We are delighted to present the Emerging Trends in Abdominal and Pelvic Pain 2022 article collection. This collection showcases the high-quality work of internationally recognized researchers in the early to mid stages of their research careers. These rising star researchers have been recognized by the Frontiers in Pain Research Editors for their potential to influence future directions in their respective fields. The work presented here highlights the diversity of research performed across the entire breadth of abdominal and pelvic pain and presents advances in theory, experimental techniques, and methodology along with their application. New articles will be added to this collection as they are published.

University of Connecticut

School of Medicine, University of Colorado Anschutz Medical Campus

Frontiers in Pain Research

Abdominal and Pelvic Pain

Emerging Trends in Abdominal And Pelvic Pain

Editorial on the Research Topic <a href="https://www.frontiersin.org/researchtopic/47036/Emerging-trends-in-abdominal-and-pelvic-pain">Emerging trends in abdominal and pelvic pain</a>Abdominal pain is a cardinal symptom of many disorders of the lower urinary, gastrointestinal and reproductive tracts that requires effective therapeutic management. Pathological changes in one of the pelvic viscera may significantly affect the function/sensation/pain in an adjacent organ, and disrupt normal physiological coordination between the organs (<a href="#B1">1</a>). The development and persistence of chronic abdominal and pelvic pain is associated with long-lasting modifications in neural, endocrine, paracrine and immune mechanisms supporting daily physiological activity of the involved organs (<a href="#B2">2</a>). Existence of cross-innervation, functional cross-talk between pelvic organs, as well as involvement of peripheral and central sensitization in chronic pain makes it difficult to identify the original source of pain in the clinic (<a href="#B3">3</a>). Extensive research has been devoted to understanding the mechanisms of prevalent pain-related conditions, and is necessary to advance the development of novel therapeutic approaches to reduce the impact of abdominal pain on patients' daily lives (<a href="#B4">4</a>).Dysmenorrhea, a condition characterized by painful menstrual cramps in women, causes a significant decline in productivity and quality of life. Two recent studies have investigated the underlying mechanisms of dysmenorrhea, examining the role of intestinal gas and catastrophizing as potential contributing factors (<a href="https://doi.org/10.3389/fpain.2023.1202590">Zhang et al.</a>; <a href="https://doi.org/10.3389/fpain.2022.1057830">Redwood et al.</a>). Additional research methods, such as magnetic resonance imaging (MRI) for measuring colonic volume and specialized questionnaires for dysmenorrhea catastrophizing, have been implemented. Due to the adverse effects of opioid-based pain management, complementary and integrative methods like electrical neuromodulation have gained more acceptance among doctors and chronic pain patients. Studies of the mechanisms and signaling pathways of neuromodulation using pre-clinical animal models will help further advance the clinical efficacy of neuromodulation. To that end, <a href="https://doi.org/10.3389/fpain.2023.1202590">Zhang et al.</a> aimed to test a new anesthesia protocol for assessing visceral pain in mice and evaluating the effectiveness of invasive neuromodulation. Additionally, a perspective article by <a href="https://doi.org/10.3389/fpain.2022.1057830">Redwood et al.</a> evaluated aged-garlic extract (AGE) as a non-opioid prophylactic treatment for endometrial pain.The study titled “Menstrual Cycle Variation in MRI-Based Quantification of Intraluminal Gas in Women With and Without Dysmenorrhea” by <a href="https://doi.org/10.3389/fpain.2022.720141">Oh et al.</a> explored the potential contribution of intraluminal gas to dysmenorrheal symptoms. Using MRI, the authors measured colonic gas volumes in women with and without dysmenorrhea. Common symptoms during the perimenstrual period included abdominal pain, bloating, and flatulence. The findings revealed that menstrual cycle variations did not directly influence gas accumulation, as there were no significant differences in intraluminal gas volume between different phases of the menstrual cycle. Additionally, women with dysmenorrhea had less intraluminal gas during menstruation compared to pain-free participants. The obtained results challenge the hypothesis that increased intraluminal gas volume can contribute to abdominal symptoms during menses. Other factors like alterations in the intestinal microbiome or increased visceral sensitivity also may play a role in dysmenorrheal pain. These findings emphasize the need for further investigation into the complex mechanisms of abdominal symptoms during menstruation.The manuscript titled “Dysmenorrhea Catastrophizing and Functional Impairment in Female Pelvic Pain” explored the relationship between dysmenorrhea catastrophizing and pain interference in women with chronic pelvic pain (CPP) (<a href="https://doi.org/10.3389/fpain.2022.1053026">Li et al.