Nonopioid motor effects of dynorphin A and related peptides: structure dependence and role of the N-methyl-D-aspartate receptor.
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 approximately Dyn A-(1-13) > [Ala1]Dyn A-(1-13) approximately Dyn A-(2-13) > alpha-Neo-End > Dyn A-(1-8) approximately Dyn B approximately 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 Ki value of 0.41 microM. 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.
Shukla
V K
VK
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Prasad
J A
JA
Lemaire
S
S
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013329:Structure-Activity Relationship
D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; D016291:Dizocilpine Maleate; D004399:Dynorphins; D015763:2-Amino-5-phosphonovalerate