AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

Fei Zeng, Qiaosheng Zhang, Yaling Liu, Guanghao Sun, Anna Li, Robert S Talay, Jing Wang, Fei Zeng, Qiaosheng Zhang, Yaling Liu, Guanghao Sun, Anna Li, Robert S Talay, Jing Wang

Abstract

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

Keywords: AMPAkine; CX 546; Nucleus accumbens; Pain; Prelimbic cortex.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Experimental design and location of intracranial viral injections and cannula placements. a Schematic for in vivo optogenetic targeting of the PL and AMPAkine treatment in the NAc. b Histologic expression of Channelrhodopsin (ChR2) in the PL. c Representative brain slice showing the intracranial infusion site in the NAc core. d Schematic showing tip of injectors in the NAc core
Fig. 2
Fig. 2
AMPAkine potentiation of the NAc partially reconstitutes the anti-nociceptive effects of PL. a Optogenetic activation of the PL has a greater impact than AMPAkine infusions into the NAc core on reducing sensory withdrawals on Hargreaves test. ChR2 group, n = 7; YFP group, n = 7; YFP + AMPAkine vs YFP + saline (*p = 0.0114); ChR2 + AMPAkine vs ChR2 + saline (p > 0.9999); ChR2 + AMPAkine vs YFP + AMPAkine (****p < 0.0001), ChR2 + saline vs YFP + saline (****p < 0.0001); Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. b Schematic of the CPP assay with optogenetic activation of the PL in the presence of noxious pin prick (PP) after AMPAkine or saline infusion into the NAc core. AMPAkine or saline was infused into the NAc 15 min prior to the CPP assay. During the CPP assay, one of the chambers was paired with optogenetic activation of the PL and PP; the other chamber was paired with PP alone. During the preconditioning or testing phase, no stimuli were given and rats were allowed free movement. c Control (saline-infused) rats, when presented with noxious stimuli (PP), preferred the chamber associated with optogenetic PL activation. n = 6, *p = 0.0101, paired Student’s t-test. d Control rats that had YFP injection did not demonstrate a preference for either chamber. n = 6, p = 0.5973, paired Student’s t-test. e CPP score for PL activation in the presence of noxious mechanical stimuli after saline infusion into the NAc core. n = 6, ** p = 0.0098, unpaired Student’s t test. f Rats that received AMPAkine infusion prior to the CPP test, when presented with PP, did not demonstrate preference or aversion for the chamber associated with optogenetic PL activation. n = 6, p = 0.7524, paired Student’s t-test. g AMPAkine-infused rats that received YFP injection also demonstrated no preference or aversion for either chamber. n = 6, p = 0.1990, paired Student’s t-test. h After AMPAkine infusion into NAc core, the CPP score for PL activation was not increased compared with YFP control. n = 6, p = 0.5238, unpaired Student’s t test. i CPP scores indicate that AMPAkine treatment in the NAc eliminated the preference of chamber associated with PL activation. n = 6, **p = 0.0031, unpaired Student’s t test
Fig. 3
Fig. 3
AMPAkine in the NAc partially reconstitutes the anti-nociceptive effects of PL on chronic inflammatory pain. a CFA treatment induces mechanical allodynia, compared with saline-treated rats. CFA group, n = 12; Saline group, n = 13; ****p < 0.0001, Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. b AMPAkine infusion into the NAc core and activation of PL did not change mechanical hypersensitivity in control rats. ChR2 group, n = 7; YFP group, n = 6; ChR2 vs YFP, after AMPAkine infusion (p > 0.9999), after saline infusion (p = 0.2760); AMPAkine vs saline, in ChR2 rats (p > 0.9999), in YFP rats (p = 0.3044); Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. c Optogenetic activation of the PL has greater impact than AMPAkine potentiation of the NAc core on the reduction of sensory withdrawal. ChR2 group, n = 6; YFP group, n = 6; ChR2 vs YFP, after AMPAkine infusion (**p = 0.0025), after saline infusion (****p < 0.0001); AMPAkine vs saline, in ChR2 rats (p > 0.9999), in YFP rats (*p = 0.0340); Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons
Fig. 4
Fig. 4
