# Pain Perception and Modulation: Fundamental Neurobiology and Recent Advances

## TL;DR

This paper reviews the neurobiology of pain perception and modulation, highlighting brain circuits and factors influencing chronic pain variability.

## Contribution

The paper synthesizes recent findings on neural structures and neuromodulators to support personalized pain management strategies.

## Key findings

- Pain perception involves dynamic interactions between ascending input and descending modulation.
- Neuroplastic changes in chronic pain are linked to spinal, subcortical, and cortical mechanisms.
- Key neuromodulators like opioids and cannabinoids play roles in pain modulation.

## Abstract

Chronic pain is a major mental health burden with significant individual and societal impact. A major challenge in clinical practice is the considerable variability in treatment responses, reflecting the complexity of associated biopsychosocial factors and their neurobiological underpinnings. This narrative review presents an up‐to‐date overview of neural structures, circuits, and neurochemical systems involved in pain perception and modulation, integrating foundational and recent findings from human and animal studies. We outline current models of nociceptive processing and pain perception, emphasizing dynamic interactions between ascending nociceptive input, descending modulation, and distributed cortical networks. Additionally, we describe mechanisms at spinal, subcortical, and cortical levels, along with neuroplastic changes in chronic pain. Finally, we review key neuromodulators, including opioids, monoamines, cannabinoids, and GABA. Together, these insights support the development of personalized pain management strategies grounded in systems‐level neurobiology.

Chronic pain is a major burden with variable treatment responses reflecting complex biopsychosocial and neurobiological factors. This narrative review synthesizes evidence on neural structures, circuits, and mediators involved in pain perception and modulation. We highlight spinal, subcortical, and cortical mechanisms, neuroplastic changes, and key neuromodulators. Created in BioRender. van Strien, W. (2025) https://BioRender.com/pcqvyj4.