Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

M. Sammons; R. Assa Polansky; I. Zayalat; S. Breslauer Morris; L. Deng; H. Azulay-Debby; N. Singer; I. Chiu; A. Rolls

doi:10.64898/2026.11.02.763662

AI summary · DOI: 10.64898/2026.11.02.763662 · bioRxiv: Neuroscience

Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

M. Sammons, R. Assa Polansky, I. Zayalat, S. Breslauer Morris, L. Deng, H. Azulay-Debby, N. Singer, I. Chiu,

and 1 more author

A. Rolls

Original paper Published on 03 Nov. 2026 bioRxiv preprint License: CC BY-NC-ND 4.0 Also in: fr

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The essentials

The study reports that nociceptive signaling helps organize inflammation-related brain activity and is needed for later immune recall in mouse experiments.

Question

Does nociceptive input during inflammation help the brain organize and store a retrievable representation of the immune event? The authors also ask whether reducing or increasing that input alters subsequent immune recall.

Method

The authors reanalyzed longitudinal fMRI from 7 people given endotoxin and mapped activity in mice with zymosan-induced peritonitis. In mice, they ablated TRPV1⁺ neurons with resiniferatoxin or reduced pain with acetaminophen, then labeled inflammation-active posterior insular cortex neurons and chemogenetically reactivated them 3–4 weeks later to assess peritoneal immune cells; a low RTX dose was also used to increase nociceptive signaling.

Findings

Result In the human dataset, endotoxin was associated with progressive whole-brain connectivity changes and reduced functional segregation.
Result In mice, TRPV1⁺ neuron ablation altered regional co-activation, with loss of synchronization in several clusters and disruption of cortical-subcortical coordination.
See the passage in the paper
Thus, nociceptor ablation systematically altered brain-wide synchronization.
Result Reactivation of inflammation-labeled posterior insular cortex neurons produced different peripheral immune responses in control and TRPV1⁺-ablated mice, despite comparable acute inflammatory responses.
See the passage in the paper
Ablated mice showed markedly fewer reactivation-induced CD11b+ myeloid cells and lower Ly6G+ and Ly6C+ frequencies (Fig. 3G-I).
Result Acetaminophen during the initial inflammatory episode reduced Ly6G⁺ and Ly6C⁺ cell frequencies after later reactivation of the labeled insular neurons.
See the passage in the paper
Flow cytometric analysis showed a significant reduction in the frequency of Ly6G+ and Ly6C+ cells compared to controls (p = 0.0013 and 0.0347, respectively) (Fig. 4C, D).
Authors’ interpretation Increasing nociceptive signaling during inflammation changed the subsequent recalled immune profile, supporting the authors’ interpretation that nociceptive input can modulate immune recall.
See the passage in the paper
Nociceptive input thus acts as a gain control, setting not only whether an immune representation forms, but what that representation encodes.

Limitations

The human fMRI analysis was based on a small sample of seven participants.
See the passage in the paper
Although the dataset is small (n = 7), its longitudinal design enabled us to track within-subject connectivity changes as inflammation progressed (Fig. 1A).
The experiments did not establish whether sensory inputs beyond TRPV1⁺ nociceptors contribute to immune engram formation.
See the passage in the paper
Whether these parallel sensory inputs also contribute to immune engram formation is not addressed by our experiments.
The functional meaning of the altered adaptive immune profile after increased nociceptive signaling remains unresolved.
See the passage in the paper
While uncovering the functional meaning of these findings is beyond the scope of this study, our data demonstrates that pIC neurons encode not only whether inflammation occurred, but how intensely it was perceived, with nociceptive input acting as a gain control that sets the balance of subsequent immune recall.

