Abstract
The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.
Highlights
Urinary tract infections (UTI) are the second most common bacterial infection, with about 50% of women developing an infection during their lifetime and about 13% of women experiencing recurrent infections[1]
To explore the role of TRPV1 in post-urinary tract infection (UTI) chronic pain, we examined the effects of the TRPV1 antagonist capsazepine in mice infected with the E. coli strain SΦ874
These results show that post-UTI pain was altered by targeting TRPV1 only when capsazepine was given at the time of infection, suggesting that TRPV1 plays a role in the establishment, of post-UTI chronic pain but not in maintenance of post-UTI pain
Summary
Urinary tract infections (UTI) are the second most common bacterial infection, with about 50% of women developing an infection during their lifetime and about 13% of women experiencing recurrent infections[1]. The host mounts an immune response to clear the bladder of the invading pathogen[4] This is achieved through toll-like receptor 4 (TLR4) recognition of bacterial lipopolysaccharide (LPS) leading to expression of IL-6 and IL-8 and recruitment of neutrophils to infected tissue[4]. UPEC strain NU14 harboring a deletion of the wz* gene cluster that encodes O-antigen exhibited a chronic pain phenotype by inducing chronic pelvic allodynia that persisted after bacterial clearance, whereas complementation of the UPEC wz* deletion mutant with various wz* gene clusters modulated the bacterial pain phenotype[6] This pain modulation included restoring the acute pain phenotype of wild type NU14 by complementing NU14Δwz* with an NU14wz* fosmid or suppressing pain phenotype of NU14Δwz* with a wz* fosmid derived from asymptomatic bacteriuria-associated E. coli strain 83972, a strain that exhibits an analgesic phenotype[7]. The percent change of behavioral responses relative to baseline at PID 0. (B) Numerical change in behavioral responses relative to baseline (*P < 0.05)
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