lee, Seog Bae Oh · 2025 · bioRxiv · Not summarized yet

   Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice identifies a circuit for analgesia, not inflammation encoding or immune recall.

   Abstract

   Application of cold or cold-mimicking chemicals to injury has long been recognized as an effective means of pain relief and is widely utilized in daily life. However, underlying neural mechanisms remain elusive. Here, we identified a cold-responsive neuronal subset within lateral parabrachial nucleus (lPBN), the thermosensory relay region in the hindbrain, that mediates cold-induced analgesia in mice. Selective activation of these neurons and their projection to ventrolateral periaqueductal gray (vlPAG) increased nociceptive threshold via opioid receptor signaling in vlPAG. Conversely, ablation of these neurons attenuated analgesia induced by cold-mimicking chemicals. We further identified t…

7. Close Broader context Cited by this paper Not relevant

   Scaling Up Cortical Control Inhibits Pain

   Jahrane A. Dale, Hao-Cheng Zhou, Qiao-Sheng Zhang et al. · 2018 · Cell Reports · cited 81 times · Not summarized yet

   Scaling Up Cortical Control Inhibits Pain measures prefrontal responses to acute and chronic pain, rather than insular representations of inflammatory events.

   Abstract

   SUMMARY Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC) is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nea…

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   Upregulation of AK7 in ACC-VTA glutamatergic projections contributes to chronic inflammation pain in male mice

   Jie Huang, Meng-Ge Li, Ru-Yu Yan et al. · 2026 · EMBO Reports · Not summarized yet

   Upregulation of AK7 in ACC-VTA glutamatergic projections contributes to chronic inflammation pain studies brain circuits in inflammatory pain, rather than immune-event memory.

   Abstract

   Chronic inflammation pain is a complex pathological condition involving multiple mechanisms in both the peripheral and central nervous systems. Growing evidence indicates that an imbalance in central nervous system function plays a crucial role in the progression of chronic pain, yet the underlying neural circuits and molecular targets remain largely unclear. Here we identify the anterior cingulate cortex (ACC) as a key mediator in chronic inflammation pain. Noxious stimulation significantly increases c-Fos expression and calcium activity in both the ACC and the ventral tegmental area (VTA). Upregulation of adenosine kinase 7 (AK7) in ACC glutamatergic neurons emerges as an important factor …

Prior work it builds on

1. Close Same question Not relevant

   The Central Inflammatory Network: A Hypothalamic fMRI Study of Experimental Endotoxemia in Humans

   Natalia Färber, Jorge Manuel, M. May et al. · 2021 · Neuroimmunomodulation · cited 6 times · Not summarized yet

   The Central Inflammatory Network uses human fMRI during endotoxemia to identify brain activity associated with systemic inflammation.

   Abstract

   Introduction: Inflammation is a mechanism of the immune system that is part of the reaction to pathogens or injury. The central nervous system closely regulates inflammation via neuroendocrine or direct neuroimmune mechanisms, but our current knowledge of the underlying circuitry is limited. Therefore, we aimed to identify hypothalamic centres involved in sensing or modulating inflammation and to study their association with known large-scale brain networks. Methods: Using high-resolution functional magnetic resonance imaging (fMRI), we recorded brain activity in healthy male subjects undergoing experimental inflammation from intravenous endotoxin. Four fMRI runs covered key phases of the de…

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   Multiple Posterior Insula Projections to the Brainstem Descending Pain Modulatory System

   D. Liang, Charalampos Labrakakis · 2024 · International Journal of Molecular Sciences · cited 14 times · Not summarized yet

   Multiple Posterior Insula Projections to the Brainstem Descending Pain Modulatory System traces insular connections involved in pain modulation, not immune encoding.

   Abstract

   The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular’s connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raph…

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   An fMRI-Based Neurologic Signature of Physical Pain

   T. Wager, L. Atlas, M. Lindquist et al. · 2013 · New England Journal of Medicine · cited 1,466 times · Not summarized yet

   An fMRI-Based Neurologic Signature of Physical Pain develops a brain-activity measure for physical pain, rather than inflammatory-state representations.

   Abstract

   BACKGROUND Persistent pain is measured by means of self-report, the sole reliance on which hampers diagnosis and treatment. Functional magnetic resonance imaging (fMRI) holds promise for identifying objective measures of pain, but brain measures that are sensitive and specific to physical pain have not yet been identified. METHODS In four studies involving a total of 114 participants, we developed an fMRI-based measure that predicts pain intensity at the level of the individual person. In study 1, we used machine-learning analyses to identify a pattern of fMRI activity across brain regions — a neurologic signature — that was associated with heat-induced pain. The pattern included the thalamu…

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   Different immune cells mediate mechanical pain hypersensitivity in male and female mice

   R. Sorge, Josiane C. S. Mapplebeck, S. Rosen et al. · 2015 · Nature Neuroscience · cited 1,316 times · Not summarized yet

   Different immune cells mediate mechanical pain hypersensitivity in male and female mice examines immune contributions to pain, not nociceptive contributions to immune recall.

   Abstract

   A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

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   TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain.

   T. K. E. Maximiano, J. A. Carneiro, V. Fattori et al. · 2024 · Cell Calcium · cited 92 times · Not summarized yet

   TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain reviews the sensory channel targeted to reduce or increase nociceptive signaling.

   Abstract

   In the 1990s, the identification of a non-selective ion channel, especially responsive to capsaicin, revolutionized the studies of somatosensation and pain that were to follow. The TRPV1 channel is expressed mainly in neuronal cells, more specifically, in sensory neurons responsible for the perception of noxious stimuli. However, its presence has also been detected in other non-neuronal cells, such as immune cells, β- pancreatic cells, muscle cells and adipocytes. Activation of the channel occurs in response to a wide range of stimuli, such as noxious heat, low pH, gasses, toxins, endocannabinoids, lipid-derived endovanilloid, and chemical agents, such as capsaicin and resiniferatoxin. This …