Increasing Pain Sensation Eliminates the Inhibitory Effect of Depression on Evoked Pain in Rats.

Although previous studies have suggested that depression may be associated with inhibition of evoked pain but facilitation of spontaneous pain, the mechanisms underlying these relationships are unclear. The present study investigated whether the difference between evoked and spontaneous pain on sensory (descending inhibition) and affective (avoidance motivation) components contributes to the divergent effects of depression on them. Depressive-like behavior was produced in male Wistar rats by unpredictable chronic mild stress (UCMS). Tone-laser conditioning and formalin-induced conditioned place avoidance (F-CPA) were used to explore avoidance motivation in evoked and spontaneous pain, respectively. Behavioral pharmacology experiments were conducted to examine descending inhibition of both evoked (thermal stimulation) and spontaneous pain behavior (formalin pain). The results revealed that the inhibitory effect of depression on evoked pain was eliminated following repeated thermal stimuli. Avoidance behavior in the tone-laser conditioning task was reduced in UCMS rats, relative to controls. However, avoidance motivation for formalin pain in the UCMS group was similar to controls. 5-HT1A receptor antagonism interfered with inhibition of pain responses over time. The present study demonstrated that the inhibitory effect of depression on evoked pain dissipates with increased nociception and that the sensory-discriminative and affective-motivational components of pain are jointly involved in the divergent effects of depression on pain.

Chronic administration of 5-HT1A receptor agonist relieves depression and depression-induced hypoalgesia.

Previous studies have shown that depressed patients as well as animal models of depression exhibit decreased sensitivity to evoked pain stimuli, and serotonin is indicated to be involved in depression-induced hypoalgesia. The purpose of this study was to investigate the potential role of 5-HT1A receptor in the depression-induced hypoalgesia. Acute or chronic administration of 5-HT1A receptor agonist, 8-OH-DPAT, was performed in olfactory bulbectomy (OB) and sham-operated rats. The depression-like behavior and pain thresholds were measured using open-field test and radiant heat thermal pain test, respectively. We found that acute administration of 8-OH-DPAT increased locomotor activity and pain thresholds in the sham rats but had no effect on the OB rats. In contrast, chronic administration of 8-OH-DPAT reduced locomotor activity and pain thresholds and restored them to normal level. Increased pain thresholds were also observed in the sham rats after the chronic administration. These results demonstrated that chronic administration of 8-OH-DPAT reversed the depression-induced decrease in pain sensitivity in rats, suggesting that 5-HT1A receptor may play a role in the depression-associated hypoalgesia.

Depressive-like history alters persistent pain behavior in rats: Opposite contribution of frontal cortex and amygdala implied.

Numerous studies have shown that pain perception is strongly influenced by depression. However, very few studies have examined whether pain perception is altered in the remission period of depression, and what role the fronto-limbic circuits may play in the behavioral changes associated with remission. Using an unpredictable chronic mild stress (UCMS) animal model of depression, the present study investigated pain-related behaviors in rats with prior exposure to a UCMS stimulus. The γ-aminobutyric acid (GABA)A receptor agonist muscimol was microinjected bilaterally into the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) to examine the modulation of pain by these brain regions in the recovery state. Rats with a depression-like history displayed increased ongoing pain behavior in the formalin test, although their thermal pain thresholds were unchanged. Intra-BLA muscimol during the recovery phase dramatically decreased formalin-induced pain behavior and also significantly increased rats' sucrose preference. By contrast, in the mPFC, muscimol produced the opposite effect, suggesting different, perhaps opposing, roles of the BLA and mPFC in mediating the influence of prior UCMS exposure on pain perception. Taken together, these results demonstrated that a depressive experience may cause long-term alterations in limbic circuit excitability and thus lead to long-lasting changes in pain perception.

Increased thermal and mechanical nociceptive thresholds in rats with depressive-like behaviors.

Clinical observations suggest that depressed patients were less sensitive to experimental pain than healthy subjects. However, few animal studies are reported concerning the association of depression and pain. The purpose of this study was to investigate the effects of unpredictable chronic mild stress (UCMS) induced depression on the perceived intensity of painful stimulation in rats. We measured the thermal and mechanical paw withdrawal thresholds (PWT) of normal and spinal nerve ligated (SNL) rats using hot plate test and von Frey test, respectively. The results showed that rats exposed to UCMS exhibited significantly higher thermal and mechanical pain thresholds in comparison to the non-depressed controls. In particular, the PWT of the SNL group was restored to nearly normal level after three weeks of UCMS, and even comparable to that of the control group. These results strongly suggest that the depressed subjects have decreased sensitivity to externally applied noxious stimulation, which is consistent with our previous findings.

The differential effects of depression on evoked and spontaneous pain behaviors in olfactory bulbectomized rats.

Although it has been accepted that depression and pain are common comorbidities, their interaction is not fully understood. The current study was aimed to investigate the effects of depression on both evoked pain behavior (thermal-induced nociception) and spontaneous pain behavior (formalin pain) using an olfactory bulbectomy (OB) rat model of depression. Emotional behaviors were assessed by open field and Morris water maze tests. The results showed that the depressed rats exhibited stronger tolerance to noxious thermal stimulation compared to non-depressed animals. In contrast, the spontaneous nociceptive behaviors induced by formalin injection were significantly enhanced in the OB rats in comparison to control rats. These results demonstrated that depression can have differential effects on stimulus-evoked pain and spontaneous pain, with alleviation in the former while aggravation in the latter. The present study has confirmed our previous findings that depression can inhibit evoked pain but facilitate spontaneous pain, and provides evidence that the OB depression model is a feasible model for studying the relationship between depression and pain.