Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization

Abstract

Background: Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization. Methods: The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function. Results: Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis. Conclusion: Increased CXCR4 in the DRG and SDH contributes to colon inflammationinduced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.

MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study

“…Other investigations have implicated MIF in mediating inflammatory and neuropathic pain [19], and a spinal site of action has been identified [20,30]. In addition, a recent study reported that spinal CXCR4 receptors mediate colon inflammation-induced bladder hyperalgesia in rats [32]. Thus, taken together, previous evidence and our current results suggest that spinal MIF and its receptors play a role in modulating spinal mechanisms mediating pain, particularly persistent bladder pain.…”

Autonomic Nervous System Dysfunction Is Related to Chronic Prostatitis/Chronic Pelvic Pain Syndrome

“…The convergent neurons in the DRG have dichotomous afferents; the cell bodies of sensory nerve fibers from two different organs are present in the same DRG. Therefore, it can be activated due to inflammation in one organ to produce these substances and transfer them to another organ, promoting the occurrence and development of neurogenic inflammation of cross-activation between organs [ 23 24 ]. In addition, sensory nerves play an essential role in the generation and development of pain.…”

“…Additionally, the central centers that direct sympathetic and parasympathetic nerves influence organ functions if activated and sensitive. It is how prostatitis could affect the cardiovascular system, ejaculatory function, skin reactions, and bladder activity [ 23 24 72 ].…”