The Occurrence of Pain-Induced Depression Is Different between Rat Models of Inflammatory and Neuropathic Pain

Abstract

Various pain conditions may be associated with depressed mood. However, the effect of inflammatory or neuropathic pain on depression-like behavior and its associated time frame has not been well established in rat models. This frontward study investigated the differences in pain behavior, depression-like behavior, and serotonin transporter (SERT) distribution in the brain between rats subjected to spared nerve injury (SNI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain. A dynamic plantar aesthesiometer and an acetone spray test were used to evaluate mechanical and cold allodynia responses, and depression-like behavior was examined using a forced swimming test and sucrose preference test. We also investigated SERT expression by using positron emission tomography. We found that the inflammation-induced pain was less severe than neuropathic pain from days 3 to 28 after induced pain; however, the CFA-injected rats exhibited more noticeable depression-like behavior and had significantly reduced SERT expression in the brain regions (thalamus and striatum) at an early stage (on days 14, 21, and 28 in two groups of CFA-injected rats versus day 28 in SNI rats). We speculated that not only the pain response after initial injury but also the subsequent neuroinflammation may have been the crucial factors influencing depression-like behavior in rats.

Keywords: depression-like behavior; inflammatory pain; neuropathic pain; positron emission tomography; serotonin transporter.

Figure 1

(A) PWT for the mechanical allodynia test. Rats were randomly assigned to one of four experimental groups (n = 6): the sham (without nerve injury, injection of normal saline) group (●), SNI (nerve injury, injection of normal saline) group (○), CFA (without nerve injury, injection of CFA) group (▼), and diluted CFA (without nerve injury, injection of diluted CFA) group (△). Mechanical allodynia responses were examined using a DPA. * p  <  0.05 compared with the sham group. # p  <  0.05 compared with the SNI group. (F(3, 20) = 5.443; F(3,20) = 169.517; F(3,20) =116.519; F(3,20) = 50.419; F(3,20) = 87.124; F(3,20) = 246.681; F(3,20) = 374.424). (B) Latency time of the cold allodynia test. Behavioral responses in the four groups. * p  <  0.05 compared with the sham group. # p  <  0.05 compared with the SNI group. (F(3,20) = 2.458; F(3,20) = 13.777; F(3,20) = 24.516; F(3,20) = 50.872; F(3,20) = 140.446; F(3,20) =106.188; F(3,20) =263.093).

Figure 2

(A) Photographs of the footpads of rats 1 day after the injection of 100 μL of saline or CFA. From left to right are the sham, SNI, CFA, and diluted CFA groups. (B) Paw thickness changes (%) = (surgical side/contralateral side). * p  <  0.05 compared with the sham group. + p  <  0.05 compared with the SNI group, n = 6. (C) The enhanced chemokine expression of TMP-1 and CXCL1 induced by CFA on day 1. * p  <  0.05 compared with the sham group. (F(1,10) = 6.493).

Figure 3

FST rat immobility scores on days 7, 14, 21, and 28. Results are expressed as mean ± standard deviation. * p  <  0.05 compared with the sham group. # p  <  0.05 compared with the SNI group. Each group had six rats. (F(3,20) = 0.976; F(3,20) = 8.419; F(3,20) = 12.46; F(3,20) = 20.085).

Figure 4

SPT percentage on days 7, 14, 21, and 28. Results are expressed as mean ± standard deviation. * p  <  0.05 compared with the sham group. # p  <  0.05 compared with the SNI group. Each group had six rats. (F(3,20) = 0.547; F(3,20) = 6.428; F(3,20) = 5.46; F(3,20) = 14.023).

Figure 5

PET images of rat brains and SURs on (A) day 7, (B) day 14, (C) day 21, and (D) day 28. The black arrow indicates the thalamus region, and the blue arrow indicates the striatum region. Results are expressed as mean ± standard deviation. * p  <  0.05 compared with the sham group. # p  <  0.05 compared with the SNI group. Each group had six rats. Thalamus SUR (F(3,20) = 11.354; F(3,20) = 59.193; F(3,20) = 15.721; F(3,20) = 17.149), striatum SUR (F(3,20) = 2.522; F(3,20) = 41.563; F(3,20) = 17.488; F(3,20) =27.399).