Next Article in Journal
Identification of Prognosis-Related Oxidative Stress Model with Immunosuppression in HCC
Previous Article in Journal
Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers
Previous Article in Special Issue
Impact of Chronic Exposure to Endometriosis on Perinatal Outcomes: Establishment of a Mouse Model
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 3
10.3390/biomedicines11030696
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Unmet Needs for Studying Chronic Pelvic/Visceral Pain Using Animal Models

by
Ana Catarina Neto
1,2,†,
Mariana Santos-Pereira
1,2,†,
Pedro Abreu-Mendes
2,3,4,
Delminda Neves
1,2,
Henrique Almeida
1,2,5,
Francisco Cruz
2,3,4 and
Ana Charrua
1,2,*
1
Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of University of Porto, 4200-319 Porto, Portugal
2
I3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal
3
Department of Urology, Centro Hospitalar de São João, 4200-319 Porto, Portugal
4
Physiology and Surgery Department, Faculty of Medicine of University of Porto, 4200-319 Porto, Portugal
5
Ginecologia-Obstetrícia, Hospital-CUF Porto, 4100-180 Porto, Portugal
*
Author to whom correspondence should be addressed.
†
These authors share the first authorship.
Biomedicines 2023, 11(3), 696; https://doi.org/10.3390/biomedicines11030696
Submission received: 16 January 2023 / Revised: 13 February 2023 / Accepted: 16 February 2023 / Published: 24 February 2023
(This article belongs to the Special Issue Animal Models of Endometriosis, from the Bench to the Clinic)
Browse Figures
Review Reports Versions Notes

Abstract

:
The different definitions of chronic pelvic/visceral pain used by international societies have changed over the years. These differences have a great impact on the way researchers study chronic pelvic/visceral pain. Recently, the role of systemic changes, including the role of the central nervous system, in the perpetuation and chronification of pelvic/visceral pain has gained weight. Consequently, researchers are using animal models that resemble those systemic changes rather than using models that are organ- or tissue-specific. In this review, we discuss the advantages and disadvantages of using bladder-centric and systemic models, enumerating some of the central nervous system changes and pain-related behaviors occurring in each model. We also present some drawbacks when using animal models and pain-related behavior tests and raise questions about possible, yet to be demonstrated, investigator-related bias. We also suggest new approaches to study chronic pelvic/visceral pain by refining existing animal models or using new ones.

1. The Implications of the Definitions and Terminologies of Chronic Pelvic and Visceral Pain

According to the International Association for the Study of Pain (IASP), chronic primary pain is defined as a persistent pain lasting for 3 months that is associated with emotional and/or functional impairment and cannot be associated with another condition [1]. If pain is associated with the head/neck viscera, thoracic viscera, abdominal visceral, or pelvic viscera with referral pain patterns from specific visceral organs, it is called chronic primary visceral pain (CPVP) [1]. If pain is felt in the pelvic region with referral pain patterns from specific pelvic organs without a diagnosed cause, after excluding all other causes it is called chronic primary pelvic pain syndrome (CPPPS) [1]. Endometriosis pain syndrome (EPS) is an example of CPPPS and should not be confused with endometriosis, whose lower abdominal pain is related to ectopic endometrium and, therefore, considered a chronic secondary visceral pain syndrome caused by persistent inflammation/vascular mechanisms (Table 1) [1,2,3]. However, the American Association of Gynecologic Laparoscopists, the European Society for Gynecological Endoscopy, the European Society of Human Reproduction and Embryology, and the World Endometriosis Society do not distinguish the chronic pain associated with EPS and endometriosis, assembling the patients under an umbrella term of endometriosis [4,5]. According to the IASP, if the pain is felt in the urinary bladder and there is at least one lower urinary tract symptom, without apparent cause or bladder inflammation, it is called chronic primary bladder pain syndrome (CPBPS), formerly known as interstitial cystitis, painful bladder syndrome, and PBS/IC or BPS/IC (Table 1) [1]. The 2022 European Association of Urology Guidelines on Chronic Pelvic Pain followed the IASP definitions and nomenclature [6]. The 2022 American Urology Association Guidelines did not approach the chronic pelvic/visceral pain terminology issue [7].
According to the International Continence Society (ICS) definitions, chronic pelvic pain (CPP) is a persistent, recurrent, or continuous pain for 6 months that is related to the pelvic/abdominal region and is often associated with gynecological and lower urinary tract symptoms. If central sensitization and other chronic pain mechanisms are identified, the definition of chronic pelvic pain also applies, even if the general rule of six months is yet to be confirmed [8]. According to the ICS, whenever chronic pelvic pain cannot be associated with a well-defined pathology, it is called chronic pelvic pain syndrome (CPPS) [9]. Bladder pain syndrome (BPS) is an example of CPPS (Table 1). The European Society for the Study of IC/BPS (ESSIC) follows the same definition as the ICS [10]. According to the ICS, if chronic pain is associated with visceral organ damage, inflammation, or pressure and is detected by visceral organ nociceptors, it is called chronic visceral pain (CVP) [8]. Endometriosis is an example of CVP with an organic cause, specifically with an inflammatory origin (Table 1) [8]. The ICS does not have a definition for EPS.
Table
Table 1. Summary of IASP and ICS classifications of pain related to endometriosis, endometriosis pain syndrome (EPS), and bladder pain syndrome (BPS) and chronic primary bladder pain syndrome (CPBPS).
Table 1. Summary of IASP and ICS classifications of pain related to endometriosis, endometriosis pain syndrome (EPS), and bladder pain syndrome (BPS) and chronic primary bladder pain syndrome (CPBPS).
IASP/EAUICS/ESSIC
EndometriosisChronic secondary visceral pain syndromeChronic visceral pain
EPSChronic primary visceral pain—chronic primary pelvic pain syndrome-
CPBPS/BPSChronic primary visceral painChronic pelvic pain
Interstitial cystitis-Chronic pelvic pain
Both the IASP/EAU and ICS/ESSIC classifications consider that endometriosis is associated with visceral pain. However, while in the IASP/EAU definition pain is due to the possible extra-pelvic location of the lesion [1,2,6] and the term secondary indicates that it is associated with tissue inflammation, in the ICS/ESSIC definition pain results from the tissue inflammation detected by nociceptors [9].
The ICS/ESSIC do not have a definition for EPS. The ICS classification is based on symptoms, and therefore it may not distinguish endometriosis from EPS [9]. Hence, endometriosis may have been used to define EPS in many clinical studies and reports. Accordingly, the ICS/ESSIC pain classification also does not distinguish bladder pain syndrome from interstitial cystitis, as patients may present similar pain symptoms, although it approaches them as two different conditions. The evolution of the bladder pain syndrome nomenclature showed that in the past, interstitial cystitis was used to define bladder pain syndrome in clinical studies and reports.
Although EPS patients may have extra-pelvic lesions and/or may report extra-pelvic pain, the IASP/EAU define it as pelvic pain. On the other hand, CPBPS is not considered a pelvic pain syndrome by the IASP/EAU, probably because the location of pain, although difficult to identify, is mostly (but not exclusively [11]) found in the visceral region. In the ICS/ESSIC definition, however, the pelvic classification is due to the lack of connection of the pain to a visceral organ impairment [9].
The different criteria used by the IASP/EAU (origin and location) and the ICS/ESSIC (functional/symptoms) definitions of pain related to endometriosis and bladder pain syndrome influence the approaches to study these conditions. While using the IASP/EAU classification, the three identified conditions are endometriosis, EPS, and CPBPS (without IC). Using the ICS/ESSIC classification, the three identified conditions are endometriosis, BPS, and IC.

2. The Implications of Symptom Identification in the Study of Chronic Pelvic/Visceral Pain

One of the characteristics of EPS is that it was previously diagnosed as endometriosis, which justifies the origin of the pelvic pain [1,2]. However, after the surgical removal of the ectopic endometrium or its hormonal treatment, the pain may remain [1]. Therefore, the existence of ectopic endometrium in EPS patients may be, in some cases, irrelevant to the pain phenotype [1]. CPBPS, on the other hand, does not require the existence of inflammation and tissue damage in its diagnostic, although some patients might present inflammatory cells in the urinary bladder wall [1].
One approach to understanding if the mechanisms of chronic pain associated with EPS and CPBPS overlap is to identify the common features of these conditions. One common aspect is the location of pain described by patients. Most of the work published concerning the mapping of pain in endometriosis was performed pre-surgery and complemented by post-surgery diagnosis. Hence, it is not clear which pain locations were related to endometriosis and which were related to EPS or even if locations were related to EPS and changed after the removal of the lesions. Nevertheless, there was an extensive overlap in the mapping of the pain of endometriosis and CPBPS, as shown in Figure 1.
Biomedicines 11 00696 g001 550
Figure 1. Illustrative image of pain mapping in women with endometriosis (grey dots, adapted from [12]) and CPBPS (black dots, adapted from [11]), regardless of the reported intensity of the pain.
Figure 1. Illustrative image of pain mapping in women with endometriosis (grey dots, adapted from [12]) and CPBPS (black dots, adapted from [11]), regardless of the reported intensity of the pain.
Biomedicines 11 00696 g001
Another common aspect in both syndromes is that patients present cognitive, behavioral, sexual, and/or emotional modifications, which are reflected in comorbidities such as depression and anxiety [1,13,14,15]. Moreover, the same patient may be diagnosed simultaneously with EPS and CPBPS [16]. It is not surprising, therefore, that both syndromes are associated with changes in the central nervous system [16], with the insula and the thalamus being the most commonly altered brain structures in both syndromes [17,18,19,20]. It is also noteworthy that both EPS and CPBPS present changes in the hypothalamic–pituitary–adrenal (HPA) axis, altering the stress-mediated response to noxious stimuli [16,21,22]. In fact, changes in cortisol levels have been associated with pain intensity (negative correlation) in these conditions [22,23]. Concurrent with HPA-axis hormonal changes, patients with both syndromes simultaneously present changes in the autonomic nervous system [24,25]. Therefore, both EPS and CPBPS patients present several phenotypes, which may explain why the available therapies are not pan-effective. As a corollary, many clinicians strongly support clustering patients by clinical and histological findings and by their responses to specific therapies or even to individualized management.

