Inhibition of the N-methyl-d-aspartate receptor unmasks the antinociception of endogenous opioids in the periphery.
Although N-methyl-d-aspartate (NMDA) receptor antagonists potentiate antinociceptive effects induced by various exogenous opioids at the spinal, supraspinal, or peripheral level, less is known regarding the interaction between NMDA and endogenous opioids in antinociception. We therefore assessed the effects of NMDA receptor antagonists on endogenous opioids in antinociception at the peripheral level by testing the ability of the locally administered receptor antagonists to modify pain-related behavior induced by carrageenan injection into the knee joint. The NMDA receptor antagonist AP-5 or the exogenous opioid morphine was injected intra-articularly before carrageenan injection and 5h after carrageenan injection, respectively. We evaluated whether intra-articular injection of the opioid receptor antagonist naloxone reversed the analgesic effect of AP-5. In addition, we tested the effects of AP-5 on carrageenan-induced levels of the beta-endorphin protein in dorsal root ganglia (DRG), saphenous nerve and synovial membrane. We found that AP-5 prevented and morphine reversed carrageenan-induced pain-related behavior. Intriguingly, injection of naloxone 5h after carrageenan injection reversed the antinociceptive effects of AP-5 pre-treatment, although naloxone alone had no effect on carrageenan-induced pain-related behavior. Western blots showed that AP-5 pre-treatment followed by carrageenan injection resulted in a higher level of beta-endorphin protein in the DRG and saphenous nerve, but not in the synovial membrane, than that observed following saline control treatment. These results suggest that inhibition of the NMDA receptor unmasks antinociception induced by endogenous opioids at the peripheral level, partly through the increased protein level of the endogenous mu-opioid peptide beta-endorphin in DRG and saphenous nerve.
Department of Physiology, College of Medicine, Korea University, 126-1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136-705, Republic of Korea Department of Physiology and Biophysics, College of Medicine, Eulji University, 143-5 Youngdu-dong, Jung-gu, Daejeon 301-832, Republic of Korea Department of Basic Nursing Science, Korea University School of Nursing, Seoul 136-713, Republic of Korea Department of Pathology, Hanyang University Hospital, 17 Haengdang-dong, Sungdong-gu, Seoul 133-792, Republic of Korea.
Guo Hua
GH
Zhang
Sun Seek
SS
Min
Geun Hee
GH
Seol
Kyu Sang
KS
Lee
Hongxiu
H
Han
Yang
Y
In Kim
Hee Chul
HC
Han
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D001168:Arthritis / Q000139:chemically induced / Q000150:complications; D002351:Carrageenan / Q000494:pharmacology; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000819:agonists* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013583:Synovial Membrane / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D001615:beta-Endorphin / Q000378:metabolism
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D001615:beta-Endorphin; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; D002351:Carrageenan