Figure 8.

Schematic representation of cholinergic signaling in peripheral nociception in meninges. Meninges have a dual innervation by somatic trigeminal nerves and postganglionic parasympathetic nerve fibers. Acetylcholine (ACh) released from parasympathetic nerves can activate mast cells via muscarinic ACh receptor (mAChR) and trigeminal nerve endings both via mAChR and nicotinic ACh receptor (nAChR). This concerted activation of ACh receptors (AChRs) results in generation of the nociceptive firing in primary afferents. The lifespan of ACh is limited by activity of acetylcholinesterase (AChE), which destroys this neurotransmitter. Potentially, ACh can also approach small meningeal vessels producing vasodilation and plasma protein extravasation most likely via mAChRs (8). At the level of the brainstem, these two systems can interact via the trigemino–parasympathetic reflex leading to sustained neuronal activity. The outcome of cholinergic activation in meninges is the release of pro-inflammatory transmitters and cytokines from mast cells, extravasation, excitation, and sensitization of nociceptive afferents resulting in trigeminal pain.