Depression shows divergent effects on evoked and spontaneous pain behaviors in rats

Abstract

Although it has been accepted that depression and pain are common comorbidities, their interaction is not fully understood. The present study was aimed to investigate the effects of depression on both evoked pain behavior (thermal-induced nociception and hyperalgesia) and spontaneous pain behavior (formalin pain) in rats. An unpredictable chronic mild stress (UCMS) paradigm was employed to develop a classical depression. The emotional behaviors were assessed by sucrose preference test, open field test, and elevated plus-maze test. The results showed that the depressed rats always exhibited stronger tolerance to noxious thermal stimulation under both normal and complete Freund's adjuvant (CFA)-induced chronic pain conditions, when compared to nondepressed animals. Interestingly, the spontaneous nociceptive behaviors induced by formalin injection were significantly enhanced in rats exposed to UCMS in comparison to those without UCMS. Systemic administration of antidepressant fluoxetine significantly restored the nociceptive behaviors to normal level in depressed animals. An additional finding was that the inflammatory rats tended to display depressive-like behaviors without being exposed to UCMS. These results demonstrated that depression can have different effects on stimulus-evoked pain and spontaneous pain, with alleviation in the former while aggravation in the latter.

Perspective: The present study provides evidence that depression can have divergent effects on stimulus-evoked and spontaneous pain by confirming that rats exposed to chronic mild stress tend to exhibit decreased pain sensitivity to experimental stimuli but increased intensity of ongoing pain. This may contribute to further understanding of the perplexing relationship between clinical depression and chronic pain.

Fig 1

The depressive-like behaviors after six weeks of UCMS procedure. (A) Body weight. Over the six-week UCMS exposure, the body weights in the UCMS group were significantly decreased (n = 46 – 47). (B) Sucrose preference. Two weeks after UCMS, there was a significant reduction in sucrose consumption in the UCMS-exposed rats (n = 47 – 48). (C) Locomotor behaviors. The UCMS-treated rats displayed significantly higher level of activity and lower level of exploratory behavior compared to the control group (n = 24). (D) EPM test. The time spent in the open arms significantly prolonged in the UCMS group in comparison to that in the control group (n = 25 – 26). (E) Activity of HPA. The adrenal weights in the UCMS group were significantly increased, but the concentration of plasma corticosterone did not change (n = 17 – 18). Data are presented as mean ± SEM. * P < 0.05; ** P < 0.01; *** P < 0.001, compared to their respective control group.

Fig. 2

The effect of depression on the evoked versus spontaneous pain behaviors. (A) Acute thermal evoked pain. The paw withdrawal latency (PWL) to noxious heat stimuli was significantly increased in the stressed rats (n = 16). (B) Thermal-evoked hyperalgesia in chronic pain state. During the UCMS procedure, CFA was injected into the rat hind paw to induce chronic inflammatory pain. The PWL was significantly higher in the UCMS-exposed rats than the nonstressed ones (n = 16). (C1-2) Spontaneous pain. Subcutaneous injection of formalin into the rat hind paw was used to produce spontaneous pain. Compared with the control rats, the licking behaviors in the UCMS rats were significantly enhanced in the early and late phases as well as in the interphase (n = 16 – 17). Data are presented as mean ± SEM. * P < 0.05; ** P < 0.01; *** P < 0.001, compared to their respective control group.

Fig. 3

The correlation between nociceptive behaviors and sucrose preference. There is a negative correlation between sucrose preference and thermal pain thresholds in both the acute (A) and chronic pain (B) states. Also, the intensity of spontaneous pain induced by formalin is negtively correlated with sucrose consumption in the early and late phases as well as in the interphase (C).

Fig. 4

The therapeutical effect of fluoxetine on depression. Rats recieved fluoxetine (10 mg/kg/day, IP) administration for consecutive 21 days. Fluoxetine treatment significantly reversed sucrose intake reduction in the UCMS-exposed rats in comparison with those administered with normal saline Data are presented as mean ± SEM. * P < 0.05, *** P < 0.001, compared to their respective non-UCMS group; # P < 0.05, ###, P < 0.001, compared to their respective NS-treated group. n = 12.

Fig. 5

The effect of fluoxetine on the depression-induced changes in pain behavior. In both acute (A) and chronic pain (B) states, the elevated nociceptive thermal thresholds by UCMS exposure were reversed and approached normal level following systemic administration of fluoxetine, indicating the therapeutic effect of fluoxetine as an antidepressant. In addition, the PWLs of rats in the control group were increased by fluoxetine treatment, suggesting an antinociceptive effect of fluoxetine per se. (C1-2) In spontaneous pain state, the enhanced licking behaviors by UCMS exposure were reversed by fluoxetine. Additionally, in control rats, the licking behaviors were suppressed by fluoxetine injection. Data are presented as mean ± SEM. * P < 0.05;** P < 0.01; *** P < 0.001, compared to their respective control group; # P < 0.05; ## P < 0.01; ### P < 0.001, compared to their respective NS-treated group. n = 9–10.

Fig. 6

The depressive-like behaviors resulted from chronic inflammatory pain. The rats with chronic inflammatory pain showed lower sucrose preference (near significant level, B). Other behavioral indices, including body weight (A), OF test (C), and HPA activity (D), did not show significant changes during the development of chronic pain. Data are presented as mean ± SEM. ** P < 0.01, compared to their respective NS-treated group. n = 16.