3 In 1953, SP was recognized as a sensory neurotransmitter by Lembeck et al.4 It was more than 10 years later that SP was isolated from bovine hypothalamus and sequenced by Susan Leeman and colleagues, culminating her efforts to identify a tissue component that stimulates salivation in rats.5 Another 10 years later, the other two mammalian tachykinins were discovered: the cationic peptide neurokinin A (NKA, formerly named substance K) and the anionic peptide neurokinin B(NKB).6-8 The tachykinins (tachys = swift) evoke a sharp contraction of the smooth muscle of the gut.9

Inhibitors,research,lifescience,medical These tachykinins are involved in multiple physiological processes, as demonstrated by their widespread distribution. In the periphery, they function as potential regulators of blood flow, vascular permeability, salivation, gastrointestinal motility, intestinal secretion, micturition, and leukocyte activity. Moreover,

they act as pain transmitters from the periphery. In the central nervous system (CNS), tachykinins act as neurotransmitters and neuromodulators. Tachykinin genes and synthesis There are two genes Inhibitors,research,lifescience,medical encoding for the synthesis of the three tachykinins SP, NKA, and NKB: the preprotachykinin I (PPTI) gene encodes for SP and NKA, while the PPTII gene encodes for NKB.10 Through alternative splicing, the PPTI gene can express four different forms (α β, γ, and δ) of mRNA. All Inhibitors,research,lifescience,medical of these forms are precursors of substance Inhibitors,research,lifescience,medical P, but only the β and γ forms also encode for the synthesis of NKA and its elongated forms neuropeptide K and neuropeptide γ.11-13 Translation of the mRNA generates the so-called grandfather peptide, the prepropeptide. The enzymatic cleavage to the “paternal” propeptide is done inside the endoplasmic reticulum. The last step in generating the active peptide is carried out by converting enzymes in cytoplasmic vesicles.

Once the neuropeptides have been released, they are inactivated by catabolic peptidases. The tachykinins are degraded by multiple peptidases in the tissue including Inhibitors,research,lifescience,medical the angiotensin-converting enzyme (ACE).14,15 There is no reuptake mechanism, as known for the monoamine neurotransmitters.16 Anatomic distribution of tachykinins within the CNS SP is widely distributed throughout the CNS and the myenteric and submucous nerve plexuses of the gut. In the brain, SP is found in the midbrain periaquacductal gray, nucleus raphe magnus, and nucleus reticularis gigantocellularis pars a, which are important structures in the endogenous through pain control system.17 Large numbers of SP-containing neurons have been found in the human posterior hypothalamus and basal forebrain, indicating an see more involvement of SP in hypothalamic functions such as sexual behavior or pituitary hormone release.18 SP is also found in the basal ganglia, nucleus accumbens, and – in lower levels – in the cerebral cortex.19 Moreover, there is evidence that SP interacts with dopaminergic neurons of nigrostriatal, limbic, and forebrain nuclei.