NK‐3 receptors mediate enhancement of substance P release from capsaicin‐sensitive spinal cord afferent terminals

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Abstract
The effects of NK‐3 receptor agonists on the release of substance P‐immunoreactivity (SP‐LI) have been investigated using superfused rat spinal cord synaptosomes. The Ca2+‐dependent overflow of SP‐LI evoked by 35 mM KCl was concentration‐dependently enhanced by senktide (EC50=52 nM; maximal effect=70%) or [MePhe7]NKB (EC50=5.5 nM; maximal effect=125%), both selective agonists at receptors of the NK‐3 type. The potentiation of the SP‐LI overflow elicited by 100 nM senktide or [MePhe7]NKB was prevented by the NK‐3 receptor antagonist (+)‐SR142801. The antagonist halved, at 10 nM, and almost abolished, at 100 nM, the effect of both agonists. The effect of senktide or [MePhe7]NKB was insensitive to antagonists at NK‐1 or NK‐2 receptors. Capsaicin (0.1–1 μM) stimulated SP‐LI release in a concentration‐dependent manner from spinal cord synaptosomes. The SP‐LI overflow elicited by 1 μM capsaicin was completely dependent on external Ca2+. Senktide could not affect the capsaicin‐evoked release of SP‐LI. Senktide failed to potentiate the K+‐evoked overflow of SP‐LI from synaptosomes previously exposed for 15 min in superfusion to capsaicin. The results show that release‐enhancing NK‐3 receptors are located on axon terminals of capsaicin‐sensitive primary afferent neurones in the spinal cord. Antagonists at NK‐3 receptors might help controlling pain transmission. British Journal of Pharmacology (1998) 125, 621–626; doi:10.1038/sj.bjp.0702093