Inhibition of the N-methyl-d-aspartate receptor unmasks the antinociception of endogenous opioids in the periphery

Zhang, Guo Hua; Min, Sun Seek; Seol, Geun Hee; Lee, Kyu Sang; Han, Hongxiu; Kim, Yang In; Han, Hee Chul

doi:10.1016/j.pain.2009.03.007

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Volume 143, Issue 3 , Pages 233-237, June 2009

Inhibition of the N-methyl-d-aspartate receptor unmasks the antinociception of endogenous opioids in the periphery

Guo Hua Zhang
- Department of Physiology, College of Medicine, Korea University, 126-1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136-705, Republic of Korea
Sun Seek Min
- Department of Physiology and Biophysics, College of Medicine, Eulji University, 143-5 Youngdu-dong, Jung-gu, Daejeon 301-832, Republic of Korea
- Corresponding authors. Tel.: +82 2 920 6189; fax: +82 2 929 1485 (H.C. Han); Tel.: +82 42 259 1633; fax: +82 42 259 1639 (S.S. Min).
Geun Hee Seol
- Department of Basic Nursing Science, Korea University School of Nursing, Seoul 136-713, Republic of Korea
Kyu Sang Lee
- Department of Physiology, College of Medicine, Korea University, 126-1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136-705, Republic of Korea
Hongxiu Han
- Department of Pathology, Hanyang University Hospital, 17 Haengdang-dong, Sungdong-gu, Seoul 133-792, Republic of Korea
Yang In Kim
- Department of Physiology, College of Medicine, Korea University, 126-1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136-705, Republic of Korea
Hee Chul Han
- Department of Physiology, College of Medicine, Korea University, 126-1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136-705, Republic of Korea
- Corresponding authors. Tel.: +82 2 920 6189; fax: +82 2 929 1485 (H.C. Han); Tel.: +82 42 259 1633; fax: +82 42 259 1639 (S.S. Min).

Received 8 May 2008; received in revised form 6 March 2009; accepted 6 March 2009. published online 10 April 2009.

Abstract

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 β-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 β-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 μ-opioid peptide β-endorphin in DRG and saphenous nerve.