3. Back-translation of Patient Symptoms According to Their Associations with Chronic Pelvic/Visceral Pain

The clustering of patients according to their symptoms and signs is a complex issue. The multiplicity of phenotypes presented by patients and the multiplicity of scientific organizations make the definition of a worldwide accepted cluster very complex. Nevertheless, some attempts have been made. The UPOINT system proposed by Nickel and co-workers for phenotyping CPBPS patients is a good example of a simple tool to phenotype patients [26]. In the UPOINT algorithm, symptoms and signs are not exclusively related to the urinary bladder [26,27]. Rather, UPOINT is an acronym for the different domains observed in or reported by patients, which include urinary symptoms, psychosocial dysfunction, organ-specific findings, infection, neurologic/systemic comorbidities, and tenderness (related to pain) [26]. By broadening the urinary symptoms concept into functional symptoms, UPOINT may help to cluster patients with EPS, CPBPS, and even other chronic pelvic/visceral pain syndromes. The UPOINT score has shown strong positive correlations with the score obtained using the Interstitial Cystitis Symptom Index (ICSI) questionnaire and with the pain score obtained using a visual analogue scale (VAS) [26,27]. UPOINT has evolved to include other symptoms, including sexual dysfunction [28], and has already been used to define the therapeutic approach according to the patient’s phenotype [29,30]. That is, the presence and severity of the symptoms observed in each subdomain of UPOINT determine if a single or a multimodal therapy should be offered to the patient [29].
Back-translation of the UPOINT may help researchers to choose and refine the animal models used to study chronic visceral/pelvic pain. Some aspects of EPS and CPBPS are more easily back-translated than others, either due to methodological limitations or due to the pain characteristics of individual subjects. Taking the organ-specific findings as an example, in EPS one of the most common organ-specific findings is the presence of endometrial lesions. Nonetheless, the number of lesions in patients does not correlate with the intensity of pain [31]. Moreover, the presence of lesions in patients is not a necessary condition for the development of pain [32,33]. This is an important concept, as back-translated data are generally supported by clinical studies that use patients with chronic pain without endometrial lesions as controls for patients that present endometrial lesions.
Recent works have suggested that, independent of being related to endometriotic lesions, the pain associated with EPS results from changes in the way it is integrated in the central nervous system (CNS) [32]. Hence, when using the induction of lesions in an EPS animal model, those lesions should induce changes in the same way that the patients’ CNSs integrate pain. Moreover, to better replicate what is observed in EPS patients, the CNS changes should persist after the removal of those lesions (as occurs during EPS) to ensure that the observed animal pain behavior is not a consequence of the inflammation generated by the lesions (as occurs during endometriosis). However, this is methodologically complex, time-consuming, and, to our knowledge, has never been performed. Hence, the finding of specific markers for these CNS changes will help to surpass this methodological drawback.
In CPBPS, one of the most common organ-specific findings is urothelium functional impairment (not denudation, as in the case of IC). The urothelium barrier impairment has been associated with submucosa inflammation of the urinary bladder in patients with CPBPS and other bladder pathologies [34,35]. The urothelial barrier impairment is thought to be the mechanism by which the urine content activates bladder nociceptors that, in turn, induce neurogenic inflammation locally and promote CNS changes that lead to pain chronification [36]. This hypothesis, however, is difficult to test using bladder-centric CPBPS animal models, not only because of the technical complexity but also because of the difficulty in defining if the animal pain-like behavior is due to neurogenic inflammation (as might predominate in IC) or due to the changes induced in the CNS (as happens during CPBPS). Hence, the identification of which/how symptoms correlate with the etiology of chronic pelvic/visceral pain phenotypes is difficult in animals, especially when it is apparent that different insults/events may lead to similar chronic pelvic/visceral pain phenotypes.

4. Systemic Symptoms Prompt Systemic Models for the Study of Chronic Pelvic/Visceral Pain

EPS and CPBPS patients commonly present systemic symptoms, potentially reflecting the existent comorbidities and CNS changes that translate into the multiple pain sites observed in Figure 1. Hence, animal models with CNS alterations that lead to pain behaviors and/or contribute to the development of symptoms of comorbidities (changes in organ activity and/or sensitivity as well as depression and/or anxiety symptoms, among others) may potentially provide more information about the chronic pain associated with EPS (white, Table 2) and CPBPS (grey, Table 2) than organ-centered models. In Table 2, the most used complex rodent models of EPS/endometriosis and CPBPS [37] and how they relate to UPOINT are summarized.
Table
Table 2. Rodent models used recently to study EPS (white background) and CPBPS (grey background). The animals’ characteristics are organized according to their similarity to patients’ symptoms and signs in each UPOINT subdomain.
Table 2. Rodent models used recently to study EPS (white background) and CPBPS (grey background). The animals’ characteristics are organized according to their similarity to patients’ symptoms and signs in each UPOINT subdomain.
ModelUPOINTReferences
Retrograde menstruation +[38]
Autologous transplantation+++ ++[39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63]
Allogenic transplantation +[39]
Autologous transplantation to the sciatic nerve ++[64,65,66,67,68,69,70]
Autologous transplantation to muscle +[71,72,73,74,75]
Syngeneic transplantation+ + ++[76,77]
Xenograft transplantation +[78]
Intraperitoneal injection of endometrial tissue +[79,80,81]
Peritonitis ++[82,83]
Colonic instillation of TNBS+ + ++[84,85,86,87,88,89]
Uterine pain + [90]
Autoimmune+ + ++[91,92,93,94,95,96]
Prostatic inflammation+ ++ [97,98,99,100]
Pseudorabies virus ++++[101,102,103,104,105,106,107,108]
Systemic administration of molecules+ ++[109,110,111]
Restraint stress+ + + [112,113,114,115]
Water avoidance stress+++ ++[116,117,118,119,120,121]
Chronic variable stress+ + [122]
Cold stress+ [123,124]
Social stress+ + + [125,126,127]
Foot shock stress + ++[128,129]
Early-life stress by odor–shock conditioning + ++[130,131]
Early-life stress by neonatal maternal deprivation+++ + [132,133,134]
Among the EPS/endometriosis and CPBPS/BPS/IC models in use, those that more similarly back-translate the systemic symptoms are those that present urinary/functional symptoms, psychosocial dysfunction, and neurologic/systemic (comorbidities) impairments. This is the case of the autologous transplantation, water avoidance stress (WAS), and neonatal maternal deprivation (NMD) models. However, even these models need further refinements if the goal is to unveil the pathophysiological mechanism or find new treatments for EPS and CPBPS.
Considering the autologous transplantation model (ATM), endometrial tissue transplantation must be performed because the rodents do not have a menstrual cycle and consequently do not spontaneously develop endometrial lesions. The only exception is the spiny mouse [135]. Nevertheless, as in any other rodent species, the spiny mouse also possesses an ovarian bursa that encapsulates the ovaries and the oviducts, not allowing the endometrium tissue to escape to the peritoneal cavity. Only recently, an ovarian endometriosis model was developed in spiny mice via bursectomy [136], which provides a more physiologic endometrial peritoneal lesion model for investigation. The most used ATM, normally induced in BALB/c mice, offers the possibility, within its limitations, to study the chronic pain associated with endometriosis once the transplantation is performed and the ectopic lesions are formed [135]. However, as stated before, the pain induced in this model may be of inflammatory/neurogenic origin and may not reflect the CNS changes observed in patients with EPS. In fact, variations (species and lesion location, among others) in ATM model induction may be enough to induce different modulations of the brain activity, which are then reflected in distinct pain-related behavior. For instance, the use of the ATM in Sprague-Dawley rats (implantation in the peritoneal wall) induces increased regional homogeneity of the anterior cingulate cortex, in the CA1 field of the hippocampus, in the thalamus, and in the brainstem, showing that these regions have abnormal neuronal activity [137]. A high number of neuronal cells show the activation of the apoptosis cascade [137]. Apart from the thalamus, the overactive neurons found in these nuclei show higher TRPV1 mRNA levels [137]. In addition, the overactive neurons from the hippocampus present increased levels of NMDA receptor mRNA [137]. On the other hand, there is a decrease in the regional homogeneity of the basomedial nucleus of the amygdala and in the primary motor cortex [137], providing evidence of altered basal brain activity. All these changes are concomitant with the development of thermal hyperalgesia and mechanical allodynia but not anxious behavior [137]. The ATM induced in C57BL/6 mice (implantation in the peritoneal wall) presents some similarities to the induction of the ATM in Sprague-Dawley rats (such as changes in hippocampus activity) but presents other important differences, such as changes in the activity of different brain areas, namely the insula [138]. Moreover, the observed changes in neuronal activity in the amygdala may differ, as in C57BL/6 mice, considering that the ATM increased the expression of the emotional regulation gene Lcn2, which may explain the increased anxiety induced by the ATM in these animals [138]. From a behavior phenotype point of view, the ATM induces thermal hyperalgesia in C57BL/6 mice but decreases locomotor activity [138]. On the other hand, this animal model presents changes in the thalamus and anterior cingulate cortex that are concomitant with anxiety behavior and mechanical allodynia [77].
Another model is the water avoidance stress (WAS) model. In this model, pain induction involves the activation of the peripheral adrenergic system [116]. How long does the pain phenotype induced by stress last? WAS carried out for 10 consecutive days was shown to induce a pain-related visceromotor response that lasted, in some animals, for 40 days but induced somatic nociception, which faded away much sooner. Is a 10-day WAS protocol sufficient to make an imprint in the CNS? When studying chronic pelvic/visceral pain using animal models of EPS and CPBPS, CNS pain integration changes may need more time to occur/establish than the other symptoms commonly associated with these syndromes. The great advantage of the neonatal maternal deprivation (NMD) model is that the pain-related phenotype occurs and is studied in adulthood, when the early-life insult is long gone. However, NMD is not free of drawbacks. The spontaneous pain behavior may not be easily observed, although the changes in the CNS pain integration pathway are already provoked.
Which test should be used to study chronic pelvic/visceral pain? What endpoint should be looked for? Many reviews have brought to light the advantages and disadvantages of using spontaneous and induced pain behavior tests [139,140]. The induced pain behavior tests, such as von Frey filament stimulation or the hot plate test, are normally based on the reflexive and conscious withdrawal of body parts submitted to a stimulus [139]. Therefore, their principal endpoints, based on nocifensive behaviors, are normally the latency time to a response or equivalent to an LD50 threshold [139]. Although these tests are indisputably associated with a bothersome/painful sensation, the focal location of such a sensation is hard to determine in the case of chronic pelvic/visceral pain. Additionally, they do not allow the spontaneous pain felt by the animals to be measured. Hence, it is imperative to find adjusted endpoints to study chronic pelvic/visceral pain that may overcome the drawbacks of the classically used tests, including the concomitant use of behavior tests with other techniques, such as neuroimaging or functional/electrophysiological measurements. In fact, tests that are based on pain-related spontaneous and/or cognitive behaviors (psychosocial dysfunction and the neurologic/systemic aspect of the UPOINT approach) associated with animal quality of life have been used more recently [139]. However, such tests are more susceptible to some pitfalls that are not directly associated with the tests per se, which may endanger their interlaboratory comparison and impair their validity. These pitfalls are related to the animals’ species-specific characteristics, animal husbandry and manipulation conditions, and/or data acquisition requirements, which are often overlooked and therefore not included in standard operating protocols. Additionally, the use of social cues also raises the question of the impact of genetic/epigenetics, which are known to be implicated in the balance of the HPA axis, in the study of chronic pelvic/visceral pain. The induction of WAS for 7 days is known to induce changes in the expression of glucocorticoid receptor and corticotropin-releasing factor genes of neuronal cells of the amygdala of male F-344 rats that are intimately related with increases in pain-related visceromotor responses through epigenetic mechanisms [141]. Therefore, we should evaluate if, for example, outliers should be disregarded. Moreover, investigators should not expect all animals to develop pain phenotypes after the induction in each experimental model, a piece of evidence that raises the question of how to handle the groups. Should we use different strains in the same protocol? What is the real impact of litter balancing in the study of chronic pelvic/visceral pain?
It is clear that the animal models of EPS and CPBPS require better characterization before deciding which tests should be used in the evaluation of the pathophysiological mechanisms of chronic pain or even pain treatments. For NMD, it should be elucidated which symptoms and signs NMD replicates and which pathways induce the NMD pain/sensitization pathway and associated behavior changes, such as anxiety. For instance, NMD is known to increase perigenital sensitivity and increase the number of voiding episodes in adult male mice [133]. NMD also influences the sensitivity of the colon, as it increases the visceromotor response to colorectal balloon distention in adult male rats [142], a fact that may accelerate the progression of endometrial lesions in female mice [143]. NMD causes mastocytosis in the bladder and prostate in adult male mice [133,144]. NMD also promotes the impairment of hippocampal neurogenesis and alters stress-related gene expression within the hypothalamic–pituitary–adrenal axis [145]. Moreover, it was recently postulated that NMD may prime a glial response that is reflected in adulthood in the development of pelvic/visceral pain, similar to what is observed in somatic pain [146].
Besides the rodent models, non-human primates (NHP) and domestic cats have been used to study EPS and CPBPS, respectively [147,148,149,150]. NHPs share similar reproductive system anatomy and endocrinology with humans. Baboons and some macaca species (such as rhesus, pigtail, and cynomolgus) menstruate and may develop spontaneous endometriosis [151,152,153]. The EPS in macaques is very similar to the condition in humans, as they present pain behavior, and the functional magnetic resonance imaging of their brains revealed a sensitized insula and thalamus [154]. Moreover, their endometrium and endometriosis tissues present mitochondrial impairment, which may be related to oxidative stress [155], a feature also observed in patients. As happens with some endometriosis patients, some macaques are anemic [156]. Furthermore, it is possible to find other species that spontaneously develop endometriosis in non-menstruating animals such as gorillas, horses, dogs, and guinea pigs, among others [157,158,159]. Despite the straightforward phylogenetic gap between humans, rodents are, at the end of the day, animal models with a high level of physiological homology. The ethical problems associated with the use of many other species, the maintenance expenses, and the decreased number of animals available for experimentation when compared to rodents make non-rodent models difficult to use routinely. The same holds true for CPBPS. Cats may develop feline interstitial cystitis (FIC), which is a similar form of CPBPS [160]. These cats exhibit flare-like symptoms, lower urinary tract abnormalities, and central nervous changes, and in some cases they present comorbidities such as behavioral, endocrine, cardiovascular, and gastrointestinal alterations [150]. However, the low availability of cats with FIC and the high cost necessary for their maintenance when compared with rodents make this FIC model less attractive [160,161].