</a>). The study involved 104 women with CPP who completed several questionnaires to assess dysmenorrhea catastrophizing, pain interference, and other related factors. The results revealed a significant association between dysmenorrhea catastrophizing, as well as dysmenorrhea interference and CPP-associated pain interference. The intensity of dysmenorrhea was identified as the most important predictor of catastrophizing. These findings highlight the importance of addressing dysmenorrhea catastrophizing to mitigate the functional impact of the condition, and to improve patients' quality of life. Effective management of dysmenorrhea symptoms to reduce pain intensity is crucial in alleviating interference caused by the condition (<a href="#B2">2</a>). Furthermore, targeting dysmenorrhea catastrophizing early on may prevent or reduce the severity of future CPP. This research fills a significant gap in understanding the role of dysmenorrhea-specific catastrophizing in pelvic pain interference, and emphasizes the consideration of cognitive and emotional responses in developing novel interventions to treat female pelvic pain.Managing visceral pain associated with irritable bowel syndrome (IBS) remains a clinical challenge. Objective biomarkers are crucial for early diagnosis and development of effective treatments. Colorectal distension (CRD) is one of the validated approaches to assess visceral sensitivity. However, measuring visceromotor responses (VMR) in response to CRD in awake rodents is hindered by movement artifacts, thereby, limiting its effectiveness for testing pain management strategies. To overcome these limitations, Zhang et al. tested an optimized anesthesia protocol for reliable VMR recordings during CRD in deeply anesthetized mice (<a href="https://doi.org/10.3389/fpain.2023.1202590">Zhang et al.</a>). The researchers employed a two-hour window with prolonged urethane infusion followed by surgical procedures under 2% isoflurane anesthesia. The surgical protocol included suturing wire electrodes to the abdominal muscles, placing a polyethylene catheter for urethane infusion, and inserting a plastic-film balloon intra-anally. The mice were then switched to the new urethane anesthesia protocol, involving an initial infusion and continuous low-dose infusion throughout the experiment. The study investigated the correlation between balloon depth on VMR to CRD, and observed depth-dependent responses. Additionally, VMR was assessed in mice with TNBS-induced transient colonic inflammation, revealing a previously unreported sex difference (<a href="https://doi.org/10.3389/fpain.2023.1202590">Zhang et al.</a>). The optimized anesthesia protocol provided a valuable tool with improved consistency of VMR recordings, allowing objective assessment of various neuromodulatory strategies to alleviate visceral and pelvic pain.Endometriosis, a debilitating CPP condition with limited treatment options, may benefit from aged-garlic extract (AGE), according to a recent study by <a href="https://doi.org/10.3389/fpain.2022.1057830">Redwood et al.</a>. AGE contains biologically active compounds with immunomodulatory and antioxidant properties, making it a potential prophylactic option for managing endometriosis-related pain. Endometriosis involves the growth of uterine tissue outside of the uterus, causing chronic pelvic pain and reduced quality of life. Current treatments offer temporary relief or have unwanted side effects. Garlic, known for its anti-inflammatory and antioxidant effects, has demonstrated some promise in reducing endometrial pain. Human trials previously showed a pain reduction through decreased oxidative stress and endometrial cell proliferation. Garlic extracts inhibit the proliferation of endometrial stromal cells, and reduce the expression of adhesion molecules. Therefore, garlic's antioxidant properties may counteract inflammation-induced oxidative stress. N-acetylcysteine (NAC), found in garlic, exhibits anti-proliferative effects on endometriomas and downregulates inflammatory pathways. AGE, in particular, contains concentrated immunomodulatory and antioxidant compounds that can benefit endometriosis management. Further research and clinical trials are necessary to validate its effectiveness in managing endometriosis and alleviating CPP.In summary, the diagnosis of pelvic pain and respective co-morbidities requires careful investigation of all pelvic organs that could potentially contribute to CCP. Clinical “endo-phenotyping” is a way to identify and group patients based on the trigger points, pain profiles and possible susceptibility to a certain treatment. The development and use of translational animal models, which closely mimic clinical conditions is beneficial to study the mechanisms of pelvic pain, and to identify potential biomarkers for CPP disorders. The latest technological advances including machine learning and artificial intelligence should be tested and incorporated in the development of automatic pain assessments for future use in the pain clinics and clinical research studies (<a href="#B5">5</a>). Overall, clinical investigations of patients and research on human subjects should be more closely integrated with animal models to improve the diagnosis and treatment of abdominal and pelvic pain, making integrative and interactive research a top priority in the CPP field.BF: Validation, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. AM: Validation, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Emerging trends in abdominal and pelvic pain

