Fig. 11.

Schematic representation of ATP role in peripheral nociception in meninges and in trigeminal ganglion in the frame of “purinergic hypothesis of migraine.” ATP could be released from various cell types (endothelium, mast cells, neurons) via pannexin 1 (Panx1) hemichannels due to cortical spreading depression or other type of stress. In meninges, ATP induces nociceptive firing in trigeminal nerve endings via high affinity P2X3 receptors. ATP and ADP are quickly degraded via NTPDases to inactive AMP and adenosine. Extracellular adenosine could be inactivated by reuptake or by enzymatic breakdown to inosine. Both meninges and trigeminal ganglia contain, in peptidergic neurons, the main migraine mediator neuropeptide CGRP, which could be released in Ca²⁺ dependent manner to sensitize ATP-gated P2X receptors, in particular P2X3 subtype [21]. In the trigeminal ganglia, ATP can activate also P2X7 receptors in surrounding glia whereas ADP is a full agonist of metabotropic P2Y1 and P2Y2 receptors in satellite glial cells [40]. Activation of various P2 receptors along with pro-inflammatory action of CGRP initiates neurogenic inflammation. The final outcome of ATP-driven mechanisms include the following: (i) excitation of nociceptive primary afferents, (ii) neuro-inflammation, and (iii) trigeminal migraine pain