5. Going beyond the Existing Models to Study the Chronic Pelvic/Visceral Pain Associated with EPS and CPBPS

To study EPS, the ATM can be combined with procedures/protocols that alter the way the CNS processes pain (Figure 2). For instance, the combination of the ATM with stress models (known to alter the HPA axis and/or induce CNS changes [141,162]) or with autoimmune models (known to induce CNS sensitization due to prolonged inflammation and/or tissue damage [163]) may help to refine the ATM to study EPS. In fact, female Balb/C mice submitted to NMD presented depression-like and anxiety-like symptoms in adulthood [143]. However, it was only after the induction of endometrial lesions in these animals that it was possible to observe endometriosis-associated generalized hyperalgesia [143]. Another putative approach is the use of longer ATM protocols to understand if, at longer time points, the CNS changes that lead to chronic pain are already observed.
Biomedicines 11 00696 g002 550
Figure 2. Possible refinement strategies to improve the study of chronic pelvic/visceral pain using animal models or animals that naturally develop EPS or CPBPS.
Figure 2. Possible refinement strategies to improve the study of chronic pelvic/visceral pain using animal models or animals that naturally develop EPS or CPBPS.
Biomedicines 11 00696 g002
A frequently disregarded aspect regarding chronic pelvic/visceral pain is the role of visceral fat. EPS/endometriosis are related to an imbalance in the levels of estrogen, a hormone known to modulate the distribution and amount of fat tissue in the body [164,165]. Moreover, the lesions commonly observed in EPS/endometriosis occur in close proximity to the visceral fat present in the pelvic cavity [166,167,168,169]. The visceral fat is known to secrete pro-inflammatory molecules, which may promote tissue inflammation, even in the absence of endometrial lesions. In a study involving 3026 patients with osteoarthritis, visceral fat was associated with an increased pain phenotype, regardless of BMI [170], showing that the systemic inflammation induced by visceral fat promotes changes in the pain phenotype. In a study with 795 participants, it was observed that visceral fat was associated with sympathetic system activity [171]. Accordingly, visceral fat innervation is known to develop crosstalk with brain centers, namely the paraventricular nucleus (PVN) of the hypothalamus [172]. The hyperactivation of the PVN nucleus, as occurs in stressful situations, is thought to have a role in endometriosis/EPS, as it promotes HPA axis activation, modulating cortisol release concomitantly with endometrial dysfunction [170,173]. Therefore, combining a high-fat diet with lesion induction might provide a valid approach for studying EPS (Figure 2), as shown by Heard and colleagues in 2016 [174]. Moreover, changes in PVN activity, namely the increased release of corticotropin-releasing hormone (CRH), might also have a role in CPBPS, as these patients present urothelial expression changes in those hormone receptors [175]. The change in CRH receptors is intimately related to pain scores and markers in those patients [175]. Hence, high-fat-diet animal models may provide the chance to study features that are overlapped in EPS and CPBPS.
Besides the induction of chronic pelvic pain in animal models, a more exhaustive study of biological samples (ectopic endometrial tissue, blood, saliva, and urine) taken from animals that naturally develop EPS or CPBPS, together with other veterinary analyses that might be performed on those animals, should be considered. Important lessons can be taken, such as the possibility of performing a phylogenetic evaluation of the disease. An example of this is the recent genetic comparison between humans and the rhesus macaque that unveiled the importance of the coding variants in neuropeptide S receptor 1 in the pain treatment associated with endometriosis [158]. The phylogenetic evaluation of the disease may provide important clues based not only on the similarities but also on the most noticeable differences. It should be recalled that FIC affects both genders in a relatively equal way [150,160], a characteristic that may help investigators to understand CPBPS in the male population.

6. Conclusions

Altogether, the refinement of the translational chronic pelvic/visceral pain model to better understand the similarities with human conditions is essential to perform more meaningful studies. In addition, the study of specific cellular and subcellular mechanisms in the peripheral organs and the central nervous system nuclei will be fundamental to understanding the pathophysiology of EPS and CPBPS and to developing more effective treatments in a systemic setting.