Why it matters

The authors argue that nociception does more than signal tissue damage: it helps organize cortical representation of inflammatory events and influences whether and how those events can later be recalled. They suggest that analgesia during inflammation may have longer-term neuroimmune consequences, which remain to be examined.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: inflammation nociception brain connectivity immune memory posterior insular cortex

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Comprehensive Summary
Layman's Summary
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Original abstract

The paper asks whether pain during inflammation does more than signal tissue damage—specifically, whether nociceptive input helps the brain organize and remember inflammatory events. The study combined a reanalysis of human functional MRI data with experiments in mice. In the human dataset, seven healthy participants were scanned before and at three stages after receiving intravenous endotoxin, which induces systemic inflammation. Brain-wide connectivity was measured across 116 regions. Connectivity shifted progressively from baseline, with significant divergence at the onset, acute, and peak stages. The shift increased further from the acute to peak stage (p = 0.0009). At peak inflammation, functional segregation was reduced (p = 0.031), consistent with more integrated brain activity. The small sample limits the strength of conclusions about humans, and differences between individual network pairs did not survive correction for multiple comparisons. The observed pattern also did not significantly overlap with a recognized fMRI signature of pain (p = 0.83), suggesting a broader response than activation of pain-specific regions alone. In mice, the authors used zymosan-induced peritonitis and activity-dependent labeling to map brain activity. They found a more integrated pattern of regional co-activation, broadly consistent with the human findings. To test whether nociceptors were necessary, they chemically ablated TRPV1-expressing sensory neurons with resiniferatoxin (RTX). Ablation altered coordination among brain regions without changing the total number of labeled neurons. Several cortical, brainstem, and midbrain clusters lost internal synchrony, while a thalamic-hypothalamic cluster became more active but less coupled to cortical regions. These results suggest that subcortical regions continue to detect inflammatory signals, while nociceptive input helps recruit and coordinate cortical processing. The researchers then tested whether nociceptive input was needed for later immune recall. They labeled posterior insular cortex (pIC) neurons that were active during inflammation and reactivated them weeks later using chemogenetic tools. In mice with TRPV1-neuron ablation, pIC reactivation produced a different peripheral immune-cell profile, including reduced numbers of myeloid, Ly6G-positive, and Ly6C-positive cells. Ablation did not substantially change the acute inflammatory response. Recall effects were observed in males but not females, so subsequent experiments used male mice. In a complementary experiment, the researchers reduced pain with acetaminophen during the initial inflammatory episode. The drug reduced pain-related responses, while measured acute immune-cell recruitment remained comparable between groups. Later reactivation of the inflammation-tagged pIC ensemble produced fewer Ly6G-positive and Ly6C-positive cells in treated mice than in controls (p = 0.0013 and p = 0.0347, respectively). Conversely, low-dose RTX, used to increase nociceptive signaling during inflammation, was associated with stronger and qualitatively different recall: reactivation increased some myeloid and T-cell measures while reducing TLR2 expression on Ly6G-positive cells. Together, these findings support the authors’ proposal that nociceptive input influences both whether an immune response is encoded and the character of its later recall. The authors conclude that pain-related signaling can help transform peripheral inflammation into a coordinated, cortically represented state that can later influence immune activity. They interpret nociception as a gain-control or salience signal, but this proposed mechanism has not been fully established. Limitations include the small human sample, reliance on animal models and pharmacological manipulations, sex-specific results, and uncertainty about which aspects of nociception—or which other sensory neuron types—contribute to the observed effects. These experiments do not determine the clinical significance of using analgesics during human infections or inflammatory illness.

Does Pain Help the Brain Remember Inflammation?

Pain is often understood as an alarm: it warns us that the body may be injured. But could pain-related signals do more than report what is happening? The study “Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses,” by M. Sammons, R. Assa Polansky, I. Zayalat, S. Breslauer Morris, L. Deng, H. Azulay-Debby et al., explores whether signals from pain-sensing neurons help the brain organize inflammation and shape how the immune system responds later.

The researchers combined human brain imaging with experiments in mice. Their results suggest that nociceptive input—the nervous system’s detection of potentially harmful stimuli—may help turn inflammation into a coordinated brain state that can later influence immune activity. The findings are intriguing, but they do not establish how pain relief should be used during human illness.

Inflammation Reshapes Brain Connectivity

In the human portion, seven healthy participants underwent functional MRI scans before and at three stages after receiving intravenous endotoxin, which induces systemic inflammation. The researchers measured connectivity across 116 brain regions. Rather than focusing only on whether particular regions became more active, they examined how activity across the brain was coordinated.

