Inflammatory Signal Persistence in Pain: Lymphatic Regulation and Neuroimmune Integration.

Inflammatory pain arises from the interaction between nociceptive activation and immune signalling within injured or inflamed tissues. While the production of inflammatory mediators has been extensively investigated, less attention has been directed toward mechanisms governing their clearance and spatial redistribution. In this review, we examine how lymphatic vessels actively regulate inflammatory signal persistence in the interstitial space by integrating endothelial barrier behaviour, structural remodelling and intrinsic contractility. The lymphatic system, traditionally regarded as a passive conduit for fluid return and immune cell trafficking, is increasingly recognised as a dynamic regulator of tissue homeostasis. Neuropeptides released from nociceptive afferents, including calcitonin gene-related peptide (CGRP) and substance P (SP), influence lymphatic permeability, lymphangiogenesis and lymph propulsion, thereby shaping the kinetics of inflammatory mediator clearance. Endogenous opioid signalling and pain-related anaesthetic agents may further modulate lymphatic function through effects on lymphatic muscle excitability and endothelial dynamics. Collectively, we propose a systems-level framework in which lymphatic physiology operates as a regulatory interface linking neural activation to immune resolution. Recognising this integrative role may refine current concepts of inflammatory pain and provide a physiologically grounded basis for future translational investigation.