Author Contributions

All authors participated in the original draft preparation and in the review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777500. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. The statements and opinions presented here reflect the authors’ views. IMI, the European Union, EFPIA, and any associated partners are not responsible for any use that may be made of the information contained herein (www.imi.europa.eu; www.imi-paincare.eu).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Nicholas, M.; Vlaeyen, J.W.S.; Rief, W.; Barke, A.; Aziz, Q.; Benoliel, R.; Cohen, M.; Evers, S.; Giamberardino, M.A.; Goebel, A.; et al. The IASP Classification of Chronic Pain for ICD-11: Chronic Primary Pain. Pain 2019, 160, 28–37. [Google Scholar] [CrossRef] [PubMed]
  2. Aziz, Q.; Giamberardino, M.A.; Barke, A.; Korwisi, B.; Baranowski, A.P.; Wesselmann, U.; Rief, W.; Treede, R.D. The IASP Classification of Chronic Pain for ICD-11: Chronic Secondary Visceral Pain. Pain 2019, 160, 69–76. [Google Scholar] [CrossRef]
  3. International Association for the Study of Pain. Classification of Chronic Pain, Second Edition (Revised); Merskey, H., Bogduk, N., Eds.; IASP Press: Seattle, WA, USA, 1994. [Google Scholar]
  4. Becker, C.M.; Bokor, A.; Heikinheimo, O.; Horne, A.; Jansen, F.; Kiesel, L.; King, K.; Kvaskoff, M.; Nap, A.; Petersen, K.; et al. ESHRE Guideline: Endometriosis. Hum. Reprod. Open 2022, 2022, hoac009. [Google Scholar] [CrossRef]
  5. International Working Group of AAGL, ESGE, ESHRE and WES; Tomassetti, C.; Johnson, N.P.; Petrozza, J.; Abrao, M.S.; Einarsson, J.I.; Horne, A.W.; Lee, T.T.M.; Missmer, S.; Vermeulen, N.; et al. An International Terminology for Endometriosis, 2021. Hum. Reprod. Open 2021, 2021, hoab029. [Google Scholar] [CrossRef] [PubMed]
  6. Fall, M.; Baranowski, A.; Elneil, S.; Engeler, D.; Hughes, J.; Messelink, E.; Oberpenning, F.; de C Williams, A.; European Association of Urology. EAU Guidelines on Chronic Pelvic Pain. Eur. Urol. 2010, 57, 35–48. [Google Scholar] [CrossRef]
  7. Quentin Clemens, J.; Erickson, D.R.; Varela, N.P.; Henry Lai, H. Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome. J. Urol. 2022, 208, 34–42. [Google Scholar] [CrossRef]
  8. Doggweiler, R.; Whitmore, K.E.; Meijlink, J.M.; Drake, M.J.; Frawley, H.; Nordling, J.; Hanno, P.; Fraser, M.O.; Homma, Y.; Garrido, G.; et al. A Standard for Terminology in Chronic Pelvic Pain Syndromes: A Report from the Chronic Pelvic Pain Working Group of the International Continence Society. Neurourol. Urodyn. 2017, 36, 984–1008. [Google Scholar] [CrossRef]
  9. Kocjancic, E.; Chung, E.; Garzon, J.A.; Haylen, B.; Iacovelli, V.; Jaunarena, J.; Locke, J.; Millman, A.; Nahon, I.; Ohlander, S.; et al. International Continence Society (ICS) Report on the Terminology for Sexual Health in Men with Lower Urinary Tract (LUT) and Pelvic Floor (PF) Dysfunction. Neurourol. Urodyn. 2022, 41, 140–165. [Google Scholar] [CrossRef]
  10. van de Merwe, J.P.; Nordling, J.; Bouchelouche, P.; Bouchelouche, K.; Cervigni, M.; Daha, L.K.; Elneil, S.; Fall, M.; Hohlbrugger, G.; Irwin, P.; et al. Diagnostic Criteria, Classification, and Nomenclature for Painful Bladder Syndrome/Interstitial Cystitis: An ESSIC Proposal. Eur. Urol. 2008, 53, 60–67. [Google Scholar] [CrossRef]
  11. Tripp, D.A.; Nickel, J.C.; Wong, J.; Pontari, M.; Moldwin, R.; Mayer, R.; Carr, L.K.; Doggweiler, R.; Yang, C.C.; Mishra, N.; et al. Mapping of Pain Phenotypes in Female Patients with Bladder Pain Syndrome/Interstitial Cystitis and Controls. Eur. Urol. 2012, 62, 1188–1194. [Google Scholar] [CrossRef] [PubMed]
  12. Schliep, K.C.; Mumford, S.L.; Peterson, C.M.; Chen, Z.; Johnstone, E.B.; Sharp, H.T.; Stanford, J.B.; Hammoud, A.O.; Sun, L.; Buck Louis, G.M. Pain Typology and Incident Endometriosis. Hum. Reprod. 2015, 30, 2427–2438. [Google Scholar] [CrossRef] [Green Version]
  13. Chen, L.-C.; Hsu, J.-W.; Huang, K.-L.; Bai, Y.-M.; Su, T.-P.; Li, C.-T.; Yang, A.C.; Chang, W.-H.; Chen, T.-J.; Tsai, S.-J.; et al. Risk of Developing Major Depression and Anxiety Disorders among Women with Endometriosis: A Longitudinal Follow-up Study. J. Affect. Disord. 2016, 190, 282–285. [Google Scholar] [CrossRef]
  14. Keller, J.J.; Chen, Y.-K.; Lin, H.-C. Comorbidities of Bladder Pain Syndrome/Interstitial Cystitis: A Population-BasedStudy. BJU Int. 2012, 110, E903–E909. [Google Scholar] [CrossRef]
  15. Keller, J.J.; Liu, S.P.; Lin, H.C. A Case-Control Study on the Association between Rheumatoid Arthritis and Bladder Pain Syndrome/Interstitial Cystitis. Neurourol. Urodyn. 2013, 32, 980–985. [Google Scholar] [CrossRef] [PubMed]
  16. McNamara, H.C.; Frawley, H.C.; Donoghue, J.F.; Readman, E.; Healey, M.; Ellett, L.; Reddington, C.; Hicks, L.J.; Harlow, K.; Rogers, P.A.W.; et al. Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes. Front. Reprod. Health 2021, 3, 729642. [Google Scholar] [CrossRef]
  17. As-Sanie, S.; Harris, R.E.; Napadow, V.; Kim, J.; Neshewat, G.; Kairys, A.; Williams, D.; Clauw, D.J.; Schmidt-Wilcke, T. Changes in Regional Gray Matter Volume in Women with Chronic Pelvic Pain: AVoxel-Based Morphometry Study. Pain 2012, 153, 1006–1014. [Google Scholar] [CrossRef] [Green Version]
  18. As-Sanie, S.; Kim, J.; Schmidt-Wilcke, T.; Sundgren, P.C.; Clauw, D.J.; Napadow, V.; Harris, R.E. Functional Connectivity Is Associated With Altered Brain Chemistry in Women with Endometriosis-Associated Chronic Pelvic Pain. J. Pain 2016, 17, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Kleinhans, N.M.; Yang, C.C.; Strachan, E.D.; Buchwald, D.S.; Maravilla, K.R. Alterations in Connectivity on Functional Magnetic Resonance Imaging with Provocation of Lower Urinary Tract Symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes. J. Urol. 2016, 195, 639–645. [Google Scholar] [CrossRef] [Green Version]
  20. Kilpatrick, L.A.; Kutch, J.J.; Tillisch, K.; Naliboff, B.D.; Labus, J.S.; Jiang, Z.; Farmer, M.A.; Apkarian, A.V.; Mackey, S.; Martucci, K.T.; et al. Alterations in Resting State Oscillations and Connectivity in Sensory and Motor Networks in Women with Interstitial Cystitis/Painful Bladder Syndrome. J. Urol. 2014, 192, 947–955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Twiss, C.; Kilpatrick, L.; Craske, M.; Buffington, C.A.T.; Ornitz, E.; Rodríguez, L.V.; Mayer, E.A.; Naliboff, B.D. Increased Startle Responses in Interstitial Cystitis: Evidence for Central Hyperresponsiveness to Visceral Related Threat. J. Urol. 2009, 181, 2127–2133. [Google Scholar] [CrossRef]
  22. Lutgendorf, S.K.; Kreder, K.J.; Rothrock, N.E.; Hoffman, A.; Kirschbaum, C.; Sternberg, E.M.; Bridget Zimmerman, M.; Ratliff, T.L. Diurnal Cortisol Variations and Symptoms in Patients with Interstitial Cystitis. J. Urol. 2002, 167, 1338–1343. [Google Scholar] [CrossRef]
  23. Vincent, K.; Warnaby, C.; Stagg, C.J.; Moore, J.; Kennedy, S.; Tracey, I. Dysmenorrhoea Is Associated with Central Changes in Otherwise Healthy Women. Pain 2011, 152, 1966–1975. [Google Scholar] [CrossRef] [PubMed]
  24. de França Moreira, M.; Gamboa, O.L.; Pinho Oliveira, M.A. Association between Severity of Pain, Perceived Stress and Vagally-Mediated Heart Rate Variability in Women with Endometriosis. Women Health 2021, 61, 937–946. [Google Scholar] [CrossRef]
  25. Charrua, A.; Pinto, R.; Taylor, A.; Canelas, A.; Ribeiro-da-Silva, A.; Cruz, C.D.; Birder, L.A.; Cruz, F. Can the Adrenergic System Be Implicated in the Pathophysiology of Bladder Pain Syndrome/Interstitial Cystitis? A Clinical and Experimental Study. Neurourol. Urodyn. 2015, 34, 489–496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Nickel, J.C.; Shoskes, D.; Irvine-Bird, K. Clinical Phenotyping of Women with Interstitial Cystitis/Painful Bladder Syndrome: AKey to Classification and Potentially Improved Management. J. Urol. 2009, 182, 155–160. [Google Scholar] [CrossRef]
  27. Fuoco, M.B.; Irvine-Bird, K.; Curtis Nickel, J. Multiple Sensitivity Phenotype in Interstitial Cystitis/Bladder Pain Syndrome. Can. Urol. Assoc. J. 2014, 8, E758–E761. [Google Scholar] [CrossRef] [Green Version]
  28. Liu, B.; Su, M.; Zhan, H.; Yang, F.; Li, W.; Zhou, X. Adding a Sexual Dysfunction Domain to UPOINT System Improves Association withSymptoms in Women with Interstitial Cystitis and Bladder Pain Syndrome. Urology 2014, 84, 1308–1313. [Google Scholar] [CrossRef] [PubMed]
  29. Kartha, G.K.; Kerr, H.; Shoskes, D.A. Clinical Phenotyping of Urologic Pain Patients. Curr. Opin. Urol. 2013, 23, 560–564. [Google Scholar] [CrossRef] [PubMed]
  30. Lai, H.H.; Thu, J.H.L.; Moh, F.V.; Paradis, A.; Vetter, J. Clustering of Patients with Interstitial Cystitis/Bladder Pain Syndrome and ChronicProstatitis/Chronic Pelvic Pain Syndrome. J. Urol. 2019, 202, 546–551. [Google Scholar] [CrossRef]
  31. Nezhat, C.; Vang, N.; Tanaka, P.P.; Nezhat, C. Optimal Management of Endometriosis and Pain. Obstet. Gynecol. 2019, 134, 834–839. [Google Scholar] [CrossRef] [Green Version]
  32. Stratton, P.; Berkley, K.J. Chronic Pelvic Pain and Endometriosis: Translational Evidence of the Relationship and Implications. Hum. Reprod. Update 2011, 17, 327–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Abbott, J.; Hawe, J.; Hunter, D.; Holmes, M.; Finn, P.; Garry, R. Laparoscopic Excision of Endometriosis: A Randomized, Placebo-Controlled Trial. Fertil. Steril. 2004, 82, 878–884. [Google Scholar] [CrossRef] [PubMed]
