P2X7 receptor mediates activation of microglial cells in prostate of chemically irritated rats

Abstract

Purpose: Evidence shows that adenosine triphosphate (ATP) is involved in the transmission of multiple chronic pain via P 2 X 7 receptor. This study was to investigate the P 2 X 7 and microglial cells in the chronic prostatitis pain. Materials and Methods: Rats were divided into control group and chronic prostatitis group (n = 24 per group). A chronic prostatitis animal model was established by injecting complete Freund's adjuvant (CFA) to the prostate of rats, and the thermal withdrawal latency (TWL) was detected on days 0, 4, 12 and 24 (n = 6 at each time point in each group). Animals were sacrificed and the pathological examination of the prostate, detection of mRNA expression of P 2 X 7 and ionized calcium binding adaptor molecule 1 (IBA-1) and measurement of content of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the dorsal horn of L 5 -S 2 spinal cord were performed on days 0, 4, 12 and 24. In addition, the content of TNF-α and IL-1β in the dorsal horn of L 5 -S 2 spinal cord was measured after intrathecal injection of inhibitors of microglial cells and/or P 2 X 7 for 5 days. Results: The chronic prostatitis was confirmed by pathological examination. The expression of P 2 X 7 and IBA-1 and the content of TNF-α and IL-1β in rats with chronic prostatitis were significantly higher than those in the control group. On day 4, the expressions of pro-inflammatory cytokines became to increase, reaching a maximal level on day 12 and started to reduce on day 24, but remained higher than that in the control group. Following suppression of microglial cells and P 2 X 7 receptor, the secretion of TNF-α and IL-1β was markedly reduced. Conclusion: In chronic prostatitis pain, the microglial cells and P 2 X 7 receptor are activated resulting in the increased expression of TNF-α and IL-1β in the L 5 -S 2 spinal cord, which might attribute to the maintenance and intensification of pain in chronic prostatitis. INTRODUCTIONChronic prostatitis, a common urological condition in young and middle-age men, is caused by multiple etiological factors. Pain is a major presentation of chronic prostatitis (1). Previous studies focused on the pathological changes in the prostate, while the pathways related to neurotransmission and the regulatory mechanisms of chronic prostatitis pain have not been studied. Recent studies have identified the chronic prostatitis pain as a visceral referred pain, which is usually accompanied by the dysfunction of pelvic floor muscles. The prostate is innervated largely by the pelvic nerves arising from the L 5 -S 2 spinal cord (2,3). P2X7 receptor mediates activation of microglial cells in prostate of chemically irritated rats _______________________________________________ 277It has also been shown that the transmission and regulation of pain are associated with not only the neurons but the microglia and astrocytes (4,5). Studies also demonstrated that astrocytes and microglias may secrete pro-inflammatory cytokines such as tumor necrosis factors (TNF), interleukin-1 (IL-1), nerve growth fac...

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

“…3 , 144 , 145 Spinal microglia been found to contribute to pain in male animals with chronic prostatitis. 146 , 147 To our knowledge, however, there are currently no comprehensive studies investigating glial contributions to pain associated with visceral diseases that have been restricted to, or with a substantial focus on, females. This alternative scope in research could reveal distinct female pain mechanisms that may be exploited to improve pain management.…”

Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

“…After stimulating the bladder and prostate with acetic acid or formalin, the number of c-fos-positive cells in the lumbosacral spinal cord was significantly increased [10], indicating that the lumbosacral spinal cord is involved in the neural circuit of prostate pain. Furthermore, immunohistochemistry and pharmacological blockade experiments have also illustrated that CP/CPPS can activate microglia in the rat L5-S2 spinal cord through the P2X7 receptor [11, 12] and that inhibition of microglia activation can alleviate persistent prostate pain [11]. There is increasing evidence that spinal microglia and astrocytes play important roles in chronic pain sensitization by releasing cellular mediators such as cytokines, chemokines, and growth factors [13–15].…”

Involvement of microglial P2X7 receptor in pain modulation

“…105 Similarly, in urological diseases like chronic prostatitis, characterized by painful symptoms, microglial activation in the posterior horn of spinal cord and heightened P2X7R expression were observed. 106 Overall, P2X7R emerges as a central player in the onset, progression, and regression of multiple inflammation-induced pain-related diseases.…”

“…Bmk I, a sodium channel activator and inflammation/pain mediator, was found to upregulate microglial P2X7R expression in the dorsal horn of the spinal cord through plantar injections, activating the p38 pathway and inducing substantial IL‐1β production, ultimately suppressing inflammatory pain 105 . Similarly, in urological diseases like chronic prostatitis, characterized by painful symptoms, microglial activation in the posterior horn of spinal cord and heightened P2X7R expression were observed 106 . Overall, P2X7R emerges as a central player in the onset, progression, and regression of multiple inflammation‐induced pain‐related diseases.…”