Experimental autoimmune prostatitis induces microglial activation in the spinal cord

Wong, Larry; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen

doi:10.1002/pros.22891

Cited by 32 publications

(46 citation statements)

References 44 publications

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“…Our study revealed that TRPV1 KO mice with EAP (TRPV1 KO‐EAP) do not show evidence of sensitization or changes in response frequency at any time point compared to naive TRPV1 KO (TRPV1 KO‐Naive) mice (Figure A). In contrast, B6 mice with EAP have an increased response frequency compared to naive cohorts at days 7, 14, and 20 (Figure B) with this response known to be chronic beyond day 20 (an additional 17 days) . The present data suggests that TRPV1 channels play an essential role in the development of pelvic tactile allodynia in our mouse model of CP/CPPS.…”

Section: Resultsmentioning

confidence: 55%

TRPV1 in experimental autoimmune prostatitis

et al. 2019

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Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS. Methods Male C57BL/6J (B6) and TRPV1 knockout (TRPV1 KO) mice (5‐7 weeks old) were used to study the development of pelvic allodynia in a murine model of CP/CPPS called experimental autoimmune prostatitis (EAP). The prostate lobes, dorsal root ganglia (DRG), and spinal cord were excised at day 20. The prostate lobes were assessed for inflammation, TRPV1 expression, and mast cell activity. DRG and spinal cord, between the L6‐S4 regions, were analyzed to determine the levels of phosphorylated ERK1/2 (p‐ERK 1/2). To examine the therapeutic potential of TRPV1, B6 mice with EAP received intraurethral infusion of a TRPV1 antagonist at day 20 (repeated every 2 days) and pelvic pain was evaluated at days 20, 25, 30, and 35. Results Our data showed that B6 mice with EAP developed pelvic tactile allodynia at days 7, 14, and 20. In contrast, TRPV1 KO mice with EAP do not develop pelvic tactile allodynia at any time point. Although we observed no change in the levels of TRPV1 protein expression in the prostate from B6 mice with EAP, there was evidence of significant inflammation and elevated mast cell activation. Interestingly, the prostate from TRPV1 KO mice with EAP showed a lack of mast cell activation despite evidence of prostate inflammation. Next, we observed a significant increase of p‐ERK1/2 in the DRG and spinal cord from B6 mice with EAP; however, p‐ERK1/2 expression was unaltered in TRPV1 KO mice with EAP. Finally, we confirmed that intraurethral administration of a TRPV1 antagonist peptide reduced pelvic tactile allodynia in B6 mice with EAP after day 20. Conclusions We demonstrated that in a murine model of CP/CPPS, the TRPV1 channel is key to persistent pelvic tactile allodynia and blocking TRPV1 in the prostate may be a promising strategy to quell chronic pelvic pain.

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Section: Resultsmentioning

confidence: 55%

TRPV1 in experimental autoimmune prostatitis

et al. 2019

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“…EAP induced chronic pelvic pain, which is consistent with many other studies. Many proinflammatory cytokines in the prostate are associated with peripheral and central neuronal signaling, resulting in pelvic pain . We found for the first time that HCP too leads to chronic pelvic pain.…”

Section: Discussionmentioning

confidence: 67%

“…Many proinflammatory cytokines in the prostate are associated with peripheral and central neuronal signaling, resulting in pelvic pain. 10,21 We found for the first time that HCP too leads to chronic pelvic pain. We do not yet know the mechanisms of induction of chronic pelvic pain in the HCP model, but we previously observed inflammation and fibrosis accompanied by a significant increase in the protein levels of TNF-α, IL-6, and IL-8 in the inflamed prostate.…”

Section: Discussionmentioning

confidence: 82%

Voiding behavior and chronic pelvic pain in two types of rat nonbacterial prostatitis models: Attenuation of chronic pelvic pain by repeated administration of tadalafil

et al. 2018

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Background Experimental autoimmune prostatitis (EAP) and prostatitis induced by 17β‐estradiol treatment combined with castration (hormone/castration‐induced prostatitis; HCP) are the most commonly used rodent models of nonbacterial prostatitis. We studied the effect of the phosphodiesterase 5 inhibitor tadalafil on chronic pelvic pain in two such models in rats. Methods EAP was induced by intradermal injection of rat prostate antigen and complete Freund's adjuvant on Days 0 and 28. HCP was induced by castration followed by daily subcutaneous injection of 17β‐estradiol for 30 days. On Day 42 after antigen injection in the EAP model and Day 30 after castration in the HCP model, we investigated voiding behavior, pelvic pain (measured by applying von Frey filaments to the lower abdomen), and inflammatory changes, including changes in histopathology and IL‐1β, CCL2, and CCL3 mRNA levels. We investigated the effect of repeated administration of tadalafil on chronic pelvic pain in both models. Results In the EAP model, we observed inflammation in the ventral prostate, while in the HCP model, we observed inflammation in the lateral lobe of the prostate. Neither model showed any change in voiding behavior. As well as in the EAP model, in which chronic pelvic pain was observed, we found for the first time that HCP led to a significant increase in chronic pelvic pain. Repeated treatment with tadalafil attenuated the chronic pelvic pain in both models. Conclusions Chronic pelvic pain was induced in both EAP and HCP models. Tadalafil significantly attenuated the chronic pelvic pain in both models.

