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Keywords:

  • bladder pain syndrome;
  • interstitial cystitis;
  • neural cross-talk;
  • sensitization;
  • transient receptor potential A1

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

Although the pathogenesis of interstitial cystitis/bladder pain syndrome remains unknown, there is a significant correlation of interstitial cystitis/bladder pain syndrome with other chronic pain disorders, such as irritable bowel syndrome, endometriosis and fibromyalgia syndrome. In this review, we highlight evidence supporting neural cross-talk in the dorsal root ganglia, spinal cord and brain levels, which might play a role in the development of chronic pain disorders through central sensitization. In addition, we focus on transient receptor potential V1 and transient receptor potential A1 as the receptor targets for chronic pain conditions, because transient receptor potential V1 and transient receptor potential A1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons. Furthermore, peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of transient receptor potential V1 and transient receptor potential A1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously. The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk. Because oxidative stress is considered to induce activation of transient receptor potential A1, we also discuss exogenous and endogenous oxidative stress to elucidate its role in the pathogenesis of interstitial cystitis/bladder pain syndrome and other chronic pain conditions.


Abbreviations & Acronyms
ATP =

adenosine triphosphate

B2 =

bradykinin receptor B2

CGRP =

calcitonin gene-related peptide

DRG =

dorsal root ganglion

EP =

prostaglandin E2 receptor

FMS =

fibromyalgia syndrome

HCl =

hydrochloric acid

HNE =

4-hydroxy-trans-2-nonenal

IBS =

irritable bowel syndrome

IC/BPS =

interstitial cystitis/bladder pain syndrome

NGF =

nerve growth factor

NK1 =

substance P receptor

PAG =

periaqueductal gray

PAR2 =

protease activated receptor 2

PGE2 =

prostaglandin E2

PMC =

pontine micturition center

P2X/P2Y =

ATP receptors

RCS =

reactive carbonyl species

ROS =

reactive oxygen species

TNBS =

trinitrobenzene sulfonic acid

TRKA =

tyrosine kinase receptor A

TRP =

transient receptor potential

TRPA1 =

transient receptor potential A1

TRPV1 =

transient receptor potential V1

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

Although the pathogenesis of IC/BPS often associated with bladder inflammation remains unknown, IC/BPS patients often have comorbidities of other chronic pelvic pain conditions, such as IBS and endometriosis, as well as more systemic pain conditions, such as FMS.1 In fact, over one-third of patients diagnosed with IC/BPS also show symptoms of IBS;2,3 and conversly, 26–56% of patients diagnosed with IBS also have symptoms of IC/BPS.4,5 In other reports, 17–22% of patients with IC/BPS also have concurrent pain of endometriosis,2,6 and as many as 75% of patients with endometriosis also show IC/BPS-like symptoms.7 Furthermore, 12–18% of patients with IC/BPS show symptoms and fulfill diagnostic criteria for FMS;8,9 correspondingly, 23–27% of patients with FMS have IC/BPS-like symptoms, such as bladder fullness, urgency and pelvic pain.8 However, although the pathogenesis of IC/BPS, IBS, FMS and other chronic pain disorders has mostly been studied independently, few investigators have examined multi-organ mechanisms in the development of chronic pain despite their striking clinical overlap.10 The high concurrence rate of chronic pain disorders supports a role of sensitized convergent afferent pathways in peripheral and central nervous systems, which might occur as a result of infectious, inflammatory, neurogenic, metabolic or other neuropathic mechanisms.11

