Substance P and the trigeminovascular system: From preclinical mechanisms to human headache induction

Substance P, a neuropeptide associated with pain and inflammation, has been implicated in migraine pathophysiology through its action within the trigeminovascular system. This narrative review summarizes current evidence on the synthesis, release, receptor binding and downstream effects of substance P. It integrates preclinical and clinical findings to reassess its therapeutic relevance. Substance P is released from primary afferent neurons and acts on neurokinin-1 receptors, which are widely expressed in both peripheral tissues and central pain-processing regions. In the meninges, substance P contributes to vasodilation, plasma protein extravasation, mast cell degranulation and immune cell recruitment, all of which facilitate neurogenic inflammation and possibly lower the activation threshold of meningeal nociceptors. In the central nervous system, substance P promotes excitatory neurotransmission, potentiates glutaminergic activity and attenuates inhibitory GABAergic signaling, cumulatively amplifying pain transmission. Preclinical studies consistently demonstrate that neurokinin-1 receptors antagonists inhibit substance P-induced responses, such as neurogenic inflammation and neuronal activation, supporting their therapeutic potential. However, randomized controlled trials with neurokinin-1 receptors antagonists were not superior to placebo in treating migraine. A re-appraisal of these trials reveal that the disappointing results might be due to methodologic shortcomings, including underpowered samples and suboptimal efficacy endpoints. A recent randomized, double-blind, placebo-controlled, two-way crossover study showed that intravenous infusion of substance P is potent inducer of headache and arterial dilation in healthy adults. These findings align with the established biological functions of substance P and warrant renewed therapeutic interest. Advances in translational research, particularly those emphasizing direct measurement of meningeal nociceptor activity and refined clinical trial design, might overcome past limitations and clarify the role of substance P in migraine. The dismissal of substance P signaling as a therapeutic target might thus have been premature. Renewed efforts might uncover novel therapeutic strategies, offering hope for patients with migraine who remain unresponsive to existing treatment.