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. 2018 Aug 13:12:240.
doi: 10.3389/fncel.2018.00240. eCollection 2018.

Inhibition of the Prefrontal Projection to the Nucleus Accumbens Enhances Pain Sensitivity and Affect

Haocheng Zhou  1   2 , Erik Martinez  2 , Harvey H Lin  2 , Runtao Yang  2 , Jahrane Antonio Dale  2 , Kevin Liu  2 , Dong Huang  1 , Jing Wang  2   3
Affiliations

Inhibition of the Prefrontal Projection to the Nucleus Accumbens Enhances Pain Sensitivity and Affect

Haocheng Zhou et al. Front Cell Neurosci. .

Abstract

Cortical mechanisms that regulate acute or chronic pain remain poorly understood. The prefrontal cortex (PFC) exerts crucial control of sensory and affective behaviors. Recent studies show that activation of the projections from the PFC to the nucleus accumbens (NAc), an important pathway in the brain's reward circuitry, can produce inhibition of both sensory and affective components of pain. However, it is unclear whether this circuit is endogenously engaged in pain regulation. To answer this question, we disrupted this circuit using an optogenetic strategy. We expressed halorhodopsin in pyramidal neurons from the PFC, and then selectively inhibited the axonal projection from these neurons to neurons in the NAc core. Our results reveal that inhibition of the PFC or its projection to the NAc, heightens both sensory and affective symptoms of acute pain in naïve rats. Inhibition of this corticostriatal pathway also increased nociceptive sensitivity and the aversive response in a chronic neuropathic pain model. Finally, corticostriatal inhibition resulted in a similar aversive phenotype as chronic pain. These results strongly suggest that the projection from the PFC to the NAc plays an important role in endogenous pain regulation, and its impairment contributes to the pathology of chronic pain.

Keywords: acute pain; chronic pain; corticostriatal circuits; nucleus accumbens (NAc); prefrontal cortex (PFC); prelimbic cortex.