Among various noxious stimulus detectors, the TRP channel family is the largest group, which consists of a large number of cation channels and are divided into six subfamilies: TRPV (vanilloid), TRPA (ankyrin), TRPM (melastatin), TRPC (canonical), TRPP (polycystin) and TRPML (mucolipin) in mammals,12,13 with a particular emphasis on TRPV1 and TRPA1 as the receptor targets for chronic pain disorders and pathological conditions, such as hyperalgesia (exaggerated pain response) and allodynia (pain response to innocuous stimuli).14,15 In addition, tissue injury and inflammation, as well as many chronic and degenerative diseases including diabetes, atherosclerosis, hypertension, ischemia/reperfusion, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, have a strong component of oxidative stress, which occurs when the rate of ROS or RCS generation during normal/aerobic metabolism exceeds the detoxification abilities of the cell.16 During tissue damage and inflammation, ROS such as hydrogen peroxide are generated endogenously by infiltrating macrophages and neutrophils.17,18 Exposure of cellular membranes to inflammatory ROS or exogenous oxidants causes membrane lipid peroxidation, producing RCS, such as HNE and acrolein.19,20 TRPA1 is an essential transduction ion channel expressed in a subset of nociceptive sensory neurons,21 and is activated endogenously or exogenously by oxidative stress,22–24 suggesting that sensitization of TRPA1 might play a central role in chronic pain conditions. The present review highlights evidence supporting sensitization of TRPA1 induced by oxidative stress or other chemicals at peripheral terminals, leading to afferent sensitization and central sensitization through neural cross-talk, which could be involved in the pathophysiology of IC/BPS.

Neural cross-talk in peripheral and central nervous systems

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

Although there are no perfect animal models of IC/BPS, except for a naturally occurring model in cats,25 rodents with intraperitoneal injection of cyclophosphamide,26,27 or with intravesical instillation of mustard oil,28 HCl29 and protamine sulfate30,31 have often been used to study the disease process of IC/BPS. Recently, a rat model of neural cross-talk and sensitization in the pelvic organs developed by Pezzone et al. has shown that acute cystitis induced by intravesical infusion of protamine sulfate combined with potassium chloride to produce an IC/BPS-like model lowered distal colonic sensory thresholds to colorectal distention, and that acute intracolonic irritation with TNBS to produce an IBS-like model led to the development of bladder hypersensitivity.30 In other reports, a rat model with surgically-induced endometriosis had reduced micturition thresholds and increased Evans Blue dye extravasation in the bladder, suggesting that bladder hypersensitivity and inflammation might be induced by uterine irritation as a result of endometriosis.32 Recently, we also have shown that a rat model of FMS induced by HCl injection into the gluteus33 showed plantar hypersensitivity and bladder overactivity, suggesting the possibility that somatic (gluteus muscle)-to-visceral (bladder) cross-sensitization might underlie bladder hypersensitivity in patients with FMS.34

Three different neural mechanisms have been proposed to underlie neural cross-talk and sensitization (Fig. 1).35 The first mechanism is considered to be the presence of DRG neurons with branching or multiple axons, which could serve as direct neuronal connections among different organ domains. The previous studies using dual retrograde labeling in DRG sections have shown that convergent DRG neurons receiving afferent inputs from the distal colon and bladder are identified in 14–17% of the total labeled cells.36,37 The second mechanism is that afferent inputs from an inflamed structure and from other uninflamed structures converge on the same interneuron located in the dorsal horn of the spinal cord. It has been reported that the bladder, cervix and distal colon are innervated by the lumbosacral parasympathetic nerve (pelvic nerves) derived from L6-S2 and the thoracolumbar sympathetic nerve (hypogastric nerves) derived from T13-L1 in rats.11,38,39 The dorsal horns of the T13-L1 and L6-S2 segments have been searched for neurons responsive to gentle mechanical stimulation of the cervix and skin areas at the perineum and hind limbs, and to distention of the colon.40 The cervix-responsive neurons in T13-L1 and L6-S2 responded to the skin stimulation (34% and 38%, respectively), as well as to the colonic distention (59% and 51%, respectively), suggesting that afferent inputs from the pelvic organ (i.e. the cervix and distal colon) and from the skin at the perineum and hind limb regions converge in the dorsal horn of the spinal cord.40 The third mechanism underlying neural cross-talk and sensitization appears to involve higher centers of the brain. It is well known that Barrington's nucleus is the primary component of PMC. The divergent projections of Barrington's nucleus neurons to parasympathetic preganglionic neurons innervating the bladder and the colon have showed that individual neurons within Barrington's nucleus are poised to integrate signals from distal pelvic viscera.41 In addition, the study of medullary reticular formation in the brain stem has shown a significant degree of convergence from the distal colon, rectum and skin at the hind limbs.42 These findings lead us to hypothesize that IC/BPS might be induced by central sensitizaton through neural cross-talk in the DRG, spinal cord and/or brain levels.

