Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat

Scott J Thompson, Mark H Pitcher, Laura S Stone, Farid Tarum, Gang Niu, Xiaoyuan Chen, Dale O Kiesewetter, Petra Schweinhardt, M Catherine Bushnell, Scott J Thompson, Mark H Pitcher, Laura S Stone, Farid Tarum, Gang Niu, Xiaoyuan Chen, Dale O Kiesewetter, Petra Schweinhardt, M Catherine Bushnell

Abstract

The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [F]-FDPN-PET in either sham rats (n = 17) or spared nerve injury rats (n = 17), we confirmed reduced opioid receptor availability in the insula, caudate-putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate-putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate-putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.

Figures

Figure 1.
Figure 1.
Study design. Behavioral testing for mechanical and cold sensitivity was performed before surgery and again 1 week and 3 months after surgery. Rats were tested for sucrose preference as an index of anhedonia before surgery and again 3 months after surgery. [18F]FDPN-PET was performed at week 13 followed by tissue fixation for immunohistochemistry at week 14. PET, positron emission tomography.
Figure 2.
Figure 2.
Neuropathic pain–induced deficits in hypersensitivity and anhedonia. (A) Repeated-measures 2-way ANOVA analysis of mechanical thresholds yielded a significant group × time effect (F2,86 = 94.7, P < 0.001). Although post hoc assessment showed no difference in mechanical threshold between the 2 groups before surgery, at both 1 week and 3 months after surgery, nerve-injured rats had a significantly lower withdrawal thresholds compared with controls. (B) A significant group × time effect (F2,86 = 17.5, P < 0.001) was also found for cold sensitivity. Post hoc analysis showed significant differences between groups at both postsurgery time points but not at baseline. (C) Repeated-measures 2-way ANOVA analysis of sucrose preference yielded a significant group × time effect (F1,43 = 5.02, P = 0.030). Data are presented as mean ± SEM. ***P < 0.001 compared with control group. ANOVA, analysis of variance; BL, baseline; SNI, spared nerve injury.
Figure 3.
Figure 3.
[18F]-FDPN tracer binding in the control rat brain to validate the tracer. Values displayed are normalized with the cerebellum as reference region, mean ± SD. A 1-way ANOVA contrasting all brain regions was found to be significant F22,368 = 284.251, P < 0.001 with post hoc analysis contrasting each brain region to the cerebellum found each region to be significantly different from the cerebellum, which is devoid of opioid receptors (P < 0.001). ACC, anterior cingulate cortex; ANOVA, analysis of variance; MCC, mid-cingulate cortex; PAG, periaqueductal gray; PET, positron emission tomography; PFC, prefrontal cortex.
Figure 4.
Figure 4.
Reduced opioid receptor availability in the striatum. Less opioid receptor availability (P < 0.01, cluster corrected) was observed in nerve-injured rats than control rats in the ipsilateral anterior insula (Ant Ins), ipsilateral caudate–putamen (CPu), contralateral posterior insula (Post Ins), and contralateral M1/M2. There were no clusters or any single voxels that exceeded the significance threshold for the contrast of SNI > sham. SNI, spared nerve injury.
Figure 5.
Figure 5.
Reduced MOR1 expression in the striatum. (A) Representative images and quantification of NeuN-ir, neuron cell body count. Representative images taken from the caudate-putamen (CPu) at 4× magnification (insets at 20× represent region of CPu used for analysis), as well as the anterior insula (Ant Ins) and posterior insula (Post Ins) at 20× magnification. No significant difference in neuronal cell body count was observed between nerve-injured and control rats (F1,42 = 0.936, P = 0.339). (B) Representative images and quantification of ENK-ir (enkephalin immunoreactivity). No significant difference in ENK-ir was observed between nerve-injured and control rats (F1,42 = 0.166, P = 0.685). (C) Representative images and quantification of MOR1-ir (mu-opioid receptor immunoreactivity). A significant difference in MOR1-ir was observed between groups over 3 brain regions (F1,42 = 8.092, P = 0.007). Post hoc tests showed chronic pain to be associated with lower MOR1-ir intensity in 2 of the 3 brain regions: the CPu (SNI = 8437 ± 437; sham = 9832 ± 358; P = 0.048) and anterior insula (SNI = 8862 ± 452; sham = 10,390 ± 398; P = 0.031). The posterior insula (SNI = 9531 ± 620; sham = 9986 ± 587; P = 0.510) was not significantly different between groups. *P < 0.05. SNI, spared nerve injury.
Figure 6.
Figure 6.
Postinjury sucrose hedonics positively associated with [18F]-FDPN binding and MOR1 expression in the Cpu. (A) Sucrose preference scores of the nerve-injured rats at 3 months after surgery were positively correlated with opioid receptor availability in the caudate–putamen (R = 0.500, P = 0.041, n = 17) as well as with (B) MOR1-ir intensity in the caudate–putamen (R = 0.799, P = 0.017, n = 8). Sucrose preference for the sham group was not significantly correlated with either (A) opioid receptor availability (R = 0.169, P = 0.516) or (B) MOR1-ir intensity (R = 0.182, P = 0.667). P < 0.05 was considered significant in all cases. *P < 0.05. SNI, spared nerve injury.

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