IntroductionVisceral motor responses (VMR) to graded colorectal distension (CRD) have been extensively implemented to assess the level of visceral pain in awake rodents, which are inevitably confounded by movement artifacts and cannot be conveniently implemented to assess invasive neuromodulation protocols for treating visceral pain. In this report, we present an optimized protocol with prolonged urethane infusion that enables robust and repeatable recordings of VMR to CRD in mice under deep anesthesia, providing a two-hour window to objectively assess the efficacy of visceral pain management strategies.</sec>MethodsDuring all surgical procedures, C57BL/6 mice of both sexes (8–12 weeks, 25–35 g) were anesthetized with 2% isoflurane inhalation. An abdominal incision was made to allow Teflon-coated stainless steel wire electrodes to be sutured to the oblique abdominal musculature. A thin polyethylene catheter (Φ 0.2 mm) was placed intraperitoneally and externalized from the abdominal incision for delivering the prolonged urethane infusion. A cylindric plastic-film balloon (Φ 8 mm x 15 mm when distended) was inserted intra-anally, and its depth into the colorectum was precisely controlled by measuring the distance between the end of the balloon and the anus. Subsequently, the mouse was switched from isoflurane anesthesia to the new urethane anesthesia protocol, which consisted of a bout of infusion (0.6 g urethane per kg weight, g/kg) administered intraperitoneally via the catheter and continuous low-dose infusion throughout the experiment at 0.15–0.23 g per kg weight per hour (g/kg/h).</sec>ResultsUsing this new anesthesia protocol, we systematically investigated the significant impact of balloon depth into the colorectum on evoked VMR, which showed a progressive reduction with increased balloon insertion depth from the rectal region into the distal colonic region. Intracolonic TNBS treatment induced enhanced VMR to CRD of the colonic region (>10 mm from the anus) only in male mice, whereas colonic VMR was not significantly altered by TNBS in female mice.</sec>DiscussionConducting VMR to CRD in anesthetized mice using the current protocol will enable future objective assessments of various invasive neuromodulatory strategies for alleviating visceral pain.</sec>

Introduction: Visceral motor responses (VMR) to graded colorectal distension (CRD) have been extensively implemented to assess the level of visceral pain in awake rodents, which are inevitably confounded by movement artifacts and cannot be conveniently implemented to assess invasive neuromodulation protocols for treating visceral pain. In this report, we present an optimized protocol with prolonged urethane infusion that enables robust and repeatable recordings of VMR to CRD in mice under deep anesthesia, providing a two-hour window to objectively assess the efficacy of visceral pain management strategies.Methods: During all surgical procedures, C57BL/6 mice of both sexes (8–12 weeks, 25–35 g) were anesthetized with 2% isoflurane inhalation. An abdominal incision was made to allow Teflon-coated stainless steel wire electrodes to be sutured to the oblique abdominal musculature. A thin polyethylene catheter (Φ 0.2 mm) was placed intraperitoneally and externalized from the abdominal incision for delivering the prolonged urethane infusion. A cylindric plastic-film balloon (Φ 8 mm x 15 mm when distended) was inserted intra-anally, and its depth into the colorectum was precisely controlled by measuring the distance between the end of the balloon and the anus. Subsequently, the mouse was switched from isoflurane anesthesia to the new urethane anesthesia protocol, which consisted of a bout of infusion (0.6 g urethane per kg weight, g/kg) administered intraperitoneally via the catheter and continuous low-dose infusion throughout the experiment at 0.15–0.23 g per kg weight per hour (g/kg/h).Results: Using this new anesthesia protocol, we systematically investigated the significant impact of balloon depth into the colorectum on evoked VMR, which showed a progressive reduction with increased balloon insertion depth from the rectal region into the distal colonic region. Intracolonic TNBS treatment induced enhanced VMR to CRD of the colonic region (&gt;10 mm from the anus) only in male mice, whereas colonic VMR was not significantly altered by TNBS in female mice.Discussion: Conducting VMR to CRD in anesthetized mice using the current protocol will enable future objective assessments of various invasive neuromodulatory strategies for alleviating visceral pain.