image

Figure 1. Schematic representation of neural cross-talk in peripheral and central nervous systems. (i) DRG neurons with branching or multiple axons (blue route). There are 14–17% of convergent DRG neurons receiving afferent inputs from the distal colon and bladder. (ii) Convergence of afferent information in the dorsal horn of the spinal cord (red route). The bladder, cervix and distal colon are innervated by the lumbosacral parasympathetic nerve (pelvic nerves) derived from L6-S2 and the thoracolumbar sympathetic nerve (hypogastric nerves) derived from T13-L1 in rodents. (iii) Convergence of afferent inputs in the brain (green route). There are divergent projections of PMC to the bladder and colon. Afferent inputs from an inflamed structure and from other uninflamed structures converge in the DRG, spinal cord and brain levels, suggesting that neural cross-talk and sensitization might play an important role in the development of IC/BPS and other chronic pain conditions.

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Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

TRPV1 is the best characterized channel of the TRP family in terms of expression pattern, properties and clinical translation of its manipulation.13 Increased TRPV1 expression in the bladder, colon or peritoneum has been found in patients with chronic pelvic pain.43–45 TRPV1 is activated by capsaicin, noxious heat (>43°C) and low pH (a common consequence of inflammation),46,47 showing that TRPV1 can be defined as a polymodal nocisensor. It has been reported in rats that intracolonic application of TNBS can induce urinary frequency, which is abolished by the intracolonic pretreatment of resiniferatoxin as a result of the desensitization of TRPV1 in the colon,48 suggesting that activation of TRPV1 in the colon might be involved in colon-to-bladder cross-sensitization through convergence of TRPV1-expressing pelvic afferents.

In contrast, TRPA1 is a recently identified member of the TRP family that has emerged as a major mediator of inflammatory pain, and is selectively expressed in a subset of nociceptive sensory neurons that also express TRPV1.21 TRPA1 is activated by many pungent chemicals, excluding capsaicin, such as isothiocyanates (mustard, horseradish), cinnamaldehyde (cinnamon) and allicin (garlic),24,49 environmental irritants such as hydrogen peroxide, acrolein and TNBS,22–24 and calcium ions.50 Therefore, TRPA1 can also be regarded as a polymodal nocisensor. Furthermore, the evidence of TRPA1 stimulus through calcium ions raises the possibility that TRPA1 might act as an amplifier of other signals including TRPV1, which increase intracellular calcium concentration during inflammation (Fig. 2),51 and that TRPA1 and TRPV1 mutually control the transduction of noxious stimuli in TRPV1-expressing sensory neurons.52

image

Figure 2. Peripheral sensitization of TRPV1 and TRPA1 during inflammation. TRPV1 and TRPA1 can act as acute polymodal nocisensors and mutually control the transduction of noxious stimuli in TRPV1-expressing sensory neurons. They also play an important role in inflammatory pain and possibly neuropathic pain through peripheral sensitization. TRPV1 and TRPA1 mediate not only an afferent signal to the dorsal horn of the spinal cord, but also a peripheral efferent signal through secretion of inflammatory agents, such as substance P and CGRP, which causes local neurogenic inflammation (green route). Furthermore, peripheral inflammation produces multiple inflammatory mediators such as bradykinin, prostaglandins (PGE2), purines (ATP), proteases and NGF that act on their cognate receptors expressed in nociceptive sensory neurons to activate intracellular signal transduction pathways. These pathways can phosphorylate TRPV1 and TRPA1, and thereby alter their trafficking to the membrane and their activation thresholds and kinetics (blue route). NGF also can increase the expression of TRPV1 and TRPA1 in DRG neurons, which are then transported to the peripheral terminals (purple route).

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Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

According to the American Urological Association guidline, IC/BPS is defined as a symptom complex of unpleasant sensation (pain, pressure, discomfort) percieved to be related to the bladder, associated with lower urinary tract symptoms of more than a 6-week duration,53 suggesting that persistent pain and/or inflammatory conditions would exsist in the bladder. Bladder pathology, such as Hunner's ulcer and bladder bleeding after overdistension, is crucial for the definite diagnosis of IC in the clinical guideline developed by a group of East Asaian urologists.54 Therefore, TRPV1 and TRPA1 receptors could be critically involved in sensitization of nociceptive sensory neurons to stimulate the bladder continuously, although it is not well-known how this sensitization process is acomplished.

