Peripheral sensitization in migraine—role for P2X purinergic receptors in the dura–vascular sensory pathway

Abstract

Peripheral sensitization is still considered a prime contributor underlying the mechanisms of migraine. Trigeminal primary afferent neurons are the first neurons in the dural nociceptive pathway, and activation results in conscious perception of pain. Peripheral sensitization can lower the activation threshold of primary afferent neurons, rendering them more excitable, allowing for increases in release of neurotransmitter from both central and peripheral terminals. Increase in neurotransmitter release from central terminals contributes to excitation of second-order neurons, while the release of peptides from peripheral terminals has been implicated in neurogenic inflammation. Adenosine 5'-triphosphate (ATP) causes pain in human studies, and depolarize sensory neurons. There is evidence of the action of ATP at many levels in the dura–vascular sensory pathway. Animal studies have shown that some P2X receptors are located in neurons innervating the dura, including the P2X3 receptor, which is most often shown to be involved in nociceptive pathways. In this article, we briefly review peripheral sensitization in relation to migraine and provide emphasis for P2X receptor involvement where it is available.