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“…Among the different chemokines able to activate CCR1 [15], CCL3 (MIP-1a, macrophage inflammatory protein-1a) and CCL5 (RANTES, reduced upon activation normal T-cell expressed and secreted) are particularly related to nociception. CCL3 mRNA is up-regulated in the spinal cord of inflamed rats [16] and the spinal expression of CCL3 increases in mice with prostatitis [17] or nerve injury [11] being its neutralization with a specific antibody able to evoke analgesic effects [12]. CCL5 has been also previously related to hypernociceptive reactions associated with neuropathic injury [18] and tumour development [10,19,20].…”

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confidence: 98%

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

Llorián-Salvador

González-Rodríguez

Lastra

et al. 2016

Basic Clin Pharma Tox

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Chemokines are chemotactic cytokines whose involvement in nociceptive processing is being increasingly recognized. Based on the previous description of the involvement of CC chemokine receptor type 1 (CCR1) in pathological pain, we have assessed the participation of CCR1 and its endogenous ligands CCL3 and CCL5 in hyperalgesia and allodynia in mice after acute inflammation with carrageenan and chronic inflammation with complete Freund's adjuvant (CFA). The subcutaneous administration of the CCR1 antagonist J113863 (3-30 mg/kg; 30 min. before) dose dependently inhibited carrageenan-and CFA-evoked thermal hyperalgesia and mechanical allodynia produced by CFA, but not by carrageenan. The maximal dose of J113863 did not modify the increase in paw thickness induced by carrageenan or CFA. An almost ten times augmentation of CCL3 levels was detected by ELISA assays in both carrageenan and CFA paws, but not in spinal cords of inflamed mice, whereas CCL5 concentrations remained unaltered. Accordingly, a marked increase of CCL3 mRNA expression was observed in inflamed paws, with CCL3 protein detected in neutrophils and macrophages by immunohistochemical experiments. The intraplantar administration of an anti-CCL3 antibody (0.3-3 lg) blocked thermal hyperalgesia in carrageenan-and CFA-inflamed mice as well as CFA-evoked mechanical allodynia. Our data suggest that the increased concentrations of CCL3 present in inflamed tissues can be involved in acute and chronic inflammatory hyperalgesia as well as in chronic mechanical allodynia, and that these hypernociceptive symptoms can be counteracted by its neutralization with an antibody or by the blockade of CCR1 receptors.Chemokines are chemotactic cytokines involved in inflammatory processes, mainly by favouring immune cell recruitment. Several chemokines activate nociceptive pathways at both peripheral and central level, and this explains their participation in different types of pathological pain [1][2][3][4]. CC chemokine receptor type 1 (CCR1) is expressed in neurons of dorsal root ganglia (DRG) [5,6] as well as in central structures related to pain [7,8]. The stimulation of CCR1 expressed in nociceptors causes Ca 2+ influx and enhances capsaicin responsiveness [6], and the local administration of CCR1 agonists elicits nociceptive behaviours in mice [9,10]. CCR1 is up-regulated in sensory neurons [11] and the spinal cord [7,12] after nerve injury and increased CCR1 mRNA has also been measured in rats 24 hr after receiving carrageenan [13], supporting its involvement in nociceptive processing. Functionally, it has been reported that some types of neuropathic pain can be alleviated by blocking CCR1 expression with siRNA [11], and that the administration of a CCR1 antagonist can prevent some types of murine bone cancer pain [10] and partially reduce writhing responses in mice receiving intraperitoneal acetic acid or mechanical hyperalgesia in inflamed mice [14]. Among the different chemokines able to activate CCR1 [15], CCL3 (MIP-1a, macrophage inflammatory protein-1...

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Experimental autoimmune prostatitis induces microglial activation in the spinal cord

Cited by 32 publications

References 44 publications

TRPV1 in experimental autoimmune prostatitis

TRPV1 in experimental autoimmune prostatitis

Voiding behavior and chronic pelvic pain in two types of rat nonbacterial prostatitis models: Attenuation of chronic pelvic pain by repeated administration of tadalafil

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

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