伊人直播

Major sex differences in the development of "pain from mere touch" offer new clues for personalized pain management.

A research group from 伊人直播 has revealed that while oxidative stress uniformly triggers disuse-induced chronic pain, the subsequent immune-neural mechanisms diverge drastically between males and females. Specifically, the researchers uncovered major sex differences in the development of tactile allodynia, or "pain from mere touch," driven by a male-specific macrophage inflammatory response. These findings offer crucial new clues for personalized pain management and strongly support the consideration of sex as a biological variable (SABV).

A collaborative research group, including Lecturer Mika Ohmichi and Associate Professor Yusuke Ohmichi of 伊人直播, Professor Makoto Tsuda of Kyushu University, and Professor Koji Osuka of Aichi Medical University, has conducted a detailed analysis of the mechanisms underlying intractable chronic pain caused by physical inactivity (disuse), using a rat model. The study clarified that oxidative stress plays a central role in the onset and maintenance of disuse-induced chronic pain. Furthermore, it revealed that while the basic mechanism of mechanical hyperalgesia is shared between males and females, the processes leading to tactile allodynia involve significant sex differences in inflammatory, immune, and neural responses. These findings were published online in , the official journal of the International Association for the Study of Pain (IASP), on September 10, 2026.

Background
Prolonged physical immobility is a major contributing factor to chronic pain. For instance, in Complex Regional Pain Syndrome (CRPS) Type I, immobilization of a body part can be involved in its onset. The research group previously developed the "Chronic Post-Cast Pain (CPCP) rat model" to investigate how "disuse" itself affects pain, independent of fractures or direct nerve injury. In this model, hyperalgesia persists long after cast removal, activating pain pathways from peripheral nerves to the spinal cord and brain. However, exactly how oxidative stress contributes to this sensory processing, and whether these mechanisms differ between sexes, remained incompletely understood.

Key Findings
1. ? ?Oxidative stress underpins disuse-induced chronic pain: Administering the antioxidant Tempol just before cast removal markedly suppressed the subsequent widespread mechanical hyperalgesia. It also attenuated pain-related neural activity in the spinal cord and the central nucleus of the amygdala, the activation of nociceptive neurons in the dorsal root ganglion (DRG), and peripheral inflammatory responses and vascular permeability.
2. ? ?Major sex differences in tactile allodynia: In male rats, excessive oxidative stress strongly activated immune cells termed "macrophage-like cells," leading to the massive release of inflammatory cytokines. This fostered a circuit that miscommunicates normally painless tactile stimuli as "pain" (tactile allodynia). Conversely, this response was robustly suppressed in females, resulting in no manifestation of tactile allodynia.
3. ? ?Long-lasting effects of a single antioxidant intervention: A single administration of Tempol just before cast removal dramatically suppressed mechanical hyperalgesia and spontaneous pain-like behaviors in both sexes for up to 5 weeks. Furthermore, in males, it also suppressed tactile and cold allodynia--conditions where normally harmless stimuli cause pain. These results indicate that targeting oxidative stress could provide a crucial clue for the prevention and effective treatment of disuse-induced chronic pain, potentially transforming patient care and quality of life.

Impact and Future Perspectives
A significant implication of this study is the demonstration that while the fundamental, oxidative stress-dependent mechanisms of mechanical hyperalgesia are common to both sexes, the inflammatory and immune-neural responses establishing tactile allodynia are highly sex-divergent. This strongly supports the importance of the SABV (Sex as a Biological Variable) concept in preclinical research, potentially paving the way for more personalized, sex-aware strategies for pain prevention and treatment.

"For too long, pain management has relied on a 'one-size-fits-all' approach," said Dr. Yusuke Ohmichi. "Our discovery that males and females use fundamentally different immune-neural circuits to develop tactile allodynia emphasizes the urgent need for sex-specific therapeutic strategies. Moving forward, we aim to decode the specific immune signals orchestrating this divergence to develop highly personalized and effective interventions for chronic pain."

Glossary

Oxidative Stress (Reactive Oxygen Species: ROS)
Highly reactive oxygen molecules generated during cellular metabolism. While beneficial in appropriate amounts, excessive production damages cells and nerves, causing severe inflammation and pain.

Tactile Allodynia
An abnormal neural state where a light tactile stimulus that normally does not cause pain--such as brushing the skin--is perceived as severe pain.

Macrophage-Like Cells
Macrophages are immune cells that clear foreign substances. In this study, cells showing morphological characteristics of macrophages were observed accumulating; however, definitive cellular identification using specific markers has not yet been achieved. In males, these cells were confirmed to be overactive, releasing large amounts of inflammatory cytokines.

SABV (Sex as a Biological Variable)
The concept that biological differences between males and females must be factored into disease mechanisms and therapeutic drug efficacy.

Reference

Title of original paper:	Oxidative Stress Drives Disuse-Induced Chronic Pain Through Sex-Divergent Immune-Neural Mechanisms
Journal:	PAIN
DOI:

Funding information
This research was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Numbers 19K11377, 21K11180, 23K27950, and 25K14496) and 伊人直播 Assist KAKEN (K2022-5).

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Contact

Department of Anatomy II, 伊人直播
ohmy@kanazawa-med.ac.jp

Image

Figure 1. Mechanism of Disuse-Induced Chronic Pain
Overall picture of the onset mechanism of disuse-induced chronic pain and sex differences in immune-neural responses.
?2026 Yusuke Ohmichi


Figure 2. Evaluation of Inflammation via Evans Blue Leakage
Visual evidence of inflammation suppression. Following prolonged physical disuse, the affected limb exhibits severe inflammation and vascular leakage (indicated by the intense blue dye, middle). A single targeted dose of the antioxidant Tempol remarkably reduces this inflammatory response (right), bringing it closer to the healthy state (left).
?2026 Yusuke Ohmichi


Figure 3. Collaborative Optogenetic Assessment in the Laboratory?
Behind the scenes: Dr. Mika Ohmichi and Dr. Yusuke Ohmichi conducting a behavioral assessment using optogenetics. By utilizing specific wavelengths of light (473 nm) and observing through protective equipment, the research team successfully isolated and activated the neural circuits responsible for tactile allodynia ("pain from mere touch").
?2026 Yusuke Ohmichi