Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism.

Abstract Intrathecal (i.t.) administration of big dynorphin (1–10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5–15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1–30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125–2 mg/kg) and also dose-dependently, by i.t. co-administration of d (−)-2-amino-5-phosphonovaleric acid (D-APV) (1–4 nmol), a competitive N -methyl- d -aspartate (NMDA) receptor antagonist, MK-801 (0.25–4 nmol), an NMDA ion-channel blocker, and ifenprodil (2–8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [ d -Phe 7 , d -His 9 ]-substance P(6–11), a specific antagonist for substance P (NK1) receptors, and MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.