TRP Channels as Lower Urinary Tract Sensory Targets

Andersson, Karl‐Erik

doi:10.3390/medsci7050067

Cited by 34 publications

(39 citation statements)

References 127 publications

(175 reference statements)

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“…Figure 1 summarizes the mostly interrelated functional roles of insulin and the InsR and the TRPV1 receptor at system, organ and cellular levels. Although the significance of modulation of TRPV1 receptor function in the therapeutic management of pain, inflammatory states and neurogenic dysfunction, such as overactive bladder is now well established [157], further studies are warranted to exploit the possible therapeutic value of the observations summarized in this review. InsRs expressed on PSNs play a significant role in the mechanisms of neurite outgrowth of cultured PSNs and axonal regeneration in vivo.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Lázár

Jancsó

Stella

2020

IJMS

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Insulin, besides its pivotal role in energy metabolism, may also modulate neuronal processes through acting on insulin receptors (InsRs) expressed by neurons of both the central and the peripheral nervous system. Recently, the distribution and functional significance of InsRs localized on a subset of multifunctional primary sensory neurons (PSNs) have been revealed. Systematic investigations into the cellular electrophysiology, neurochemistry and morphological traits of InsR-expressing PSNs indicated complex functional interactions among specific ion channels, proteins and neuropeptides localized in these neurons. Quantitative immunohistochemical studies have revealed disparate localization of the InsRs in somatic and visceral PSNs with a dominance of InsR-positive neurons innervating visceral organs. These findings suggested that visceral spinal PSNs involved in nociceptive and inflammatory processes are more prone to the modulatory effects of insulin than somatic PSNs. Co-localization of the InsR and transient receptor potential vanilloid 1 (TRPV1) receptor with vasoactive neuropeptides calcitonin gene-related peptide and substance P bears of crucial importance in the pathogenesis of inflammatory pathologies affecting visceral organs, such as the pancreas and the urinary bladder. Recent studies have also revealed significant novel aspects of the neurotrophic propensities of insulin with respect to axonal growth, development and regeneration.

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Section: Discussionmentioning

confidence: 99%

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Lázár

Jancsó

Stella

2020

IJMS

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“…TRPA1 is known to contribute to nociceptive responses evoked by endogenous and exogenous irritants (Oyama et al, 2017), including MGO itself (Bierhaus et al, 2012;Eberhardt et al, 2012). On the other hand, TRPV1 and TRPV4 are involved in bladder activity in response to mechanical or chemical stimulus (Andersson, 2019). We found that MGO induced a marked increase in TRPA1 expression, which may account for the bladder hyperreflexia.…”

Section: Discussionmentioning

confidence: 59%

“…Moreover, nonhyperglycemic obese patients may exhibit increased plasma MGO levels (Masania et al, 2016). TRP channels are widely expressed in lower urinary tract tissues and play a critical role in the normal micturition reflex (for review: Andersson, 2019). TRPA1 is known to contribute to nociceptive responses evoked by endogenous and exogenous irritants (Oyama et al, 2017), including MGO itself (Bierhaus et al, 2012;Eberhardt et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, chronic MGO administration to rats causes diabetes-like microvascular changes (Berlanga et al, 2005), contributing to endothelial (Sena et al, 2012) and erectile dysfunctions (Dalaklioglu et al, 2018). In addition, MGO has been shown to activate transient receptor potential (TRP) channels, a superfamily of cation channels involved in several cellular functions, including nociception and mechanosensory transduction in the bladder (Andersson, 2019). Previous studies showed that activation of transient receptor potential ankyrin 1 (TRPA1) by MGO contributes to hyperalgesia in diabetic neuropathy (Bierhaus et al, 2012;Andersson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice

et al. 2020

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Diabetic bladder dysfunction (DBD) is one of the most common complication of diabetes. Methylglyoxal (MGO), a highly reactive dicarbonyl compound formed as a by-product of glycolysis, is found at high levels in plasma of diabetic patients. Here, we explored the effects of chronic administration of MGO on micturition pattern (cystometry) and bladder contractility in vitro in healthy male C57/BL6 mice. Methylglyoxal was given at 0.5% in drinking water for 4 weeks. Exposure to MGO led to bladder tissue disorganization, edema of lamina propria, partial loss of urothelium and multiple leukocyte infiltrates. Filling cystometry revealed significant increases of micturition frequency and number of non-voiding contractions (NVCs) in the MGO group, clearly indicating an overactive bladder profile. Bladder contractions induced by electrical-field stimulation (EFS) and carbachol were significantly higher in the MGO group, while the muscarinic M 2 and M 3 mRNA expressions remained unchanged between groups. Additionally, MGO exposure induced upregulation of TRPA1 and down-regulation of TRPV1 and TRPV4 in bladder tissues. Methylglyoxal did not change the mRNA expression of the advanced glycation end products receptor (RAGE), but markedly increased its downstream NF-κB-iNOS signaling. The mRNA expression of cyclooxygenase-2 (COX-2) and reactive-oxygen species (ROS) levels remained unchanged. Altogether, our data show that 4-week MGO intake in mice produces an overactive bladder phenotype in addition to bladder inflammation and increased NF-kB/iNOS signaling. TRPA1 up-regulation and TRPV1/TRPV4 down-regulation may account for the MGO-induced bladder overactivity. Scavengers of MGO could be an option to ameliorate bladder dysfunction in diabetic conditions.

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“…Additionally, these functions may act upon neurons, but may also be executed through effects on other cell types that express TRPV1 or that modulate neuronal properties. For example, human leukocytes have been reported to express TRPV1 [30], as well as urothelial cells (reviewed by Andersson [31]). Ongoing efforts will help identify IPSE's mechanisms of effect on TRPV1-associated nociception and may contribute to development of IPSE as a novel analgesic.…”

Section: Discussionmentioning

confidence: 99%

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

Ishida

Mbanefo²,

et al. 2020

Preprint

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4-and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin-and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1expressing neurons and/or may rely upon urothelial mechanisms.

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TRP Channels as Lower Urinary Tract Sensory Targets

Cited by 34 publications

References 127 publications

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

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