Connectivity shifted progressively away from baseline as inflammation developed, with significant changes at the onset, acute, and peak stages. The shift grew further between the acute and peak stages (p = 0.0009). At peak inflammation, functional segregation was reduced (p = 0.031), a pattern consistent with more integrated brain activity.

The human results need to be interpreted cautiously. With only seven participants, the study cannot support strong conclusions about people broadly. Also, differences between individual pairs of brain regions did not remain significant after correction for multiple comparisons. The pattern did not significantly overlap with a recognized fMRI signature of pain (p = 0.83), suggesting that the brain-wide shift may reflect something broader than activity in pain-associated regions alone.

Mouse Experiments Test the Role of Nociceptors

To investigate the possible role of pain-sensing neurons, the researchers studied mice with zymosan-induced peritonitis, an inflammatory condition affecting the lining of the abdomen. Using activity-dependent labeling, they mapped groups of brain regions active during inflammation. The mice showed a more integrated pattern of regional co-activation, broadly resembling the human imaging results.

The team then chemically ablated TRPV1-expressing sensory neurons using resiniferatoxin, or RTX. This changed how brain regions coordinated with one another, even though the total number of labeled neurons did not change. Several clusters spanning cortical, brainstem, and midbrain areas lost internal synchrony. Meanwhile, a thalamic-hypothalamic cluster became more active but less coupled to cortical regions.

This contrast offers a clue about what nociceptive input may do. The findings suggest that subcortical regions can still register inflammatory signals, while pain-sensing input helps recruit and coordinate cortical processing. In other words, nociception may influence how broadly and coherently the brain represents inflammation, rather than simply switching the response on or off.

Can That Brain Representation Shape Later Immunity?

The researchers next asked whether nociceptive signaling affects immune responses when an inflammatory event is recalled. They labeled neurons in the posterior insular cortex (pIC) that were active during inflammation, then used chemogenetic tools weeks later to reactivate that group of cells. In mice whose TRPV1-expressing neurons had been ablated, pIC reactivation produced a different profile of peripheral immune cells, including reduced numbers of myeloid, Ly6G-positive, and Ly6C-positive cells.

The neuron ablation did not substantially alter the acute inflammatory response itself. The recall effects appeared in males but not females, so the researchers used male mice in the later experiments. This sex-specific result is important: it indicates that the findings may not apply equally across sexes and calls for further investigation.

A complementary experiment reduced pain during the initial inflammatory episode with acetaminophen. Measured acute immune-cell recruitment remained comparable between treated mice and controls, but later reactivation of the inflammation-tagged pIC ensemble produced fewer Ly6G-positive and Ly6C-positive cells in treated animals (p = 0.0013 and p = 0.0347, respectively). Conversely, low-dose RTX, used to increase nociceptive signaling during inflammation, was associated with stronger and qualitatively different recall. Some myeloid and T-cell measures increased, while TLR2 expression on Ly6G-positive cells decreased.

What the Findings May—and May Not—Mean

Taken together, the experiments support the idea that nociceptive input can influence both the encoding of an inflammatory event and the character of its later recall. The authors propose that pain-related signals may act as a gain-control or salience signal, helping the brain treat inflammation as an event worth organizing and retaining. That mechanism remains a proposal, not a fully established explanation.

The human imaging sample was small, limiting how confidently the results can be generalized.
The causal experiments relied on mice and pharmacological manipulations, which may not capture human inflammatory illness.
Recall effects differed by sex in the tested conditions.
The study does not determine which features of nociception matter most, or how other sensory-neuron types contribute.
It does not establish the clinical consequences of using analgesics during human infections or inflammation.

The study offers a provocative view of pain: beyond signaling immediate harm, nociceptive activity may help the brain build a coordinated representation of inflammation that can influence later immune responses. Whether this framework will translate into practical guidance for pain treatment remains an open question.

Created on 09 Nov. 2026

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Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

The essentials

Question

Method

Findings

Limitations

Why it matters

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Definitions

Does Pain Help the Brain Remember Inflammation?

Inflammation Reshapes Brain Connectivity

Mouse Experiments Test the Role of Nociceptors

Can That Brain Representation Shape Later Immunity?

What the Findings May—and May Not—Mean

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