**1. Background**

Substance P (SP) was first described by von Euler and Gaddum, in 1931 [1]. The authors observed an unknown substance that stimulated contraction of the intestine ex vivo. This substance was identified and Euler and Gaddum named it substance P, from the bottle containing it, labeled P1, P2 etc., meaning "powder". In the 1970s, SP was homogeneously purified by Chang and Leeman [2] and was later determined to be an 11 amino-acid peptide, H-Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met-NH2 (RPKPQQFFGLM), with an amidation at the C-terminus [3]. SP belongs to the tachykinin family and serves as a neurotransmitter and a neuromodulator. It is encoded by preprotachykinin-1 (or tachykinin 1 (*TAC1*)) that produces SP and neurokinin A via alternative slicing and post-translational modifications [4].

SP is widely distributed in the human body, especially in nervous systems and inflammatory cells. A general assumption of the SP action describes SP as a neuropeptide released from pain-sensing fibers (nociceptors) to increase pain sensitivity through its actions in the dorsal horn of the spinal cord [5]. SP also triggers proinflammatory cytokine release resulting in inflammation, vasodilation and plasma extravasation [6]. Although considerable evidence indicates that SP transmits pain signaling and serves as a mediator of pain [7–9], accumulating studies reveal that SP also has an anti-nociceptive effect [10,11]. Interestingly, evidence showing the antinociceptive role of SP has been built over several years and can be dated back to 1976 [10]. The discrepant function of SP is believed to depend on the cell type regarding the expression of neurokinin receptors with unique underlying effector systems modulating differential ion channels.