  34. Cheng, S.F.; Jiang, Y.H.; Kuo, H.C. Urothelial Dysfunction and Chronic Inflammation Are Associated With Increased Bladder Sensation in Patients With Chronic Renal Insufficiency. Int. Neurourol. J. 2018, 22, S46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Jhang, J.F.; Jiang, Y.H.; Kuo, H.C. Current Understanding of the Pathophysiology and Novel Treatments of Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2022, 10, 2380. [Google Scholar] [CrossRef] [PubMed]
  36. Birder, L.; Andersson, K.E. Urothelial Signaling. Physiol. Rev. 2013, 93, 653–680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Nunez-Badinez, P.; de Leo, B.; Laux-Biehlmann, A.; Hoffmann, A.; Zollner, T.M.; Saunders, P.T.K.; Simitsidellis, I.; Charrua, A.; Cruz, F.; Gomez, R.; et al. Preclinical Models of Endometriosis and Interstitial Cystitis/Bladder Pain Syndrome: An Innovative Medicines Initiative-PainCare Initiative to Improve Their Value for Translational Research in Pelvic Pain. Pain 2021, 162, 2349–2365. [Google Scholar] [CrossRef]
  38. Persoons, E.; de Clercq, K.; van den Eynde, C.; Pinto, S.J.P.C.; Luyten, K.; van Bree, R.; Tomassetti, C.; Voets, T.; Vriens, J. Mimicking Sampson’s Retrograde Menstrual Theory in Rats: A New Rat Model forOngoing Endometriosis-Associated Pain. Int. J. Mol. Sci. 2020, 21, 2326. [Google Scholar] [CrossRef] [Green Version]
  39. van Aken, M.A.; Groothuis, P.G.; Panagiotou, M.; van Duin, M.; Nap, A.W.; van Rijn, T.C.; Kozicz, T.; Braat, D.D.; Peeters, A.B. An Objective and Automated Method for Evaluating Abdominal Hyperalgesia in a RatModel for Endometriosis. Lab. Anim. 2020, 54, 365–372. [Google Scholar] [CrossRef]
  40. Zhu, T.-H.; Zou, G.; Ding, S.-J.; Li, T.-T.; Zhu, L.-B.; Wang, J.-Z.; Yao, Y.-X.; Zhang, X.-M. Mast Cell Stabilizer Ketotifen Reduces Hyperalgesia in a Rodent Model ofSurgically Induced Endometriosis. J. Pain Res. 2019, 12, 1359–1369. [Google Scholar] [CrossRef] [Green Version]
  41. Pereira, F.E.X.G.; Medeiros, F.d.C.; Rocha, H.A.L.; Silva, K.S.D. Effects of Omega-6/3 and Omega-9/6 Nutraceuticals on Pain and Fertility inPeritoneal Endometriosis in Rats. Acta Cir. Bras. 2019, 34, e201900405. [Google Scholar] [CrossRef] [Green Version]
  42. Davenport, A.J.; Neagoe, I.; Bräuer, N.; Koch, M.; Rotgeri, A.; Nagel, J.; Laux-Biehlmann, A.; Machet, F.; Coelho, A.-M.; Boyce, S.; et al. Eliapixant Is a Selective P2X3 Receptor Antagonist for the Treatmentof Disorders Associated with Hypersensitive Nerve Fibers. Sci. Rep. 2021, 11, 19877. [Google Scholar] [CrossRef] [PubMed]
  43. Farahani, Z.K.; Taherianfard, M.; Naderi, M.M.; Ferrero, H. Possible Therapeutic Effect of Royal Jelly on Endometriotic Lesion Size, PainSensitivity, and Neurotrophic Factors in a Rat Model of Endometriosis. Physiol. Rep. 2021, 9, e15117. [Google Scholar] [CrossRef] [PubMed]
  44. Castro, J.; Maddern, J.; Grundy, L.; Manavis, J.; Harrington, A.M.; Schober, G.; Brierley, S.M. A Mouse Model of Endometriosis That Displays Vaginal, Colon, Cutaneous, andBladder Sensory Comorbidities. FASEB J. 2021, 35, e21430. [Google Scholar] [CrossRef] [PubMed]
  45. Hernandez, S.; Cruz, M.L.; Torres-Reveron, A.; Appleyard, C.B. Impact of Physical Activity on Pain Perception in an Animal Model ofEndometriosis. J. Endometr. Pelvic. Pain Disord. 2015, 7, 89–114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Montenegro, M.L.; Bonocher, C.M.; Meola, J.; Portella, R.L.; Ribeiro-Silva, A.; Brunaldi, M.O.; Ferriani, R.A.; Rosa-E-Silva, J.C. Effect of Physical Exercise on Endometriosis Experimentally Induced in Rats. Reprod. Sci. 2019, 26, 785–793. [Google Scholar] [CrossRef] [PubMed]
  47. Hernandez, S.; Cruz, M.L.; Seguinot, I.I.; Torres-Reveron, A.; Appleyard, C.B. Impact of Psychological Stress on Pain Perception in an Animal Model ofEndometriosis. Reprod. Sci. 2017, 24, 1371–1381. [Google Scholar] [CrossRef]
  48. Jingwei, C.; Huilan, D.; Ruixiao, T.; Hua, Y.; Huirong, M. Effect of Bushenwenyanghuayu Decoction on Nerve Growth Factor andBradykinin/Bradykinin B1 Receptor in a Endometriosis Dysmenorrhea Mouse Model. J. Tradit. Chin. Med. 2015, 35, 184–191. [Google Scholar] [CrossRef] [Green Version]
  49. Iuvone, T.; Affaitati, G.; de Filippis, D.; Lopopolo, M.; Grassia, G.; Lapenna, D.; Negro, L.; Costantini, R.; Vaia, M.; Cipollone, F.; et al. Ultramicronized Palmitoylethanolamide Reduces Viscerovisceral Hyperalgesia in aRat Model of Endometriosis plus Ureteral Calculosis: Role of Mast Cells. Pain 2016, 157, 80–91. [Google Scholar] [CrossRef] [Green Version]
  50. Wang, Y.; Zhang, M.; Xie, F.; Li, X.; Bao, M.; Yang, N.; Shi, R.; Wang, Z.; Wu, A.; Guan, Y.; et al. Upregulation of A2δ-1 Calcium Channel Subunit in the Spinal Cord Contributes toPelvic Organ Cross-Sensitization in a Rat Model of Experimentally-Induced Endometriosis. Neurochem. Res. 2015, 40, 1267–1273. [Google Scholar] [CrossRef]
  51. Chen, Z.; Xie, F.; Bao, M.; Li, X.; Chao, Y.; Lin, C.; Guo, R.; Zhang, C.; Wu, A.; Yue, Y.; et al. Activation of P38 MAPK in the Rostral Ventromedial Medulla by Visceral NoxiousInputs Transmitted via the Dorsal Columns May Contribute to Pelvic Organ Cross-Sensitization in Rats with Endometriosis. Neuroscience 2015, 291, 272–278. [Google Scholar] [CrossRef]
  52. Dmitrieva, N.; Suess, G.; Shirley, R. Resolvins RvD1 and 17(R)-RvD1 Alleviate Signs of Inflammation in a Rat Model ofEndometriosis. Fertil. Steril. 2014, 102, 1191–1196. [Google Scholar] [CrossRef] [PubMed]
  53. Pala, H.G.; Erbas, O.; Pala, E.E.; Artunc Ulkumen, B.; Akman, L.; Akman, T.; Oltulu, F.; Yavasoglu, A. The Effects of Sunitinib on Endometriosis. J. Obs. Gynaecol. 2015, 35, 183–187. [Google Scholar] [CrossRef] [PubMed]
  54. Simsek, Y.; Gul, M.; Yilmaz, E.; Ozerol, I.H.; Ozerol, E.; Parlakpinar, H. Atorvastatin Exerts Anti-Nociceptive Activity and Decreases Serum Levels ofHigh-Sensitivity C-Reactive Protein and Tumor Necrosis Factor-α in a Rat Endometriosis Model. Arch. Gynecol. Obs. 2014, 290, 999–1006. [Google Scholar] [CrossRef]
  55. Lopopolo, M.; Affaitati, G.; Fabrizio, A.; Massimini, F.; Lapenna, D.; Giamberardino, M.A.; Costantini, R. Effects of Tramadol on Viscero-Visceral Hyperalgesia in a Rat Model ofEndometriosis plus Ureteral Calculosis. Fundam. Clin. Pharm. 2014, 28, 331–341. [Google Scholar] [CrossRef]
  56. McAllister, S.L.; McGinty, K.A.; Resuehr, D.; Berkley, K.J. Endometriosis-Induced Vaginal Hyperalgesia in the Rat: Role of the EctopicGrowths and Their Innervation. Pain 2009, 147, 255–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Zhao, T.; Liu, X.; Zhen, X.; Guo, S.-W. Levo-Tetrahydropalmatine Retards the Growth of Ectopic Endometrial Implants andAlleviates Generalized Hyperalgesia in Experimentally Induced Endometriosis in Rats. Reprod. Sci 2011, 18, 28–45. [Google Scholar] [CrossRef]
  58. Lu, Y.; Nie, J.; Liu, X.; Zheng, Y.; Guo, S.-W. Trichostatin A, a Histone Deacetylase Inhibitor, Reduces Lesion Growth andHyperalgesia in Experimentally Induced Endometriosis in Mice. Hum. Reprod. 2010, 25, 1014–1025. [Google Scholar] [CrossRef] [Green Version]
  59. Nagabukuro, H.; Berkley, K.J. Influence of Endometriosis on Visceromotor and Cardiovascular Responses Inducedby Vaginal Distention in the Rat. Pain 2007, 132 (Suppl. S1), S96–S103. [Google Scholar] [CrossRef] [Green Version]
  60. Cason, A.M.; Samuelsen, C.L.; Berkley, K.J. Estrous Changes in Vaginal Nociception in a Rat Model of Endometriosis. Horm. Behav. 2003, 44, 123–131. [Google Scholar] [CrossRef]
  61. Giamberardino, M.A.; Berkley, K.J.; Affaitati, G.; Lerza, R.; Centurione, L.; Lapenna, D.; Vecchiet, L. Influence of Endometriosis on Pain Behaviors and Muscle Hyperalgesia Induced by aUreteral Calculosis in Female Rats. Pain 2002, 95, 247–257. [Google Scholar] [CrossRef]
  62. Filho, P.W.L.L.; Chaves Filho, A.J.M.; Vieira, C.F.X.; Oliveira, T.d.Q.; Soares, M.V.R.; Jucá, P.M.; Quevedo, J.; Barichello, T.; Macedo, D.; das Chagas Medeiros, F. Peritoneal Endometriosis Induces Time-Related Depressive- and Anxiety-likeAlterations in Female Rats: Involvement of Hippoca.ampal pro-Oxidative and BDNF Alterations. Metab. Brain Dis. 2019, 34, 909–925. [Google Scholar] [CrossRef] [PubMed]
  63. McAllister, S.L.; Dmitrieva, N.; Berkley, K.J. Sprouted Innervation into Uterine Transplants Contributes to the Development ofHyperalgesia in a Rat Model of Endometriosis. PLoS ONE 2012, 7, e31758. [Google Scholar] [CrossRef] [PubMed]
  64. Liu, Z.; Chen, S.; Qiu, C.; Sun, Y.; Li, W.; Jiang, J.; Zhang, J.-M. Fractalkine/CX3CR1 Contributes to Endometriosis-Induced Neuropathic Pain andMechanical Hypersensitivity in Rats. Front. Cell. Neurosci. 2018, 12, 495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Liu, Y.; Qin, X.; Lu, X.; Jiang, J. Effects of Inhibiting the PI3K/Akt/MTOR Signaling Pathway on the Pain of SciaticEndometriosis in a Rat Model. Can. J. Physiol. Pharm. 2019, 97, 963–970. [Google Scholar] [CrossRef]
  66. Liu, M.; Liu, X.; Zhang, Y.; Guo, S.-W. Valproic Acid and Progestin Inhibit Lesion Growth and Reduce Hyperalgesia inExperimentally Induced Endometriosis in Rats. Reprod. Sci. 2012, 19, 360–373. [Google Scholar] [CrossRef]
  67. Liu, Y.; Zhang, Z.; Lu, X.; Meng, J.; Qin, X.; Jiang, J. Anti-Nociceptive and Anti-Inflammatory Effects of Sulforaphane on SciaticEndometriosis in a Rat Model. Neurosci. Lett. 2020, 723, 134858. [Google Scholar] [CrossRef]
  68. Fattori, V.; Franklin, N.S.; Gonzalez-Cano, R.; Peterse, D.; Ghalali, A.; Madrian, E.; Verri, W.A.J.; Andrews, N.; Woolf, C.J.; Rogers, M.S. Nonsurgical Mouse Model of Endometriosis-Associated Pain That Responds toClinically Active Drugs. Pain 2020, 161, 1321–1331. [Google Scholar] [CrossRef]
