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Intrathecally Injected Ile-Pro-Ile, an Inhibitor of Membrane Ectoenzyme Dipeptidyl Peptidase IV, Is Antihyperalgesic in Rats by Switching the Enzyme From Hydrolase to Synthase Functional Mode to Generate Endomorphin 2

Intrathecally Injected Ile-Pro-Ile, an Inhibitor of Membrane Ectoenzyme Dipeptidyl Peptidase IV, Is Antihyperalgesic in Rats by Switching the Enzyme From Hydrolase to Synthase Functional Mode to Generate Endomorphin 2

Kornél Király, Balázs Szalay, Judit Szalai, István Barna, Klára Gyires, Mathieu Verbeken, András Z Rónai

Eur J Pharmacol. 2009 Oct 12;620(1-3):21-6.

PMID: 19695241

Abstract:

We have found recently that membrane-bound dipeptidyl peptidase IV (DPP-IV) generated extracellularly immunoreactive endomorphin-2 from Tyr-Pro precursor in a depolarisation-sensitive manner in rat isolated L4,5 dorsal root ganglia when the enzyme was switched to synthase mode by the hydrolase inhibitor Ile-Pro-Ile. Presently, we induced hyperalgesia in rats by injecting carrageenan into the right hindpaw and measured the reduction in nociceptive threshold (hyperalgesia) to pressure (Randall-Selitto test). The hyperalgesia, peaking at 180 min after injection, was fully reversed by intrathecal administration of 30 nmol/rat Ile-Pro-Ile. The antihyperalgesic action was antagonized by s.c. naloxone (1 mg/kg) and intrathecally injected specific antiserum to endomorphin-2 indicating that the opioid receptor-mediated effect was produced by an endogenously generated endomorphin-2-like immunoreactive substance. Intrathecal Ile-Pro-Ile was ineffective as an analgesic in the acute nociceptive test such as the rat tail-flick, whereas endomorphin-2 (EC(50)=13.3 nmol/rat), endomorphin-1 (6.8 nmol/rat), morphine (0.11 nmol/rat) and DAMGO (0.0059 nmol/rat) exerted opioid receptor-mediated analgesia given by the same route. We concluded that carrageenan-induced C-fiber barrage (wind-up) may create ideal conditions for the de novo synthesis of endomorphin-2 in rat spinal cord dorsal horns if the DPP-IV enzyme is switched to the synthase functional mode by Ile-Pro-Ile.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP90614485	Ile-Pro-Ile		90614-48-5	Price

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