Substance p release

Neurokinin effects are terrninated by proteolysis. In vitro acetylcholinesterase (ACE) and enkephalinase can hydrolyze substance P. However, there appears to be no clear evidence that either acetylcholinesterase or ACE limit the actions of released substance P. Enkephalinase inhibitors, eg, thiorphan, can augment substance P release or action in some systems but the distribution of enkephalinase in the brain does not precisely mirror that of substance P. There appears to be a substance P-selective enzyme in brain and spinal cord. 

Four principal mechanisms have been cited to explain the diverse physiological mechanisms of ginger. Broadly, these are (1) eicosanoid inhibition, (2) serotonin antagonism, (3) substance P release, and (4) Ca2-i-/ATPase activity. 

Ohkubo, T., Shibata, M., Inoue, M., Kaya, H., Takahashi, H., 1995. Regulation of substance P release mediated via prejunctional histamine H3 receptors. Eur. J. Pharmacol. 273, 83-88. 

Kondo I, Marvizon JC, Song B, et al. Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. J Neurosci. 2005 25 3651-3660. 

However, presynaptic NMDA autoreceptors may also mediate opposite effects, i.e., a reduction of glutamate release. At parallel fiber Purkinje cell synapses, activation of presynaptic NMDA receptors caused significant reductions in excitatory postsynaptic currents (Casado et al. 2002). Likewise, spontaneous and evoked glutamate release from the nerve endings of primary afferents in the spinal cord was reduced when presynaptic NMDA receptors were activated (Bardoni et al. 2004). In contrast to this, substance P release at such synapses was shown to be enhanced by the activation of presynaptic NMDA receptors (Liu et al. 1997). 

Liu H, Mantyh PW, Basbaum AI (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386 721... 

Arcaya,J. L., Cano, G., Gomez, G., Maixner, W., and Suarez-Roca, H. (1999). Dynorphin A increases substance P release from trigeminal primary afferent C-fibers. Em. J. Pharmacol. 366, 27-34. Bakshi, R., and Faden, A. I. (1990). Competitive and non-competitive NMDA antagonists limit dynorphin A-induced rat hindlimb paralysis. Brain Res. 507, 1-5. 

Seegers HC, Hood VC, Kidd BL, Cruwys SC, Walsh DA. Enhancement of angiogenesis by endogenous substance p release and neurokinin-1 receptors during neurogenic inflammation. J Pharmacol Exp Ther 2003 306 8-12. 

Arcaya J-L, Cano G, Gomez G, Maixner W, Sutirez-Roca H (1999) Dynorphin A increases substance P release from trigeminal primary riffeient C-fibers. Eur J Pharmacol 366 27-34 Arletti R, BeneRi A, Bertolini A (1993) Influence of oxytocin on nociception and moiphine antinociception. Neuropeptides 24 125-129... 

Yonehara N, Yoshimura M (1999) Effect of nitric oxide on substance P release from the peripheral endings primary afferent neurons. Neurosci Lett 271 199-201 Yoshikawa M, Ito K, Maeda M, Akahori K, Takahashi S, Jin XL, Matsuda M, Suzuki T, Oka T, Kobayashi H, Hashimoto A (2007) Activation of supraspinal NMDA receptors by both D-serine tilone or in combination with morphine leads to the potentiation of antinociception in tail-flick test of rats. Eur J Pharmacol 565 89-97... 

Lundbetg, J.M., Martling, C.R, Saria, A., Folkers, K. and Rosell, S. (1983). Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive v al afferents and substance P release. Neuroscience 10, 1361-1368. 

Capsaicin, like the other irritant RCAs, also causes bronchoconstriction, but the mechanism is uncertain. Capsaicin releases substance P that can cause bronchoconstriction directly by activation of specific receptors or by release of histamine or other mediators. It may also cause reflex bronchoconstriction by stimulating C fibers in both pulmonary and bronchial circulation. Therefore, bronchoconstriction may be secondary to substance P release, or to a vagal reflex. The altered neurophysiology of sensory neurons in the airway mucosa induces the release of tachykinins and neurokinin A, which causes neuro-mediated inflammation of the epithelium, airway, blood vessels, glands, and smooth muscles. This leads to bronchoconstriction, mucus secretion, enhanced vascular permeability, and neutrophil chemotaxis. 

Substance P Mouse Spinal cord Substance P release Inverse agonist (SR 141716) Lever and Malcangio 2002... 

Inoue M, Kobayashi M, Kozaki S, et al. Nociceptin/orphanin FQ-induced nociceptive responses through substance P release from peripheral nerve endings in mice. Proc Natl Acad Sci U S A 1998 95 10949-10953. 

The source and conditions under which substance P is released may determine the extent to which the presynaptic and postsynaptic mechanisms are integrated to shape the neuronal output from the NTS to distal synapses in the reflex pathways. Multiple central mechanisms are likely to contribute to the plasticity of cough reflex. In upregulated cough reflex, an increased substance P expression in the vagal neurons may be released at the central terminal in the NTS (Fischer et al. 1996 Chuaychoo et al. 2005). This enhanced substance P release in the NTS... 

Helke CJ, Jacobowitz DM, Thoa NB (1981) Capsaicin and potassium evoked substance P release from the nucleus tractus soUtarius and spinal trigeminal nucleus in vitro. Life Sci 29 1779-1785 Honda H, Takahama K, Kawaguchi T, Fuchikami J, Kai H, Miyata T (1990) Involvement of N-methyl-D-aspartic acid (NMDA) receptor in the central mechanism of cough reflex. Jpn J Pharmacol 52(Suppl. 1) 308... 

Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain 2002 96(l-2) 119-27. 

Akagi, H., Otsuka, M., and Yanagisawa, M., 1980, Identification by high-performance liquid chromatography of immunoreactive substance P released from isolated rat spinal cord, Neurosci. Lett. 20 259-263. 

Gamse, R., Molnar, A., and Lembeck, F., 1979c, Substance P release from spinal cord slices by capsaicin. Life Sci. 25 629-636. 

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