Substance P and antagonists
Substance P
Substance P is classified among the tachykinins called neurokinines which are peptides ending with the sequence glycine-leucine- methionine-NH2. Made of eleven amino acids, it is widely distributed in the body, in particular in the central nervous system. The highest concentrations are found in the Locus Niger, the hypotholamus, the pineal gland.
Substance P, which activates receptors called NK, for neurokinine, NK1, NK2 and NK3, has various effects:
- It induces vasodilation: in intravenous injection, substance P induces a very important vasodilation, and after intradermal injection, it elicits a redness and a pain resembling that which the histamine causes. On the contrary, when the substance P is introduced into cerebral ventricles in animals, it elicits an arterial hypertension.
- It modifies certain secretions: increase in salivary secretion, decrease of insulin secretion, decrease of biliary secretion, increase histamine release.
- The relationships between substance P and pain are complex and one finds in the literature conflicting data about it. Substance P may ensure, in the spinal cord, the transmission of the noxious impulses. Morphine could act by decreasing the release of substance P.
- Substance P could be implicated in certain mental disorders like depressive states
- Substance P induces nausea and vomiting.
Antagonists of Substance P
Selective antagonists of NK1 receptors of substance P have an antiemetic effect. Aptrepitant, Emend*, is the first molecule of this group to be marketed for prevention of nausea and vomiting elicited by emetic chemotherapy. It is not used alone but as an adjunct to a standard antiemetic treatment based on the combination of a corticoid (dexamethasone) and an antagonist 5-HT3 called – setron such as ondansetron.
It is metabolized mainly by the CYP3A4cytochromes which it inhibits partially, which can induce drug interactions which must be taken into account.
Substance P tissue depletion, capsaicin
Although the precise mechanism of action of capsaicin is not fully understood, the analgesic effect following its topical application is partly attributed to its ability to deplete substance P from local sensory C-type nerve fibers. This depletion of substance P which is obtained after repeated applications of capsaicin, reduces the transmission of pain impulses from the periphery to the CNS. Capsaicin, in topical formulation, Axsain* which also contains lidocaine, is used in the treatment of neuralgia pain, particularly of diabetic neuropathy and postherpetic neuralgia.
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