Vol. 283, Issue 2, 604-610, 1997

Nonopioid Motor Effects of Dynorphin A and Related Peptides: Structure Dependence and Role of the N-Methyl-D-aspartate Receptor¹

Vijay K. Shukla, Jyoti A. Prasad and Simon Lemaire

Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED₅₀ value of 14.32 (95% confidence limits, 10.09-20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A  Dyn A-(1-13) > [Ala¹]Dyn A-(1-13)  Dyn A-(2-13) > -Neo-End > Dyn A-(1-8)  Dyn B  Dyn A-(2-8) >>> Dyn A-(3-8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6-10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2-13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1-13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2-0.6 nmol/mouse) of the N-methyl-D-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [³H]MK-801, to rat brain membranes, with a K_i value of 0.41 µM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [³H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [³H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2-8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.