Small sensory nerves throughout the body gather information & interact with the body directly. This nerve-body interface underlies many diseases. In chronic pain, nerves cause “neurogenic inflammation” by activating blood vessels, skin, & immune cells. This is the site of action of many pain treatments.
Key nerve-body interfaces
- Neural-vascular: Sensory nerves open blood vessels. This allows fluids to move into the tissue, causing tissue swelling, redness,& warmth. This also allows immune cells in the blood to get into the tissue.
- Neural-skin: Sensory nerves in the skin connect to skin cells & influence their growth. Skin cells in turn signal injury/infection to the nerves via ATP. The nerve-skin connection underlies inflammatory skin conditions including psoriasis & atopic dermatitis.
- Neural-dendritic cell: Sensory nerves activate and are activated by some dendritic cells, the key immune cell that activates the adaptive immune system.
- Neural-mast cell: Sensory nerves are physically connected to mast cells, the key cell in allergic reactions. Nerves in turn can trigger allergic reaction causing neurogenic urticaria. This connection underlies pain in mast cell activation syndrome.
- Neural-macrophage: Sensory nerves respond to macrophages, the key patrol cell of the immunes system.
The 3 key nerve-body interfaces underlie inflammation generated directly by nerves:
- Neural-vascular: nerves open blood vessels causing redness & swelling, and attract immune cells to the tissue.
- Neural-skin: Nerves can directly control the growth of skin cells (keratinocytes), which as a the main protective barrier for the body are equipped with sensors of infection/injury. Skin cells in turn signal to the immune system.
- Neural-immune: Nerves directly activate mast cells (allergic response) & dendritic cells (adaptive response), and releases signal molecules to activate the immune system.
Pain treatment targets
Many pain treatments, new and old, target this interface:
- Triptans reduce CGRP quantity & activity
- Acupuncture reduces sensory nerve activity via P2X
- Botox reduces release of substance P, CGRP, & glutamate
- Anti-inflammatories (NSAIDs) such as ibuprofen & celecoxib block COX2 & reduce inflammation
- Ketamine block NMDAR & its metabolites block a7nAChR
- Erenumab, galcanezumab, fremanezumab, eptinezumab block the CGRP-CGRPR pathway
- Tanezumab, fulranumab, fasinumab block NGF-trkA