  69. Bove, G.M. A Model for Radiating Leg Pain of Endometriosis. J. Bodyw. Mov. 2016, 20, 931–936. [Google Scholar] [CrossRef] [Green Version]
  70. Chen, S.; Xie, W.; Strong, J.A.; Jiang, J.; Zhang, J.-M. Sciatic Endometriosis Induces Mechanical Hypersensitivity, Segmental NerveDamage, and Robust Local Inflammation in Rats. Eur. J. Pain 2016, 20, 1044–1057. [Google Scholar] [CrossRef] [Green Version]
  71. Su, W.; Cui, H.; Wu, D.; Yu, J.; Ma, L.; Zhang, X.; Huang, Y.; Ma, C. Suppression of TLR4-MyD88 Signaling Pathway Attenuated Chronic Mechanical Pain ina Rat Model of Endometriosis. J. Neuroinflamm. 2021, 18, 65. [Google Scholar] [CrossRef]
  72. Alvarez, P.; Levine, J.D. Screening the Role of Pronociceptive Molecules in a Rodent Model of EndometriosisPain. J. Pain 2014, 15, 726–733. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Alvarez, P.; Giudice, L.C.; Levine, J.D. Impact of Surgical Excision of Lesions on Pain in a Rat Model of Endometriosis. Eur. J. Pain 2015, 19, 103–110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Alvarez, P.; Bogen, O.; Chen, X.; Giudice, L.C.; Levine, J.D. Ectopic Endometrium-Derived Leptin Produces Estrogen-Dependent Chronic Pain in aRat Model of Endometriosis. Neuroscience 2014, 258, 111–120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Alvarez, P.; Chen, X.; Hendrich, J.; Irwin, J.C.; Green, P.G.; Giudice, L.C.; Levine, J.D. Ectopic Uterine Tissue as a Chronic Pain Generator. Neuroscience 2012, 225, 269–282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Maddern, J.; Grundy, L.; Harrington, A.; Schober, G.; Castro, J.; Brierley, S.M. A Syngeneic Inoculation Mouse Model of Endometriosis That Develops MultipleComorbid Visceral and Cutaneous Pain like Behaviours. Pain 2021, 163, 1622–1635. [Google Scholar] [CrossRef] [PubMed]
  77. Greaves, E.; Horne, A.W.; Jerina, H.; Mikolajczak, M.; Hilferty, L.; Mitchell, R.; Fleetwood-Walker, S.M.; Saunders, P.T.K. EP2 Receptor Antagonism Reduces Peripheral and Central Hyperalgesia in a Preclinical Mouse Model of Endometriosis. Sci. Rep. 2017, 7, 44169. [Google Scholar] [CrossRef] [Green Version]
  78. Arosh, J.A.; Lee, J.; Balasubbramanian, D.; Stanley, J.A.; Long, C.R.; Meagher, M.W.; Osteen, K.G.; Bruner-Tran, K.L.; Burghardt, R.C.; Starzinski-Powitz, A.; et al. Molecular and Preclinical Basis to Inhibit PGE2 Receptors EP2 and EP4 as a NovelNonsteroidal Therapy for Endometriosis. Proc. Natl. Acad. Sci. USA 2015, 112, 9716–9721. [Google Scholar] [CrossRef] [Green Version]
  79. Dodds, K.N.; Beckett, E.A.H.; Evans, S.F.; Hutchinson, M.R. Spinal Glial Adaptations Occur in a Minimally Invasive Mouse Model ofEndometriosis: Potential Implications for Lesion Etiology and Persistent Pelvic Pain. Reprod. Sci. 2019, 26, 357–369. [Google Scholar] [CrossRef]
  80. Wei, X.; Shao, X. Nobiletin Alleviates Endometriosis via Down-Regulating NF-ΚB Activity inEndometriosis Mouse Model. Biosci. Rep. 2018, 38. [Google Scholar] [CrossRef] [Green Version]
  81. Zhao, L.; Yang, H.; Xuan, Y.; Luo, Z.; Lin, Q.; Zhao, J.; Ren, N.; Zhou, S.; Zhao, X. Increased Expression of Fibroblast Growth Factor Receptor 1 in Endometriosis andIts Correlation with Endometriosis-Related Dysmenorrhea and Recurrence. Eur. J. Obs. Gynecol. Reprod. Biol. 2015, 184, 117–124. [Google Scholar] [CrossRef]
  82. Laux-Biehlmann, A.; Boyken, J.; Dahllöf, H.; Schmidt, N.; Zollner, T.M.; Nagel, J. Dynamic Weight Bearing as a Non-Reflexive Method for the Measurement of AbdominalPain in Mice. Eur. J. Pain 2016, 20, 742–752. [Google Scholar] [CrossRef] [PubMed]
  83. Gruen, M.; Laux-Biehlmann, A.; Zollner, T.M.; Nagel, J. Use of Dynamic Weight Bearing as a Novel End-Point for the Assessment ofAbdominal Pain in the LPS-Induced Peritonitis Model in the Rat. J. Neurosci. Methods 2014, 232, 118–124. [Google Scholar] [CrossRef] [PubMed]
  84. Liang, R.; Ustinova, E.E.; Patnam, R.; Fraser, M.O.; Gutkin, D.W.; Pezzone, M.A. Enhanced Expression of Mast Cell Growth Factor and Mast Cell Activation in the Bladder Following the Resolution of Trinitrobenzenesulfonic Acid (TNBS) Colitis in Female Rats. Neurourol. Urodyn. 2007, 26, 887–893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Kawamorita, N.; Yoshikawa, S.; Kashyap, M.; Tyagi, P.; Arai, Y.; Chancellor, M.B.; Yoshimura, N. Liposome Based Intravesical Therapy Targeting Nerve Growth Factor Ameliorates Bladder Hypersensitivity in Rats with Experimental Colitis. J. Urol. 2016, 195, 1920–1926. [Google Scholar] [CrossRef] [PubMed]
  86. Ustinova, E.E.; Gutkin, D.W.; Pezzone, M.A. Sensitization of Pelvic Nerve Afferents and Mast Cell Infiltration in the Urinary Bladder Following Chronic Colonic Irritation Is Mediated by Neuropeptides. Am. J. Physiol. Ren. Physiol. 2007, 292, F123–F130. [Google Scholar] [CrossRef]
  87. Zhang, H.; Dong, X.; Yang, Z.; Zhao, J.; Lu, Q.; Zhu, J.; Li, L.; Yi, S.; Xu, J. Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization. Drug. Des. Devel. 2022, 16, 67–81. [Google Scholar] [CrossRef]
  88. Pezzone, M.A.; Liang, R.; Fraser, M.O. A Model of Neural Cross-Talk and Irritation in the Pelvis: Implications for the Overlap of Chronic Pelvic Pain Disorders. Gastroenterology 2005, 128, 1953–1964. [Google Scholar] [CrossRef]
  89. Grundy, L.; Harrington, A.M.; Castro, J.; Garcia-Caraballo, S.; Deiteren, A.; Maddern, J.; Rychkov, G.Y.; Ge, P.; Peters, S.; Feil, R.; et al. Chronic Linaclotide Treatment Reduces Colitis-Induced Neuroplasticity and Reverses Persistent Bladder Dysfunction. JCI Insight 2018, 3, e121841. [Google Scholar] [CrossRef]
  90. Li, J.; Micevych, P.; McDonald, J.; Rapkin, A.; Chaban, V. Inflammation in the Uterus Induces Phosphorylated Extracellular Signal-Regulated Kinase and Substance P Immunoreactivity in Dorsal Root Ganglia Neurons Innervating Both Uterus and Colon in Rats. J. Neurosci. Res. 2008, 86, 2746–2752. [Google Scholar] [CrossRef] [Green Version]
  91. Jin, X.W.; Liu, B.K.; Zhang, X.; Zhao, Z.H.; Shao, Y. Establishment of a Novel Autoimmune Experimental Model of Bladder Pain Syndrome/Interstitial Cystitis in C57BL/6 Mice. Inflammation 2017, 40, 861–870. [Google Scholar] [CrossRef]
  92. Akiyama, Y.; Yao, J.R.; Kreder, K.J.; O’Donnell, M.A.; Lutgendorf, S.K.; Lyu, D.; Maeda, D.; Kume, H.; Homma, Y.; Luo, Y. Autoimmunity to Urothelial Antigen Causes Bladder Inflammation, Pelvic Pain, and Voiding Dysfunction: A Novel Animal Model for Hunner-Type Interstitial Cystitis. Am. J. Physiol. Ren. Physiol. 2021, 320, F174–F182. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, B.K.; Jin, X.W.; Lu, H.Z.; Zhang, X.; Zhao, Z.H.; Shao, Y. The Effects of Neurokinin-1 Receptor Antagonist in an Experimental Autoimmune Cystitis Model Resembling Bladder Pain Syndrome/Interstitial Cystitis. Inflammation 2019, 42, 246–254. [Google Scholar] [CrossRef] [PubMed]
  94. Izgi, K.; Altuntas, C.Z.; Bicer, F.; Ozer, A.; Sakalar, C.; Li, X.; Tuohy, V.K.; Daneshgari, F. Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice. PLoS ONE 2013, 8, e72067. [Google Scholar] [CrossRef] [Green Version]
  95. Bullock, A.; Becich, M.J.; Klutke, C.G.; Ratliff, T.L. Experimental Autoimmune Cystitis: A Potential Murine Model for Ulcerative Interstitial Cystitis. J. Urol. 1992, 148, 1951–1956. [Google Scholar] [CrossRef]
  96. Wang, X.; Liu, W.; O’Donnell, M.; Lutgendorf, S.; Bradley, C.; Schrepf, A.; Liu, L.; Kreder, K.; Luo, Y. Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study. PLoS ONE 2016, 11, e0168772. [Google Scholar] [CrossRef] [Green Version]
  97. Aydogdu, O.; Gocun, P.U.; Aronsson, P.; Carlsson, T.; Winder, M. Cross-Organ Sensitization between the Prostate and Bladder in an Experimental Rat Model of Lipopolysaccharide (LPS)-Induced Chronic Pelvic Pain Syndrome. BMC Urol. 2021, 21, 1–10. [Google Scholar] [CrossRef] [PubMed]
  98. Schwartz, E.S.; La, J.H.; Young, E.E.; Feng, B.; Joyce, S.; Gebhart, G.F. Chronic Prostatitis Induces Bladder Hypersensitivity and Sensitizes Bladder Afferents in the Mouse. J. Urol. 2016, 196, 892–901. [Google Scholar] [CrossRef]
  99. Funahashi, Y.; Takahashi, R.; Mizoguchi, S.; Suzuki, T.; Takaoka, E.; Ni, J.; Wang, Z.; DeFranco, D.B.; de Groat, W.C.; Tyagi, P.; et al. Bladder Overactivity and Afferent Hyperexcitability Induced by Prostate-to-Bladder Cross-Sensitization in Rats with Prostatic Inflammation. J. Physiol. 2019, 597, 2063–2078. [Google Scholar] [CrossRef]
  100. Mizoguchi, S.; Wolf-Johnson, A.S.; Suzuki, T.; Takaoka, E.; DeFranco, D.B.; Wang, Z.; A. Birder, L.; Yoshimura, N. MP45-06 Bladder Urothelial and Afferent Dysfunctions Underlying Bladder Overactivity in Rats with Chemically Induced Prostatic Inflammation. J. Urol. 2018, 199, e599. [Google Scholar] [CrossRef]
  101. Jasmin, L.; Janni, G.; Manz, H.J.; Rabkin, S.D. Activation of CNS Circuits Producing a Neurogenic Cystitis: Evidence for Centrally Induced Peripheral Inflammation. J. Neurosci. 1998, 18, 10016–10029. [Google Scholar] [CrossRef] [Green Version]
  102. Chen, M.C.; Mudge, C.S.; Klumpp, D.J. Urothelial Lesion Formation Is Mediated by TNFR1 during Neurogenic Cystitis. Am. J. Physiol. Ren. Physiol. 2006, 291, 741–749. [Google Scholar] [CrossRef]
  103. Chen, M.C.; Keshavan, P.; Gregory, G.D.; Klumpp, D.J. RANTES Mediates TNF-Dependent Lamina Propria Mast Cell Accumulation and Barrier Dysfunction in Neurogenic Cystitis. Am. J. Physiol. Ren. Physiol. 2007, 292, 1372–1379. [Google Scholar] [CrossRef] [PubMed]
  104. Jasmin, L.; Janni, G.; Ohara, P.T.; Rabkin, S.D. CNS Induced Neurogenic Cystitis Is Associated with Bladder Mast Cell Degranulation in the Rat. J. Urol. 2000, 164, 852–855. [Google Scholar] [CrossRef]
