Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats

• Published in: European journal of pain 2016-09, Vol.20 (8), p.1229-1240
• Main Authors: Hillhouse, T.M., Negus, S.S.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Disease Models, Animal; Dizocilpine Maleate - therapeutic use; Excitatory Amino Acid Antagonists - therapeutic use; Ketamine - therapeutic use; Male; Pain - drug therapy; Pain - psychology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Self Stimulation - drug effects
• ISSN: 1090-3801; 1532-2149
• DOI: 10.1002/ejp.847

Background Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N‐methyl‐d‐aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. Methods This study compared effects of the NMDA receptor antagonists ketamine and MK‐801 in assays of pain‐stimulated and pain‐depressed behaviour in rats. The nonsteroidal anti‐inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self‐stimulation (ICSS) in male Sprague–Dawley rats. Results Ketamine (1.0–10.0 mg/kg) blocked acid‐stimulated stretching but failed to block acid‐induced depression of ICSS, whereas MK‐801 (0.01–0.1 mg/kg) blocked both acid‐stimulated stretching and acid‐induced depression of ICSS. These doses of ketamine and MK‐801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK‐801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid‐induced stimulation of stretching and depression of ICSS without altering control ICSS. Conclusion These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain‐depressed behaviours. What does this study add NMDA receptor antagonists produce dissociable effects on pain‐depressed behaviour. Provides evidence that pain‐depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists.