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. 2018 Oct 17;4(10):eaat4751. doi: 10.1126/sciadv.aat4751

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Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

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Fig. 2 — (A) Detailed timeline of the experiments. (B) NicA2-J1 suppressed hyperalgesia during nicotine withdrawal. The two-way mixed-factorial analysis of variance (ANOVA), with group (PBS versus NicA2-J1) as the between-subjects factor and time (baseline, pre-escalation hyperalgesia, and post-escalation hyperalgesia) as the within-subjects factor, revealed significant effects of group (F_1,14 = 4.91, P = 0.04) and time (F_2,14 = 10.89, P = 0.0003) and a significant group × time interaction (F_2,28 = 5.11, P = 0.012). The Newman-Keuls post hoc analysis revealed that mechanical sensitivity significantly decreased during withdrawal (pre-escalation) in PBS-treated rats compared with their mechanical sensitivity before nicotine exposure (P = 0.017) and compared with the NicA2-J1 group (P = 0.007). Mechanical sensitivity after pretreatment with NicA2-J1 was comparable to baseline sensitivity before nicotine exposure (P > 0.05), suggesting that NicA2-J1 treatment completely reversed withdrawal-induced hyperalgesia (pre-escalation versus post-escalation, P = 0.043), whereas this effect was not detected in the PBS group, which exhibited more severe hyperalgesia during withdrawal (post-escalation versus baseline, P = 0.0018). Moreover, the Newman-Keuls post hoc analysis showed that hyperalgesia during post-escalation was completely reversed in the NicA2-J1 group (post-escalation in the PBS group versus post-escalation in the NicA2-J1 group, P = 0.041). (C) Effect of NicA2-J1 on irritability-like behavior, reflected by defensive and aggressive responses. The baseline of defensive and aggressive responses was measured during 48 hours of spontaneous nicotine withdrawal before treatment with NicA2-J1 or PBS. All the other measures were performed during 48 hours of spontaneous nicotine withdrawal after the last escalation phase after the completion of NicA2-J1 treatment (10 mg/kg). A significant decrease in defensive responses (n = 8; t = 4.5, df = 7, P < 0.01) and aggressive responses (n = 8; t = 5.22, df = 7, P < 0.01) was observed in NicA2-J1–pretreated rats. No changes from baseline were observed in the PBS group. Student’s paired t test revealed a significant reduction of aggressive responses (t = 2.27, df = 14, P < 0.05) but not defensive responses (t = 1.85, df = 14, P > 0.05) in NicA2-J1–pretreated rats compared with PBS-pretreated rats. *P < 0.05, **P < 0.01, versus baseline; ^#P < 0.05, versus pre-escalation; ^&P < 0.05, post-escalation comparisons between the PBS and NicA2-J1 groups.