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Figures

Figure 1
Figure 1
Inhibition of prefrontal cortex (PFC) pyramidal neurons enhances nocifensive reflex and affective response to acute pain. (A) Histologic expression of halorhodopsin in the prelimbic region of the PFC with low magnification (10×). (B) High-magnification (63×) view of the expression of halorhodopsin (NpHR)-YFP in the PL-PFC. From left to right: CaMK II staining; NpHR-eYFP staining; DAPI staining and merged images. (C) Schematic of optogenetic manipulation of the PL-PFC. (D) Optogenetic inhibition of the PL-PFC decreased the withdrawal latency in NpHR-treated rats. n = 8–11; p = 0.0112, unpaired Student’s t-test. (E) Schematic of the conditioned place aversion (CPA) test with optogenetic stimulation of the PL-PFC. Optogenetic stimulation was paired with PP in one chamber during conditioning phase, the other chamber was paired with PP. (F,G) Inhibition of PL-PFC increased the aversive response to acute pain. NpHR-treated rats displayed avoidance for the chamber associated with light stimulation. n = 7; p =0.0001, paired Student’s t-test. YFP-treated rats showed no preference for either chamber. n = 7; p = 0.8517, paired Student’s t-test. (H) Inactivation of PL-PFC enhanced the aversion to painful stimulation, as demonstrated by the increasing CPA score. n = 7; p = 0.0006, unpaired Student’s t-test. *p < 0.05, ***p < 0.001.
Figure 2
Figure 2
Selective inhibition of the projection from the PL-PFC to the Nucleus accumbens (NAc) core increases acute pain-related behaviors. (A) Low magnification (10×) view of NpHR-eYFP in the NAc core. (B) High magnification (100×) view of NpHR-eYFP in the NAc core. From left to right: NeuN staining; NpHR-eYFP staining; and merged images. (C) Schematic of inhibition of the PFC-NAc projection. Optic fibers were implanted bilaterally in the NAc core after injection of virus in the PL-PFC. Light treatment was delivered to the NAc core. (D) Optogenetic inactivation of the NAc core decreased the latency to paw withdrawal in Hargreaves’ test. n = 7–8; p = 0.0200, unpaired Student’s t-test. (E) Optogenetic inhibition of the PFC-NAc projection worsened the pain-related aversive response. n = 8; p = 0.0134, paired Student’s t-test. (F) YFP-treated rats demonstrated no preference to either chamber. n = 7; p = 0.8064, paired Student’s t-test. (G) Selective inhibition of the PFC-NAc core projection increased the aversive effect of painful stimulation, demonstrated by the increasing CPA score. n = 7–8; p = 0.0495, unpaired Student’s t-test *p < 0.05.
Figure 3
Figure 3
Inhibition of the PL-PFC enhances sensory allodynia and the affective response to pain in the chronic pain state. (A,B) Rats developed sensory impairment after spared nerve injury (SNI) surgery. Two-way analysis of variance (ANOVA) with repeated measures and Bonferroni’s post-test, n = 6, p < 0.0001. (C) Schematic of the light treatment in the PL-PFC. (D) Deactivation of the PL-PFC increased cold allodynia in rats with neuropathic pain. n = 6–8; p = 0.0389, unpaired Student’s t-test. (E) Schematic showing optogenetic deactivation of PL-PFC during the Conditioned Place Preference (CPP) testing for SNI-treated rats. Neither chamber was associated with peripheral stimulations, and rats were conditioned for 4 days to assess the aversive response to chronic pain. (F) CPP data shows that SNI-treated rats displayed a significant avoidance for the chamber paired with PFC inhibition. n = 6, p < 0.0001. Two-way ANOVA with repeated measures and Bonferroni post-test *p < 0.05,****p < 0.0001.
Figure 4
Figure 4
Deactivation of the PFC-NAc projection worsened both sensory and affective components of chronic pain. (A) Selective deactivation of the PFC-NAc circuit through light delivery into the NAc core. (B) Sensory symptoms were worsened with inhibition of the PFC-NAc projection in the chronic pain state. n = 7; p = 0.0082, paired Student’s t-test. (C) CPP test was performed in the SNI-treated rats with selective inhibition of the NAc core in one chamber, and no light stimulation in the other. (D) SNI-treated rats preferred the chamber associated without light stimulation in the CPP test. n = 5; p = 0.0078. Two-way ANOVA with repeated measures and Bonferroni post-test **p < 0.01.
Figure 5
Figure 5
Chronic pain induced generalized enhancement of aversive response to peripheral nociceptive inputs. (A) CPA tests were performed with a PP to the uninjured paw or the paw contralateral to surgery. One chamber was paired with PP, and the other was not paired with painful stimulation (NP). (B) Rats that underwent sham surgery presented preference to chamber paired without acute pain. n = 10, p = 0.0046. Paired Student’s t-test. (C) SNI-treated rats displayed increased an aversive response to acute pain. n = 10, p < 0.0001. Paired Student’s t-test. (D) Chronic pain induced an enhanced pain-related aversion, demonstrated by increasing CPA score. n = 10, p = 0.0170. Unpaired Student’s t-test *p < 0.05, **p < 0.01, ****p < 0.0001.
Figure 6
Figure 6
Inhibition of the corticostriatal circuit produces similar phenotypes as chronic pain. (A) Optogenetic CPA assays were performed in the rats without chronic pain. Light treatment was paired with PP in one chamber during the conditioning phase, the other chamber was paired without peripheral or optogenetic stimulation. (B) YFP-treated rats showed avoidance for the chamber with acute pain and light. n = 7, p = 0.0116. Paired Student’s t-test. (C) Inhibition of PL-PFC induced the enhanced aversive response to nociceptive inputs. n = 7, p = 0.0004. Paired Student’s t-test. (D) The CPA score demonstrated that the inhibition of PL-PFC increased the aversive effect of acute pain in rats without chronic pain. n = 7, p = 0.0399. Unpaired Student’s t-test. (E) Inhibition of the PFC-NAc projection was paired with PP during conditioning phase in the CPA testing. (F) YFP-treated rats developed avoidance for the chamber conditioned with PP and light treatment. n = 7, p = 0.0002. Paired Student’s t-test. (G) NpHR-treated rats displayed significant avoidance to the chamber paired with light and PP. n = 7, p = 0.0016. Paired Student’s t-test. (H) Inactivation of the PFC-NAc projection produced a similar aversive response to acute pain as to chronic pain, as demonstrated by the increasing CPA score. n = 7, p = 0.0463. Unpaired Student’s t-test *p < 0.05, **p < 0.01, ***p < 0.001.
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