NMDA NR2B Subunit Antagonist May Attenuate Mechanical Allodynia by Increasing the Release of Enkephalin in the Spinal Dorsal Horn

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Background：Neurons containing enkephalin（ENK）are distributed at high concentrations in the superficial dorsal horn（SDH）of the spinal cord, where they play an important role in the modulation of nociceptive information. In addition to ENK, the SDH exhibits high expression levels of the NR2B subunit of the N-methyl-d-aspartate（NMDA）receptor and large-conductance calcium-activated potassium（BK）channels. In the present behavioral experiments, we investigated the effects of the BK channel antagonist charybdotoxin（CTX）and the NR2B subunit antagonist ifenprodil（IFN）on a nociceptive behavior in peripheral-nerve-injured mice.Methods：The experiments were performed in 6- to 8-week-old male ICR mice. Partial sciatic nerve ligation（PSL）was performed as described previously（Seltzer model）. Mechanical allodynia was assessed by stimulation with von Frey filaments. On postsurgical day 7, the effects of CTX and IFN on mechanical allodynia were analyzed. Additionally, to test the possibility that the actions of CTX and IFN are mediated by an altered release of ENK, we investigated the effect of the selective μ- and δ-opioid receptor antagonists naloxone（NAL）and naltrindole（NTL）, respectively. CTX（1 pmol/10μL per mouse）, IFN（50 nmol/10μL per mouse）, and saline as a control（10μL per mouse）were intrathecally injected. Additionally, NAL（5 mg/kg）and NTL（5 mg/kg）were intraperitoneally administered. All behavioral experiments were performed in a double-blind fashion.Results：PSL significantly increased the occurrence of the withdrawal reflex to von Frey stimuli, indicating the development of mechanical allodynia. CTX significantly reduced the occurrence of the withdrawal reflex compared to the saline group. Additionally, both NAL and NTL attenuated the analgesic effect of CTX. Intrathecal IFN significantly reduced the occurrence of the withdrawal reflex, which was also reduced by NAL and NTL.Conclusion：The obtained behavioral observations suggest that the NMDA receptors and BK channels might inhibit the release of ENK in the SDH, which is speculated to be involved in the chronic pain state induced by peripheral nerve injury.

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