TRPV1 and TRPA1 are more than just acute damage sensors that mediate acute nociceptive pain; they also play an important role in inflammatory pain and possibly neuropathic pain through peripheral sensitization (Fig. 2). TRPV1 and TRPA1 mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and CGRP, which causes local neurogenic inflammation.55 Furthermore, peripheral inflammation produces multiple inflammatory mediators, such as bradykinin, prostaglandins (PGE2), purines (ATP), proteases and NGF that act on their cognate receptors expressed in nociceptive sensory neurons to activate intracellular signal transduction pathways.52 These pathways can phosphorylate TRPV1 and TRPA1,56–60 and thereby alter their trafficking to the membrane, and their activation thresholds and kinetics.61–64

In addition, several growth factors produced during inflammation, most notably NGF, are retrogradely transported to the cell body of nociceptors in the DRG.52 These growth factors increase the expression of TRPV1 and TRPA1, which are then transported to the peripheral terminals.65,66 Increased NGF levels in the bladder are detected in patients with IC/BPS.67 In animal experiments, intravesical application of NGF or injection of a viral vector encoding for NGF into the bladder wall induced bladder overactivity.68,69 In addition to the direct effects of NGF on bladder function, NGF might play an important role in neural cross-talk and sensitization, because intravesical application of NGF induced hyperalgesia of the hindpaw (visceral-to-somatic cross-sensitization),70 and injection of NGF-encoding vectors into the bladder wall enhanced the responses to colorectal distension (visceral-to-visceral cross-sensitization).71 We have also shown that pudendal nerve ligation injury induces bladder overactivity and increased NGF levels in the bladder, suggesting that increased NGF levels in the bladder and/or bladder afferent pathways induce not only bladder overactivity, but also hyperexcitability of nociceptive sensory neurons,72–75 and that somatic (pudendal nerves)-to-visceral (bladder) cross-sensitization through the increments of NGF in the bladder might be involved in the pathogenesis of IC/BPS.76

Oxidative stress and acrolein

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

During tissue injury and inflammation, oxidative stress generates ROS and RCS endogenously,17–20 and causes specific protein modification that leads to changes in the structure or function of the oxidized protein. In particular, protein carbonylation is considered to play a significant role in the etiology and/or progression of several human diseases, such as cardiovascular and neurodegenerative diseases, because protein carbonylation is irreversible and might alter the conformation of the polypeptide chain.77,78 In oxidative stress, lipid-derived RCS are more stable than ROC, and can diffuse within or even escape from the cell and attack targets far from the site of formation, showing that RCS behaves not only as cytotoxic agents, but also as second cytotoxic messengers.52

Among the variety of RCS generated by membrane lipid peroxidation, acrolein is by far the strongest electrophile, showing the highest reactivity toward nucleophilic sites on proteins.16 Although lipid peroxidation generates far more HNE than acrolein, production of acrolein metabolites in humans is 100-fold greater than HNE metabolites.20 This clearly shows that sources other than lipid peroxidation, such as amino acids and polyamines, are mainly involved in acrolein production.79 Acrolein is also known to be formed from threonine by neutrophil myeloperoxidase at the site of inflammation,80 suggesting that phagocyte-mediated formation of these products might be of central importance in promoting tissue injury. In addition, acrolein is indeed a common air pollutant, to which humans are continuously exposed, and is present in high concentrations in cigarette smoke, automobile exhaust and industrial emissions.16 Populations living or working in areas with heavy automotive traffic might be exposed to a higher level of acrolein through inhalation of automotive smoke or exhaust. Food substances are an additional source of acrolein exposure.81 Relatively high levels of acrolein are also detected in beer, wine, bread and other foods.82 On the basis of these findings, acrolein that is widely distributed in the environment and is also generated endogenously during inflammation can activate TRPA1, thereby raising the possibility that long-lasting stimulation and modification of TRPA1 induced by acrolein might underlie the pathogenesis of chronic pain conditions including IC/BPS.

