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. 2023 May 19;9(20):eadg2819. doi: 10.1126/sciadv.adg2819

Fig. 1. NI-NMDAR activity directly contributes to the reversal of hyperalgesia and dorsal horn LTP following the reactivation of sensitized pain pathways.

Fig. 1.

(A) Timeline of experimental protocol. (B and C) Changes in mechanical withdrawal thresholds induced by intraplantar injection of capsaicin (Cap), followed by a second ipsilateral intraplantar injection of capsaicin and intrathecal injection of anisomycin alone, anisomycin coadministered with APV (NMDAR glutamate site antagonist) or 7-CK (NMDAR glycine site antagonist) in (B) male and (C) female mice. Injection times are indicated by arrows. (D) Capsaicin-induced hyperalgesia was followed by intrathecal injection of NMDA + 7-CK for selective activation of NI-NMDAR signaling. 7-CK alone (intrathecal injection) or NMDA alone (intrathecal injection) did not reverse mechanical hypersensitivity. (E and F) NI-NMDAR signaling was activated by a second ipsilateral intraplantar injection of capsaicin and intrathecal injection of 7-CK, resulting in the reversal capsaicin-induced hyperalgesia in both (E) male and (F) female mice. This reversal was not observed when 7-CK was coadministered with APV. (G and H) Capsaicin-induced hyperalgesia was followed by a second ipsilateral intraplantar injection of capsaicin or vehicle (Veh), coupled with (G) intrathecal injection of L-689,560 (L689) or (H) intraperitoneal injection of AV-101. (I) AV-101 reversal of hyperalgesia using different doses of capsaicin during the second ipsilateral intraplantar injection expressed as percentage of maximum possible effect (MPE). (J) LTP of SDH field postsynaptic potentials (fPSPs) was followed by bath application of 7-CK from 90 to 150 min with or without electrical stimulation of dorsal roots. (K) Representative traces of fPSPs recorded at baseline, 90 min (LTP) and 210 min (post). (L and M) Summary data of changes in fPSP area before (LTP) and after (posttreatment) 7-CK application (L) with or (M) without dorsal root stimulation. Data are means ± SEM. Not significant (n.s.), P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001.