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. 2021 Mar 26;162(12):2865–2880. doi: 10.1097/j.pain.0000000000002279

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Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Figure 1. — Glutamate, but not indiplon, in the dorsal hippocampus reversed pain-like behaviors after SNI or SNL neuropathic injuries in rats. (A) Microinjection of glutamate (21.2 pmol in 1 µL volume) but not saline into the dorsal hippocampus (ipsilateral to SNI) reversed SNI-induced tactile allodynia. This effect lasted for 2 days and was replicated by a second injection of glutamate (n = 6 rats per group). (B) Coapplication of glutamate (5.3 pmol) with NMDA receptor antagonist APV in the dorsal hippocampus (5 nmol in 1 µL volume, 30 minutes before 5.3 pmol glutamate injection) diminished the effect of glutamate on SNI-induced tactile allodynia (n = 9 rats per group). Note the lower dose of glutamate resulted in shorter duration pain relief. (C) In Sham but not in SNI rats, activation of GABA_A receptors in the dorsal hippocampus by infusion of indiplon (positive allosteric modulator of GABA_A receptors, 10 pmol in 1 µL volume) decreased the tactile thresholds (n = 6 rats per group). (D) Representative coronal sections and histological verification for implanted cannulas. (E) In L5 SNL-induced neuropathic pain model, tactile allodynia on ipsilateral hind paws was reversed by glutamate microinjected into the dorsal hippocampus (5.3 pmol in 1 µL volume, n = 6 per group). Post hoc statistical significance of differences is indicated as follows: ***P < 0.0001 and ns P > 0.05 (compared with −1 hour before glutamate injection), #P < 0.05 (compared with the glutamate-treated SNI group at corresponding time from the start of testing). For detailed statistics, see Table S1, available at http://links.lww.com/PAIN/B350. SNI, spared nerve injury; SNL, spinal nerve ligation.