Neurokinin A and Substance P

Neurokinin A (NKA) and Substance P (SP) are members of the tachykinin family of peptides (derived from the same pretachykinin gene). They exert biological effects via specific G-protein-coupled receptors (NK1, NK2, and NK3 receptors), which are located on target cells. Tachykinins are widely distributed throughout the nervous system, where they are thought to modulate a number of biological functions, such as pain transmission, neurogenic inflammation, smooth muscle contraction, vasodilation, secretion, and activation of the immune system.11

The Role of Neurokinin A and Substance P in Headache

Preclinical evidence suggests that during migraine, activated primary sensory neurons (meningeal nociceptors) release NKA and SP from their peripherally projecting nerve endings within the meninges to cause vasodilation, mast cell degranulation, and plasma extravasation.12

Observations in humans, however, do not support the role of tachykinins in the pathophysiology of headache.11,13

SP levels are not elevated in patients with primary headache disorders and antagonists against the NK1 receptors are not efficacious for the acute treatment of migraine.14,15

One possible reason for the lack of support regarding the role of tachykinins in migraine is that although primary sensory neurons in the human trigeminovascular system (TGVS) contain SP, NKA, and calcitonin gene-related peptide (CGRP), only about 18% of these neurons are SP-immunoreactive, whereas 40% of neurons are CGRP-immunoreactive.16

11. Longmore J, Hill RG, Hargreaves RJ. Neurokinin-receptor antagonists: pharmacological tools and therapeutic drugs. Can J Physiol Pharmacol. 1997;75:612–621.
12. Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Rev. 2001;35(1):20–35.
13. May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Invest Drugs. 2001;10:673–678.
14. Goldstein DJ, Wang O, Saper R, Stoltz R, Silberstein SD, Mathew NT. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia. 1997;17:785–790.
15. Diener HC; RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia. 2003;23:183–185.
16. Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Rev. 2005;48:438–456.

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