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.
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.
Király
Kornél
K
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary. kkornel@gmx.de
Szalay
Balázs
B
Szalai
Judit
J
Barna
István
I
Gyires
Klára
K
Verbeken
Mathieu
M
Rónai
András Z
AZ
D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use; D006930:Hyperalgesia / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D007278:Injections, Spinal; D008025:Ligases / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage* / Q000096:biosynthesis* / Q000134:cerebrospinal fluid / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; C105294:endomorphin 2; D002351:Carrageenan; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4; D008025:Ligases