  105. Yang, W.; Rudick, C.N.; Hoxha, E.; Allsop, S.A.; Dimitrakoff, J.D.; Klumpp, D.J. Ca 2 /Calmodulin-Dependent Protein Kinase II Is Associated with Pelvic Pain of Neurogenic Cystitis. Am. J. Physiol. Ren. Physiol. 2012, 303, 350–356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Yang, W.; Yaggie, R.E.; Jiang, M.C.; Rudick, C.N.; Done, J.; Heckman, C.J.; Rosen, J.M.; Schaeffer, A.J.; Klumpp, D.J. Acyloxyacyl Hydrolase Modulates Pelvic Pain Severity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2018, 314, 353–365. [Google Scholar] [CrossRef]
  107. Rudick, C.N.; Bryce, P.J.; Guichelaar, L.A.; Berry, R.E.; Klumpp, D.J. Mast Cell-Derived Histamine Mediates Cystitis Pain. PLoS ONE 2008, 3, e2096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Rudick, C.N.; Chen, M.C.; Mongiu, A.K.; Klumpp, D.J. Organ Cross Talk Modulates Pelvic Pain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 293, R1191–R1198. [Google Scholar] [CrossRef] [Green Version]
  109. Soler, R.; Füllhase, C.; Santos, C.; Andersson, K.E. Development of Bladder Dysfunction in a Rat Model of Dopaminergic Brain Lesion. Neurourol. Urodyn. 2011, 30, 188–193. [Google Scholar] [CrossRef]
  110. Yoshimura, N.; Kuno, S.; Chancellor, M.B.; de Groat, W.C.; Seki, S. Dopaminergic Mechanisms Underlying Bladder Hyperactivity in Rats with a Unilateral 6-Hydroxydopamine (6-OHDA) Lesion of the Nigrostriatal Pathway. Br. J. Pharm. 2003, 139, 1425–1432. [Google Scholar] [CrossRef]
  111. Matos, R.; Cordeiro, J.M.; Coelho, A.; Ferreira, S.; Silva, C.; Igawa, Y.; Cruz, F.; Charrua, A. Bladder Pain Induced by Prolonged Peripheral Alpha 1A Adrenoceptor Stimulation Involves the Enhancement of Transient Receptor Potential Vanilloid 1 Activity and an Increase of Urothelial Adenosine Triphosphate Release. Acta Physiol. 2016, 218, 265–275. [Google Scholar] [CrossRef]
  112. Ihara, T.; Nakamura, Y.; Mitsui, T.; Tsuchiya, S.; Kanda, M.; Kira, S.; Nakagomi, H.; Sawada, N.; Kamiyama, M.; Shigetomi, E.; et al. Intermittent Restraint Stress Induces Circadian Misalignment in the Mouse Bladder, Leading to Nocturia. Sci. Rep. 2019, 9, 10069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Ercan, F.; Şan, T.; Çavdar, S. The Effects of Cold-Restraint Stress on Urinary Bladder Wall Compared with Interstitial Cystitis Morphology. Urol. Res. 1999, 27, 454–461. [Google Scholar] [CrossRef]
  114. Ercan, F.; Çetinel, Ş.; Erin, N.; Aydin, H.; Hürdaǧ, C.; Parker, T.; Parker, K.; Mayhew, T. Volume of Nerve Fibers in the Stress-Induced Bladder of Adult Rats Following Capsaicin Treatment. Urol. Int. 2003, 71, 393–398. [Google Scholar] [CrossRef]
  115. Cao, J.; Boucher, W.; Kempuraj, D.; Donelan, J.M.; Theoharides, T.C. Acute Stress and Intravesical Corticotropin-Releasing Hormone Induces Mast Cell Dependent Vascular Endothelial Growth Factor Release From Mouse Bladder Explants. J. Urol. 2006, 176, 1208–1213. [Google Scholar] [CrossRef] [PubMed]
  116. Matos, R.; Serrão, P.; Rodriguez, L.; Birder, L.A.; Cruz, F.; Charrua, A. The Water Avoidance Stress Induces Bladder Pain Due to a Prolonged Alpha1A Adrenoceptor Stimulation. Naunyn Schmiedebergs Arch. Pharm. 2017, 390, 839–844. [Google Scholar] [CrossRef]
  117. Çetinel, Ş.; Ercan, F.; Çikler, E.; Contuk, G.; Şener, G. Protective Effect of Melatonin on Water Avoidance Stress Induced Degeneration of the Bladder. J. Urol. 2005, 173, 267–270. [Google Scholar] [CrossRef] [PubMed]
  118. Smith, A.L.; Leung, J.; Kun, S.; Zhang, R.; Karagiannides, I.; Raz, S.; Lee, U.; Glovatscka, V.; Pothoulakis, C.; Bradesi, S.; et al. The Effects of Acute and Chronic Psychological Stress on Bladder Function in a Rodent Model. Urology 2011, 78, 967.e1-7. [Google Scholar] [CrossRef] [Green Version]
  119. Dias, B.; Serrão, P.; Cruz, F.; Charrua, A. Effect of Water Avoidance Stress on Serum and Urinary NGF Levels in Rats: Diagnostic and Therapeutic Implications for BPS/IC Patients. Sci. Rep. 2019, 9, 14113. [Google Scholar] [CrossRef] [Green Version]
  120. Lee, U.J.; Ackerman, A.L.; Wu, A.; Zhang, R.; Leung, J.; Bradesi, S.; Mayer, E.A.; Rodríguez, L.V. Chronic Psychological Stress in High-Anxiety Rats Induces Sustained Bladder Hyperalgesia. Physiol. Behav. 2015, 139, 541–548. [Google Scholar] [CrossRef]
  121. Sağlam, B.; Çikler, E.; Zeybek, A.; Çetinel, Ş.; Şener, G.; Ercan, F. An Aqueous Garlic Extract Alleviates Water Avoidance Stress-Induced Degeneration of the Urinary Bladder. BJU Int. 2006, 98, 1250–1254. [Google Scholar] [CrossRef]
  122. Han, D.Y.; Jeong, H.J.; Lee, M.Y. Bladder Hyperactivity Induced by Chronic Variable Stress in Rats. LUTS Low. Urin. Tract Symptoms 2015, 7, 56–61. [Google Scholar] [CrossRef]
  123. Imamura, T.; Ishizuka, O.; Nishizawa, O. Cold Stress Induces Lower Urinary Tract Symptoms. Int. J. Urol. 2013, 20, 661–669. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Imamura, T.; Ishizuka, O.; Aizawa, N.; Zhong, C.; Ogawa, T.; Nakayama, T.; Tanabe, T.; Nishizawa, O. Cold Environmental Stress Induces Detrusor Overactivity via Resiniferatoxin-Sensitive Nerves in Conscious Rats. Neurourol. Urodyn. 2008, 27, 348–352. [Google Scholar] [CrossRef] [PubMed]
  125. Mingin, G.C.; Peterson, A.; Erickson, C.S.; Nelson, M.T.; Vizzard, M.A. Social Stress Induces Changes in Urinary Bladder Function, Bladder NGF Content, and Generalized Bladder Inflammation in Mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307, R893–R900. [Google Scholar] [CrossRef] [Green Version]
  126. Mingin, G.C.; Heppner, T.J.; Tykocki, N.R.; Erickson, C.S.; Vizzard, M.A.; Nelson, M.T. Social Stress in Mice Induces Urinary Bladder Overactivity and Increases TRPV 1 Channel-Dependent Afferent Nerve Activity. Am. J. Physiol. Regul. Integr. Comp. Physiol 2015, 309, R629–R638. [Google Scholar] [CrossRef] [Green Version]
  127. Wood, S.K.; Baez, M.A.; Bhatnagar, S.; Valentino, R.J. Social Stress-Induced Bladder Dysfunction: Potential Role of Corticotropin-Releasing Factor. Am. J. Physiol Regul. Integr. Comp. Physiol. 2009, 296, 1671–1678. [Google Scholar] [CrossRef] [Green Version]
  128. Wu, P.Y.; Yang, X.; Wright, D.E.; Christianson, J.A.; Christianson, J. Foot Shock Stress Generates Persistent Widespread Hypersensitivity and Anhedonic Behavior in an Anxiety-Prone Strain of Mice. Pain 2020, 161, 211–219. [Google Scholar] [CrossRef]
  129. Robbins, M.T.; Ness, T.J. Footshock-Induced Urinary Bladder Hypersensitivity: Role of Spinal Corticotropin-Releasing Factor Receptors. J. Pain 2008, 9, 991–998. [Google Scholar] [CrossRef] [Green Version]
  130. Ligon, C.; Mohammadi, E.; Ge, P.; Hannig, G.; Higgins, C.; Greenwood-Van Meerveld, B. Linaclotide Inhibits Colonic and Urinary Bladder Hypersensitivity in Adult Female Rats Following Unpredictable Neonatal Stress. Neurogastroenterol. Motil. 2018, 30, e13375. [Google Scholar] [CrossRef]
  131. Chaloner, A.; Greenwood-Van Meerveld, B. Sexually Dimorphic Effects of Unpredictable Early Life Adversity on Visceral Pain Behavior in a Rodent Model. J. Pain 2013, 14, 270–280. [Google Scholar] [CrossRef] [PubMed]
  132. Matos, R.; Cruz, F.; Charrua, A. MP29-03 Childhood Stressful Events Induce Chronic Bladder Pain in Adulthood through a TRPV1 Dependent Mechanism. J. Urol. 2017, 197, e380–e381. [Google Scholar] [CrossRef]
  133. Fuentes, I.M.; Pierce, A.N.; di Silvestro, E.R.; Maloney, M.O.; Christianson, J.A. Differential Influence of Early Life and Adult Stress on Urogenital Sensitivity and Function in Male Mice. Front. Syst. Neurosci. 2018, 11, 97. [Google Scholar] [CrossRef] [Green Version]
  134. Pierce, A.N.; Eller-Smith, O.C.; Christianson, J.A. Voluntary Wheel Running Attenuates Urinary Bladder Hypersensitivity and Dysfunction Following Neonatal Maternal Separation in Female Mice. Neurourol. Urodyn. 2018, 37, 1623–1632. [Google Scholar] [CrossRef]
  135. Burns, K.A.; Pearson, A.M.; Slack, J.L.; Por, E.D.; Scribner, A.N.; Eti, N.A.; Burney, R.O. Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model. Front. Physiol. 2021, 12, 806574. [Google Scholar] [CrossRef]
  136. Hayashi, S.; Nakamura, T.; Motooka, Y.; Ito, F.; Jiang, L.; Akatsuka, S.; Iwase, A.; Kajiyama, H.; Kikkawa, F.; Toyokuni, S. Novel Ovarian Endometriosis Model Causes Infertility via Iron-Mediated Oxidative Stress in Mice. Redox Biol. 2020, 37, 101726. [Google Scholar] [CrossRef]
  137. Zheng, P.; Jia, S.; Guo, D.; Chen, S.; Zhang, W.; Cheng, A.; Xie, W.; Sun, G.; Leng, J.; Lang, J. Central Sensitization-Related Changes in Brain Function Activity in a Rat Endometriosis-Associated Pain Model. J. Pain Res. 2020, 13, 95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Li, T.; Mamillapalli, R.; Ding, S.; Chang, H.; Liu, Z.W.; Gao, X.B.; Taylor, H.S. Endometriosis Alters Brain Electrophysiology, Gene Expression and Increases Pain Sensitization, Anxiety, and Depression in Female Mice. Biol. Reprod. 2018, 99, 349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Mogil, J.S. The History of Pain Measurement in Humans and Animals. Front. Pain Res. 2022, 3, 156. [Google Scholar] [CrossRef]
  140. Tejada, M.; Antúnez Muñoz, C.; Nunez-Badinez, P.; de Leo, B.; Saunders, P.; Vincent, K.; Cano, A.; Nagel, J.; Gómez, R. Rodent Animal Models of Endometriosis-Associated Pain: Unmet Needs and Resources Available for Improving Translational Research in Endometriosis. Int. J. Mol. Sci. 2023, 24, 2422. [Google Scholar] [CrossRef] [PubMed]