Is TRPA1 a major nociceptive receptor for IC/BPS?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

TRPA1 activators, such as mustard oil, TNBS and acrolein (a metabolite of cyclophosphamide), have often been used in animal models of IC/BPS and pelvic organ cross-sensitization.35 We have recently shown that stimulation of TRPA1 through mustard oil in the colon or uterus induced bladder overactivity, visceral pain and bladder inflammation, although bladder overactivity was not induced by TRPV1 activation through capsaicin (a TRPV1 activator) in the colon or uterus until 3 h after the application (2011 AUA abstract 951). In addition, intravesical instillation of capsaicin for 5 min significantly reduced bladder capacity, but the effect was completely abolished 60 min after the application. In contrast, reduction of bladder capacity induced by intravesical instillation of mustard oil or acrolein for 5 min continued until at least 3 h (data not published). In other previous reports, experiments with TNBS-induced colonic inflammation in mice also showed considerable bladder overactivity shown by frequent micturition,83 and cyclophosphamide-induced cystitis in mice led to significant colonic hypersensitivity measured by visceromotor responses to colonic distention.71

As aforementioned, TRPV1 and TRPA1 are both activated and sensitized during tissue damage and inflammation (Fig. 2). It has been reported that TRPA1 was activated by hydrogen peroxide in heterologous systems and was essential for pain behavior triggered by the injection of hydrogen peroxide into the mouse paw.22,84 Acrolein activates TRPA1-mediated influx of calcium into cultured sensory neurons, although cultured sensory neurons from TRPA1 deficient mice lacked any responsiveness to this irritant.23 Using a nociceptive behavior test on wild-type or TRPA1 deficient littermates, TRPA1 deficient mice showed dramatically impaired nociceptive responses to the injection of formaldehyde to the hindpaw.85 Furthermore, TRPA1 deficient mice failed to develop thermal and mechanical hyperalgesia after the injection of bradykinin into the hindpaw.86 In contrast, TRPV1 is unlikely to represent the major reactive irritant receptor. In TRPV1 deficient mice, bradykinin-induced excitation was diminished, but not completely abrogated, in vagal airway afferent nerves.87 TRPV1 deficient mice showed normal respiratory sensitivity to acrolein, responding with profound respiratory depression.88 In electrophysiological studies, TRPV1 lacked any responsiveness to acrolein.89 These findings strongly suggest that TRPA1 might play a more important role than TRPV1 in acute and inflammatory pain, responding to a wide range of chemical compounds, including inflammatory mediators and oxidative stress.20,90

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References

Although the pathogenesis of IC/BPS remains unknown, there is a significant association of IC/BPS with other chronic pain conditions. Among the TRP channel family, TRPV1 and TRPA1 act as nocisensors to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also a efferent signal in the periphery through secretion of inflammatory agents, such as substance P and CGRP, which causes local neurogenic inflammation. Furthermore, peripheral inflammation produces multiple inflammatory mediators, such as bradykinin, prostaglandins, purines, proteases and NGF, that act on their cognate receptors expressed in nociceptive sensory neurons to activate intracellular signal transduction pathways, and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). In addition, TRPV1 and TRPA1 mutually control the transduction of noxious stimuli through calcium ions in TRPV1-expressing sensory neurons. Furthermore, sensitization of TRPV1 and TRPA1 at peripheral nerve terminals might induce central sensitization through neural cross-talk in the DRG, spinal cord and/or brain levels, leading to organ cross-sensitization in the pelvis or more systemic organs. During tissue damage and inflammation, oxidative stress endogenously generates ROS and RCS, and their highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk. In RCS, acrolein is the strongest electrophile and is widely distributed in the environment, including cigarette smoke, automobile exhaust, industrial emissions and foods. Thus, long-lasting stimulation and modification of TRPA1 receptors, which could be induced by oxidative stress, might underlie the pathogenesis of chronic pain conditions including IC/BPS.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Neural cross-talk in peripheral and central nervous systems
  5. Interaction between TRPV1 and TRPA1 in nociceptive sensory neurons
  6. Sensitization of TRPV1 and TRPA1 at peripheral nerve terminals
  7. Oxidative stress and acrolein
  8. Is TRPA1 a major nociceptive receptor for IC/BPS?
  9. Conclusions
  10. Acknowledgments
  11. Conflict of interest
  12. References