AMPAkine in the NAc core occludes the anti-aversive effect of PL on chronic inflammatory pain. a Schematic of the CPP test for tonic-aversive response in CFA-treated rats after AMPAkine or saline infusion in the NAc core. One of the chambers was paired with PL activation; the other chamber was not. No peripheral stimulus was given. b Saline-infused rats that received ChR2 injection preferred the chamber associated with PL activation. n = 6, *p = 0.0237, paired Student’s t-test. c Saline-infused rats that received YFP injection showed no preference for light treatment. n = 6, p = 0.5973, paired Student’s t-test. d CPP score for PL activation in the presence of spontaneous or tonic pain. n = 6, *p = 0.0232, unpaired Student’s t test. e AMPAkine pretreatment occluded the anti-aversive effects of PL activation. Rats which received CX546 infusion in the NAc core prior to CPP test did not demonstrate a preference for the chamber associated with PL activation. n = 6, p = 0.4405, paired Student’s t-test. f AMPAkine-infused rats which received YFP injection showed no chamber preference. n = 6, p = 0.1278, paired Student’s t-test. g AMPAkine pretreatment occluded the anti-aversive effects of PL activation in CFA-treated rats. After AMPAkine infusion into NAc core, the CPP score for PL activation was not increased compared with YFP control. n = 6, p = 0.6102, unpaired Student’s t test. h Compared with saline, AMPAkine treatment prior to CPP test occluded the anti-aversive effects of PL activation in CFA-treated rats. n = 6, *p = 0.0294, unpaired Student’s t test
Fig. 5
Fig. 5
AMPAkine in the NAc partially reconstitutes the anti-nociceptive effects of PL on chronic neuropathic pain. a Schematic of the SNI model. b SNI treatment induces mechanical allodynia, compared with SHAM-treated rats. SNI group, n = 12; SHAM group, n = 13; ****p < 0.0001, Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. c SNI treatment induces cold allodynia, compared with SHAM-treated rats. SNI group, n = 12; SHAM group, n = 13; ****p < 0.0001, Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. d Optogenetic activation of the PL decreased mechanical allodynia in SNI-treated rats; AMPAkine infusion in the NAc decreased mechanical allodynia in YFP rats but not ChR2 rats. ChR2 group, n = 6; YFP group, n = 6; ChR2 vs YFP, after AMPAkine infusion (****p < 0.0001), after saline infusion (****p < 0.0001); AMPAkine vs saline, in ChR2 rats (p > 0.9999), in YFP rats (***p = 0.0002); Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons. e Activation of the PL decreased cold allodynia in SNI-treated rats; AMPAkine infusion decreased cold allodynia in YFP but not ChR2 rats. ChR2 group, n = 6; YFP group, n = 6; ChR2 vs YFP, after AMPAkine infusion (*p = 0.0364), after saline infusion (****p < 0.0001); AMPAkine vs saline, in ChR2 rats (p > 0.9999), in YFP rats (****p < 0.0001); Two-way ANOVA with repeated measures and Bonferroni’s multiple pair-wise comparisons
Fig. 6
Fig. 6
AMPAkine in the NAc core occludes the anti-aversive effect of PL activation on chronic neuropathic pain. a Schematic of the CPP test for tonic-aversive response in SNI-treated rats after AMPAkine or saline infusion in the NAc core. One of the chambers was paired with PL activation; the other chamber was not. No peripheral stimulus was given. b Saline-infused rats that received ChR2 injection preferred the chamber associated with PL activation. n = 6, **p = 0.0053, paired Student’s t-test. c Saline-infused rats that received YFP injection showed no preference for light treatment. n = 6, p = 0.5806, paired Student’s t-test. d CPP score for PL activation in the presence of spontaneous or tonic pain. n = 6, **p = 0.0012, unpaired Student’s t test. e AMPAkine pretreatment occluded the anti-aversive effects of PL activation. Rats which received CX546 infusion in the NAc core prior to CPP test did not demonstrate a preference for the chamber associated with PL activation. n = 6, p = 0.7514, paired Student’s t-test. f AMPAkine-infused rats that received YFP injection showed no chamber preference. n = 6, p = 0.6766, paired Student’s t-test. g AMPAkine pretreatment occluded the anti-aversive effects of PL activation in SNI-treated rats. After AMPAkine infusion into NAc core, the CPP score for PL activation was not increased compared with YFP control. n = 6, p = 0.9492, unpaired Student’s t test. h Compared with saline, AMPAkine treatment prior to CPP test occluded the anti-aversive effects of PL activation in SNI-treated rats. n = 6, **p = 0.0018, unpaired Student’s t test

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