title: 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.
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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary. kkornel@gmx.de
authors.forename: Kornél
authors.initials: K
authors.lastname: Király
authors.forename: Balázs
authors.initials: B
authors.lastname: Szalay
authors.forename: Judit
authors.initials: J
authors.lastname: Szalai
authors.forename: István
authors.initials: I
authors.lastname: Barna
authors.forename: Klára
authors.initials: K
authors.lastname: Gyires
authors.forename: Mathieu
authors.initials: M
authors.lastname: Verbeken
authors.forename: András Z
authors.initials: AZ
authors.lastname: Rónai
mesh_terms: 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
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; C105294:endomorphin 2; D002351:Carrageenan; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4; D008025:Ligases