Abstract
Stress has been shown to enhance pain sensitivity resulting in stress-induced hyperalgesia. However, the underlying mechanisms have yet to be elucidated. Using single-prolonged stress combined with Complete Freund’s Adjuvant injection model, we explored the reciprocal regulatory relationship between neurons and microglia, which is critical for the maintenance of posttraumatic stress disorder (PTSD)-induced hyperalgesia. In our assay, significant mechanical allodynia was observed. Additionally, activated neurons in spinal dorsal horn were observed by analysis of Fos expression. And, microglia were also significantly activated with the presence of increased Iba-1 expression. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or minocycline (a specific microglia inhibitor) attenuated mechanical allodynia. Moreover, intrathecal administration of c-fos ASO significantly suppressed the activation of neurons and microglia. Interestingly, inhibition of microglia activation by minocycline significantly suppressed the activation of both neurons and microglia in spinal dorsal horn. P38 inhibitor SB203580 suppressed IL-6 production, and inhibition of IL-6 receptor (IL-6R) activation by tocilizumab suppressed Fos expression. Together, our data suggest that the presence of a “crosstalk” between activated microglia and neurons in the spinal dorsal horn, which might contribute to the stress-induced hyperactivated state, leading to an increased pain sensitivity.
Highlights
Chronic pain occurs after damage or dysfunction of peripheral and central sensory pathways, or after tissue inflammation[1]
Previous results showed that paw withdrawal threshold (PWT) were significantly reduced in the single prolonged stress (SPS) group from day seven (P < 0.05), the complete Freund’s adjuvant (CFA) group after CFA injection (P < 0.05), and the SPS + CFA-exposed group (P < 0.01) from day seven compared to the naïve rats
PWT was further reduced in injured hindpaws of the SPS + CFA-exposed rats from day 9 after CFA injection compared to CFA-exposed rats (P < 0.05)[7]
Summary
Chronic pain occurs after damage or dysfunction of peripheral and central sensory pathways (neuropathic pain), or after tissue inflammation (inflammatory pain)[1]. Clinical observations suggest stressful stimuli promote an increase in pain sensitivity, leading to the exacerbation of existing pain[4,5]. These phenomena are collectively termed stress-induced hyperalgesia (SIH)[6,7]. Microglia are found to exist in a hyperactivated state following stress This effect is likely to lead to the potentiation of immune responses, thereby promoting peripheral stimulation[12]. Previous studies showed that activated microglia could contribute to the enhanced pain-like state experienced by stressed mice. It has been suggested that chronic pain develops as a consequence of enhanced neuro-immune signaling and central sensitization in the spinal cord[18]. The molecular mechanisms that underpin this interaction remain to be elucidated
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