  141. Tran, L.; Chaloner, A.; Sawalha, A.H.; Greenwood Van-Meerveld, B. Importance of Epigenetic Mechanisms in Visceral Pain Induced by Chronic Water Avoidance Stress. Psychoneuroendocrinology 2013, 38, 898–906. [Google Scholar] [CrossRef]
  142. Coutinho, S.V.; Plotsky, P.M.; Sablad, M.; Miller, J.C.; Zhou, H.; Bayati, A.I.; McRoberts, J.A.; Mayer, E.A. Neonatal Maternal Separation Alters Stress-Induced Responses to Viscerosomatic Nociceptive Stimuli in Rat. Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282, G307–G316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Long, Q.; Liu, X.; Guo, S.-W. Early Maternal Separation Accelerates the Progression of Endometriosis in AdultMice. Reprod. Biol. Endocrinol. 2020, 18, 63. [Google Scholar] [CrossRef] [PubMed]
  144. Fuentes, I.M.; Pierce, A.N.; O’neil, P.T.; Christianson, J.A. Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation. J. Vis. Exp. 2015, 2015, e53181. [Google Scholar] [CrossRef] [Green Version]
  145. Fuentes, I.M.; Jones, B.M.; Brake, A.D.; Pierce, A.N.; Eller, O.C.; Supple, R.M.; Wright, D.E.; Christianson, J.A. Voluntary Wheel Running Improves Outcomes in an Early Life Stress-Induced Model of Urologic Chronic Pelvic Pain Syndrome in Male Mice. Pain 2021, 162, 1681–1691. [Google Scholar] [CrossRef]
  146. Dodds, K.N.; Beckett, E.A.H.; Evans, S.F.; Grace, P.M.; Watkins, L.R.; Hutchinson, M.R. Glial Contributions to Visceral Pain: Implications for Disease Etiology and the Female Predominance of Persistent Pain. Transl. Psychiatry 2016, 6, e888. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Atkins, H.M.; Lombardini, E.D.; Caudell, D.L.; Appt, S.E.; Dubois, A.; Cline, J.M. Decidualization of Endometriosis in Macaques. Vet. Pathol. 2016, 53, 1252–1258. [Google Scholar] [CrossRef] [Green Version]
  148. Nishimoto-Kakiuchi, A.; Netsu, S.; Matsuo, S.; Hayashi, S.; Ito, T.; Okabayashi, S.; Yasmin, L.; Yuzawa, K.; Kondoh, O.; Kato, A.; et al. Characteristics of Histologically Confirmed Endometriosis in Cynomolgus Monkeys. Hum. Reprod. 2016, 31, 2352–2359. [Google Scholar] [CrossRef] [Green Version]
  149. Hayashi, K.; Nakayama, M.; Iwatani, C.; Tsuchiya, H.; Nakamura, S.; Nonoguchi, K.; Itoh, Y.; Tsuji, S.; Ishigaki, H.; Mori, T.; et al. The Natural History of Spontaneously Occurred Endometriosis in Cynomolgus Monkeysby Monthly Follow-Up Laparoscopy for Two Years. Tohoku J. Exp. Med. 2020, 251, 241–253. [Google Scholar] [CrossRef]
  150. Westropp, J.L.; Delgado, M.; Buffington, C.A.T. Chronic Lower Urinary Tract Signs in Cats: Current Understanding of Pathophysiologyand Management. Vet. Clin. N. Am. Small Anim. Pr. 2019, 49, 187–209. [Google Scholar] [CrossRef]
  151. Lindberg, S.; Busch, C. Endometriosis in Rhesus Monkeys. Ups. J. Med. Sci. 1984, 89, 129–134. [Google Scholar] [CrossRef]
  152. Nishimoto-Kakiuchi, A.; Netsu, S.; Okabayashi, S.; Taniguchi, K.; Tanimura, H.; Kato, A.; Suzuki, M.; Sankai, T.; Konno, R. Spontaneous Endometriosis in Cynomolgus Monkeys as a Clinically Relevant Experimental Model. Hum. Reprod. 2018, 33, 1228–1236. [Google Scholar] [CrossRef]
  153. Cornillie, F.J.; D’Hooghe, T.M.; Bambra, C.S.; Lauweryns, J.M.; Isahakia, M.; Koninckx, P.R. Morphological Characteristics of Spontaneous Endometriosis in the Baboon (Papio Anubis and Papio Cynocephalus). Gynecol. Obs. Investig. 1992, 34, 225–228. [Google Scholar] [CrossRef] [PubMed]
  154. Yano, M.; Matsuda, A.; Natsume, T.; Ogawa, S.; Awaga, Y.; Hayashi, I.; Hama, A.; Takamatsu, H. Pain-Related Behavior and Brain Activation in Cynomolgus Macaques with NaturallyOccurring Endometriosis. Hum. Reprod. 2019, 34, 469–478. [Google Scholar] [CrossRef]
  155. Atkins, H.M.; Bharadwaj, M.S.; O’Brien Cox, A.; Furdui, C.M.; Appt, S.E.; Caudell, D.L. Endometrium and Endometriosis Tissue Mitochondrial Energy Metabolism in aNonhuman Primate Model. Reprod. Biol. Endocrinol. 2019, 17, 70. [Google Scholar] [CrossRef]
  156. Atkins, H.M.; Appt, S.E.; Taylor, R.N.; Torres-Mendoza, Y.; Lenk, E.E.; Rosenthal, N.S.; Caudell, D.L. Systemic Iron Deficiency in a Nonhuman Primate Model of Endometriosis. Comp. Med. 2018, 68, 298–307. [Google Scholar] [CrossRef]
  157. Baldi, A.; Lanza, A.; Menicagli, F.; Signorile, P.G.; Spugnini, E.P. Histological and Immunohistochemical Characterization of a Case of Endometriosis in a Guinea Pig (Cavia tschudii). Case Rep. Vet. Med. 2017, 2017, 4594510. [Google Scholar] [CrossRef] [Green Version]
  158. Catalini, L.; Fedder, J. Characteristics of the Endometrium in Menstruating Species: Lessons Learned from the Animal Kingdom. Biol. Reprod. 2020, 102, 1160–1169. [Google Scholar] [CrossRef] [Green Version]
  159. Doré, M.; Lagacé, A. Spontaneous External Endometriosis in a Gorilla (Gorilla gorilla). Can. Vet. J. 1985, 26, 347. [Google Scholar]
  160. Westropp, J.L.; Buffington, C.A.T. In Vivo Models of Interstitial Cystitis. J. Urol. 2002, 167, 694–702. [Google Scholar] [CrossRef] [PubMed]
  161. Birder, L.; Andersson, K.-E. Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome. Int. Neurourol. J. 2018, 22, S3–S9. [Google Scholar] [CrossRef] [PubMed]
  162. Nishi, M. Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents. Int. J. Mol. Sci. 2020, 21, 7212. [Google Scholar] [CrossRef] [PubMed]
  163. Lacagnina, M.J.; Heijnen, C.J.; Watkins, L.R.; Grace, P.M. Autoimmune Regulation of Chronic Pain. Pain Rep. 2021, 6, e905. [Google Scholar] [CrossRef] [PubMed]
  164. Jasieńska, G.; Ziomkiewicz, A.; Ellison, P.T.; Lipson, S.F.; Thune, I. Large Breasts and Narrow Waists Indicate High Reproductive Potential in Women. Proc. Biol. Sci. 2004, 271, 1213–1217. [Google Scholar] [CrossRef]
  165. Ley, C.J.; Lees, B.; Stevenson, J.C. Sex- and Menopause-Associated Changes in Body-Fat Distribution. Am. J. Clin. Nutr. 1992, 55, 950–954. [Google Scholar] [CrossRef] [Green Version]
  166. Takemura, Y.; Osuga, Y.; Harada, M.; Hirata, T.; Koga, K.; Yoshino, O.; Hirota, Y.; Morimoto, C.; Yano, T.; Taketani, Y. Concentration of Adiponectin in Peritoneal Fluid Is Decreased in Women with Endometriosis. Am. J. Reprod. Immunol. 2005, 54, 217–221. [Google Scholar] [CrossRef]
  167. Alviggi, C.; Clarizia, R.; Castaldo, G.; Matarese, G.; Colucci, C.C.; Conforti, S.; Pagano, T.; Revelli, A.; de Placido, G. Leptin Concentrations in the Peritoneal Fluid of Women with Ovarian Endometriosis Are Different According to the Presence of a “deep” or “Superficial” Ovarian Disease. Gynecol. Endocrinol. 2009, 25, 610–615. [Google Scholar] [CrossRef]
  168. Yi, K.W.; Shin, J.H.; Park, H.T.; Kim, T.; Kim, S.H.; Hur, J.Y. Resistin Concentration Is Increased in the Peritoneal Fluid of Women with Endometriosis. Am. J. Reprod. Immunol. 2010, 64, 318–323. [Google Scholar] [CrossRef]
  169. Zolbin, M.M.; Mamillapalli, R.; Nematian, S.E.; Goetz, L.; Taylor, H.S. Adipocyte Alterations in Endometriosis: Reduced Numbers of Stem Cells and MicroRNA Induced Alterations in Adipocyte Metabolic Gene Expression. Reprod. Biol. Endocrinol. 2019, 17, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Li, S.; Schwartz, A.V.; LaValley, M.P.; Wang, N.; Desai, N.; Sun, X.; Neogi, T.; Nevitt, M.; Lewis, C.E.; Guermazi, A.; et al. Visceral Adiposity Is Associated with Pain, but Not Structural Osteoarthritis. Arthritis Rheumatol. 2020, 72, 1103. [Google Scholar] [CrossRef]
  171. Hillebrand, S.; de Mutsert, R.; Christen, T.; Maan, A.C.; Jukema, J.W.; Lamb, H.J.; de Roos, A.; Rosendaal, F.R.; den Heijer, M.; Swenne, C.A. Body Fat, Especially Visceral Fat, Is Associated with Electrocardiographic Measures of Sympathetic Activation. Obesity 2014, 22, 1553–1559. [Google Scholar] [CrossRef] [PubMed]
  172. Cardoso, F.; Klein Wolterink, R.G.J.; Godinho-Silva, C.; Domingues, R.G.; Ribeiro, H.; da Silva, J.A.; Mahú, I.; Domingos, A.I.; Veiga-Fernandes, H. Neuro-Mesenchymal Units Control ILC2 and Obesity via a Brain–Adipose Circuit. Nature 2021, 597, 410–414. [Google Scholar] [CrossRef] [PubMed]
  173. Ghosh, D.; Filaretova, L.; Bharti, J.; Roy, K.K.; Sharma, J.B.; Sengupta, J. Pathophysiological Basis of Endometriosis-Linked Stress Associated with Pain and Infertility: A Conceptual Review. Reprod. Med. 2020, 1, 32–61. [Google Scholar] [CrossRef]
  174. Heard, M.E.; Melnyk, S.B.; Simmen, F.A.; Yang, Y.; Pabona, J.M.P.; Simmen, R.C.M. High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model Is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status. Endocrinology 2016, 157, 2870–2882. [Google Scholar] [CrossRef]
  175. Jhang, J.F.; Birder, L.A.; Jiang, Y.H.; Hsu, Y.H.; Ho, H.C.; Kuo, H.C. Dysregulation of Bladder Corticotropin-Releasing Hormone Receptor in the Pathogenesis of Human Interstitial Cystitis/Bladder Pain Syndrome. Sci. Rep. 2019, 9, 19169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Neto, A.C.; Santos-Pereira, M.; Abreu-Mendes, P.; Neves, D.; Almeida, H.; Cruz, F.; Charrua, A. The Unmet Needs for Studying Chronic Pelvic/Visceral Pain Using Animal Models. Biomedicines 2023, 11, 696. https://doi.org/10.3390/biomedicines11030696

AMA Style

Neto AC, Santos-Pereira M, Abreu-Mendes P, Neves D, Almeida H, Cruz F, Charrua A. The Unmet Needs for Studying Chronic Pelvic/Visceral Pain Using Animal Models. Biomedicines. 2023; 11(3):696. https://doi.org/10.3390/biomedicines11030696

Chicago/Turabian Style

Neto, Ana Catarina, Mariana Santos-Pereira, Pedro Abreu-Mendes, Delminda Neves, Henrique Almeida, Francisco Cruz, and Ana Charrua. 2023. "The Unmet Needs for Studying Chronic Pelvic/Visceral Pain Using Animal Models" Biomedicines 11, no. 3: 696. https://doi.org/10.3390/biomedicines11030696

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop