# Unraveling Chronic Pain: From Mechanisms and Risks to Diagnosis and Treatment

## TL;DR

This paper explores chronic pain subtypes and introduces new treatment approaches like cold atmospheric plasma and a hippocampal model for better diagnosis and management.

## Contribution

The paper introduces cold atmospheric plasma as a novel therapeutic and proposes a new neurobiological model involving the hippocampus in nociplastic pain.

## Key findings

- Chronic pain subtypes (nociceptive, neuropathic, nociplastic) have distinct molecular and neurobiological mechanisms.
- Cold atmospheric plasma may modulate multiple pathways to treat all three chronic pain types.
- A hippocampal model is proposed as a central sensor for nociplastic pain.

## Abstract

Chronic pain is a globally prevalent and complex condition, encompassing three primary subtypes, that is, nociceptive, neuropathic, and nociplastic, each with distinct biopsychosocial mechanisms. Chronic pain was historically viewed as a monolithic symptom and managed with opioid‐centric models, causing widespread therapeutic failure. While recognition of its heterogeneity has driven a paradigm shift toward precision medicine, tailoring multimodal strategies to the dominant pain mechanism, critical challenges persist. These include difficulty in identifying treatable root causes, limited long‐term efficacy of therapies, and significant side‐effect burdens. To address these gaps, this review systematically synthesized contemporary knowledge, predominantly from the last decade, on the molecular mechanisms, risk factors, diagnostic frameworks, and therapeutic modalities for chronic pain, framed by its pathophysiological subtypes. Furthermore, it explored two novel frontiers aimed at advancing personalized pain medicine. First, it proposed cold atmospheric plasma as an innovative therapeutic intervention capable of modulating key molecular pathways underlying diverse pain manifestations. Second, it introduced an original neurobiological model positing the hippocampus as a putative sensor for nociplastic pain, interfacing with higher‐dimensional information fields. These insights may offer transformative potential for refining diagnostic and therapeutic strategies, potentially revolutionizing the management of chronic pain.

Chronic pain arises through distinct molecular pathways categorized into nociceptive, neuropathic, and nociplastic types. Nociceptive pain begins with TRP channel activation in peripheral nociceptors, signaling via Aδ‐ and C‐fibers through the spinal dorsal horn and spinothalamic tracts to the brain, regulated by descending inhibition and involving both peripheral and central sensitization. Neuropathic pain follows nerve injury, featuring aberrant signaling in Aδ‐ and C‐fibers, central sensitization, and loss of inhibition, without peripheral tissue injury. Nociplastic pain involves central sensitization without structural damage, driven by glial activation, dysregulated descending control, and stress–axis dysfunction. While all types involve inflammation, their mechanisms differ: nociceptive pain is dominated by abnormal nociceptors, neuropathic by both abnormal transduction and CNS reorganization, and nociplastic primarily by CNS reorganization. We propose a hippocampal model, where peripheral nociceptors sense tissue injury for nociceptive pain, the hippocampus acts as a central sensor for nociplastic pain, potentially processing higher‐dimensional experiences, and neuropathic pain is viewed as abnormal signal transduction; all converge in the hypothalamus for integration before cortical conscious experience. Cold atmospheric plasma (CAP), rich in reactive oxygen and nitrogen species, may relieve chronic pain through five mechanisms: healing physical injury to reduce tissue inflammation and nociceptive pain; restoring nerve damage to suppress neuroinflammation and neuropathic pain; targeting pain‐related comorbidities; modulating FTO for improved obesity management; and crosstalking with estrogen receptors to regulate hormonal signaling. While the first three address pain sources, the latter two implicate molecular pathways like FTO and ER. Thus, CAP may act as a multimodal intervention targeting all three chronic pain types.