Previous animal studies have illustrated a modulatory effect of neonatal pain experience on subsequent pain-related behaviors. However, the relationship between chronic pain status in adulthood and future pain perception remains unclear.

Temporal estimation can be influenced by pain, which is a complex psychological and physiological phenomenon. However, the time range in which perception is most sensitive to pain remains unclear.

The ability to encode noxious stimulus intensity is essential for the neural processing of pain perception. It is well accepted that the intensity information is transmitted within both sensory and affective pathways. However, it remains unclear what the encoding patterns are in the thalamocortical brain regions, and whether the dual pain systems share similar responsibility in intensity coding.

Time perception is an important ability that is related closely to humans' and animals' daily activities. It can be distorted by various emotional states. In human studies, experimental pain has been shown to prolong the perception of time. However, related animal studies are lacking. In this study, we used a temporal bisection task to investigate how acute inflammatory pain (induced by hind-paw formalin injection) and chronic neuropathic pain [induced by spinal nerve ligation (SNL)] affected time perception in rats. Rats were trained to recognize "short" (1200-ms) and "long" (2400-ms) anchor-duration pure tones and were rewarded for corresponding lever presses. During testing, rats perceived a series of intermediate-duration and anchor-duration pure tones, and selected levers corresponding to the "short" and "long" tones. After formalin injection, rats gave more "long" lever-press responses than after saline injection. The point of subjective equality after formalin injection also increased, suggesting that formalin-induced acute pain extended time perception. In contrast, rats that had undergone SNL gave fewer "long" lever-press responses compared with the sham surgery group. This animal study suggests that formalin-induced pain and neuropathic pain may have different effects on time perception.

It is well accepted that peripheral electrical stimulation (PES) can produce an analgesic effect in patients with acute and chronic pain. However, the neural basis underlying stimulation-induced analgesia remains unclear. In the present study, we examined the pain-related neural activity modified by peripheral stimulation in rats. The stimulation frequency of pulses applied to needle electrodes in the hindlimb was 2 Hz alternating with 100 Hz, with 0.6 ms pulse width for 2 Hz and 0.2 ms for 100 Hz. The intensity of the stimulation was increased stepwise from 1 to 3 mA with each 1-mA step lasting for 10 min. The nociceptive neural and behavioral responses were examined immediately after the termination of stimulation. Using a multiple-channel recording technique, we simultaneously recorded the activity of many single neurons located in the primary somatosensory and anterior cingulate cortex (ACC), as well as the ventral posterior and medial dorsal thalamus in behaving rats. Our results showed that peripheral electrical stimulation significantly reduced the nociceptive responses in ventroposterior thalamus and somatosensory cortex, indicating an inhibition of nociceptive processing. In contrast, the analgesic stimulation produced a significant increase in mediodorsal thalamus while a less significant decrease in cingulate cortex, reflecting a complicated effect associated with combined antinociceptive activation and nociceptive suppression. These results support the idea that peripheral electrical stimulation can ultimately alter the pain perception by specifically inhibiting the nociceptive transmission in the sensory pathway while mobilizing the antinociceptive action in the affective pathway, thus to produce pain relief.

Although depression-induced altered pain perception has been described in several laboratory and clinical studies, its neurobiological mechanism in the central nervous system (CNS), particularly in the spinal dorsal horn, remains unclear. Therefore, in this study, we aimed to clarify whether nociceptive sensitivity of neuropathic pain is altered in the olfactory bulbectomy (OB) model of depression and whether glucocorticoid receptor (GR), which is involved in the etio-pathologic mechanisms of both major depression and neuropathic pain, contributes to these processes in the spinal dorsal horn of male Sprague-Dawley rats. The results showed that mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation (SNL) were attenuated in OB-SNL rats with decreased spinal GR expression and nuclear translocation, whereas non-olfactory bulbectomy (NOB)-SNL rats showed increased spinal GR nuclear translocation. In addition, decreased GR nuclear translocation with normal mechanical nociception and hypoalgesia of thermal nociception were observed in OB-Sham rats. Intrathecal injection (i.t.) of GR agonist dexamethasone (Dex; 4 μg/rat/day for 1 week) eliminated the attenuating effect of depression on nociceptive hypersensitivity in OB-SNL rats and aggravated neuropathic pain in NOB-SNL rats, which was associated with the up-regulation of brain-derived neurotrophic factor (BDNF), TrkB and NR2B expression in the spinal dorsal horn. The present study shows that depression attenuates the mechanical allodynia and thermal hyperalgesia of neuropathic pain and suggests that altered spinal GR-BDNF-TrkB signaling may be one of the reasons for depression-induced hypoalgesia.