A study of NK-3 tachykinin receptors

Thesis

The aim of this thesis was to determine the pharmacological characteristics and biochemical properties of NK-3 tachykinin receptors in the mammalian central nervous system (cerebral cortex and spinal cord) and periphery (guinea-pig ileum; GPILM).

The affinities of naturally-occurring tachykinins and several receptorselective analogues, for peripheral (GPILM) and central (guinea-pig cortex) NK-3 receptors (labelled with the selective NK-3 receptor ligand, [3H]-senktide) have been determined. A good correlation between affinities of the above peptides for NK-3 sites in the two tissues was obtained. The inhibition of [3H]-senktide binding by guanine nucleotides, in addition to the correlation between affinities of tachykinins at NK-3 sites and their biological potencies in contracting the rat portal vein (RPV; data from the literature), suggest that [3H]-senktide binding sites represent functional receptors.

Evidence for the coupling of GPILM and neonatal rat spinal cord (but not RPV or rat cerebral cortex) NK-3 receptors, to the hydrolysis of inositol phospholipids has been obtained. In GPILM, morphine was found to inhibit the formation of [3H]-inositol phosphates in response to the NK-3 agonist, senktide. This finding is in agreement with the hypothesis that the indirect contractile action of tachykinins in GPILM is due to the activation of neuronal NK-3 receptors and the release of acetylcholine (ACh). This idea has also been confirmed by contractile and [3H]-ACh release studies.

Autoradiographical studies in spinal cord, using [3H]-senktide, have shown the presence of NK-3 sites in the dorsal horn. These findings, taken together with the recent report that NK-3 agonists may be analgesic, suggest that the guinea-pig ileum might be a useful bioassay for the evaluation of potent and selective NK-3 agonists which may represent novel analgesic agents.

Authors: Guard, S; Guard, Steven

• Publication date: 1989
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Central nervous system; Tachykinins