An anesthesia protocol for robust and repeatable measurement of behavioral visceromotor responses to colorectal distension in mice

BackgroundDysmenorrhea is suggested to increase the risk of chronic pain by enhancing central sensitization. However, little is known about whether emotional and cognitive responses induced by dysmenorrhea contribute to chronic pain interference. This study examined the association between catastrophizing specific to dysmenorrhea and both dysmenorrhea and chronic pelvic pain (CPP)-associated pain interference.</sec>MethodsWomen (N = 104) receiving care for CPP through a tertiary gynecological pain clinic between 2017 and 2020 were recruited. They completed the Pain Catastrophizing Scale, the Brief Pain Inventory–pain interference, and a separate questionnaire regarding dysmenorrhea symptoms and treatment preceding the development of CPP. Dysmenorrhea catastrophizing and interference measures were developed and tested for internal consistency and construct validity. Multiple linear regression models examined dysmenorrhea catastrophizing in association with dysmenorrhea interference and CPP-associated pain interference.</sec>ResultsDysmenorrhea catastrophizing and interference measures demonstrated excellent internal consistency (Cronbach's Alpha = 0.93 and 0.92 respectively) and evidence of construct validity (correlated with dysmenorrhea severity and treatment, Ps < 0.01). Dysmenorrhea catastrophizing was moderately correlated with pain catastrophizing (ρ = 0.30, P = 0.003), and was associated with greater dysmenorrhea interference (P < 0.001) and CPP-associated pain interference (P = 0.032) accounting for general pain catastrophizing and other outcome-specific confounders. Dysmenorrhea intensity was most predictive of dysmenorrhea catastrophizing.</sec>ConclusionAmong our clinical sample of women with CPP, dysmenorrhea catastrophizing was associated with greater dysmenorrhea interference and subsequent CPP-associated pain interference. More research is needed to determine whether reduction in dysmenorrhea catastrophizing leads to reduced pain interference associated with female pelvic pain.</sec>

Background: Dysmenorrhea is suggested to increase the risk of chronic pain by enhancing central sensitization. However, little is known about whether emotional and cognitive responses induced by dysmenorrhea contribute to chronic pain interference. This study examined the association between catastrophizing specific to dysmenorrhea and both dysmenorrhea and chronic pelvic pain (CPP)-associated pain interference.Methods: Women (N = 104) receiving care for CPP through a tertiary gynecological pain clinic between 2017 and 2020 were recruited. They completed the Pain Catastrophizing Scale, the Brief Pain Inventory–pain interference, and a separate questionnaire regarding dysmenorrhea symptoms and treatment preceding the development of CPP. Dysmenorrhea catastrophizing and interference measures were developed and tested for internal consistency and construct validity. Multiple linear regression models examined dysmenorrhea catastrophizing in association with dysmenorrhea interference and CPP-associated pain interference.Results: Dysmenorrhea catastrophizing and interference measures demonstrated excellent internal consistency (Cronbach's Alpha = 0.93 and 0.92 respectively) and evidence of construct validity (correlated with dysmenorrhea severity and treatment, Ps &lt; 0.01). Dysmenorrhea catastrophizing was moderately correlated with pain catastrophizing (ρ = 0.30, P = 0.003), and was associated with greater dysmenorrhea interference (P &lt; 0.001) and CPP-associated pain interference (P = 0.032) accounting for general pain catastrophizing and other outcome-specific confounders. Dysmenorrhea intensity was most predictive of dysmenorrhea catastrophizing.Conclusion: Among our clinical sample of women with CPP, dysmenorrhea catastrophizing was associated with greater dysmenorrhea interference and subsequent CPP-associated pain interference. More research is needed to determine whether reduction in dysmenorrhea catastrophizing leads to reduced pain interference associated with female pelvic pain.

Dysmenorrhea catastrophizing and functional impairment in female pelvic pain

Endometriosis is a complex and potentially debilitating condition that has major impact on quality of life. There is emerging evidence that biological compounds found in garlic (Allium sativum) may be effective for attenuating endometrial pain. Suggested mechanisms for efficacy include modulation of inflammation and potent antioxidant effects. Aged-garlic-extract (AGE) is a centuries old process describing ethanolic extracts of garlic bulbs for 12–20 months. The AGE formulation realised contains a complex array of stabilised biologics with significant immunomodulatory effects relevant to inflammatory conditions. This perspective article puts forward a hypothesis that AGE should be considered as a prophylactic to manage endometrial pain.

Endometriosis is a complex and potentially debilitating condition that has major impact on quality of life. There is emerging evidence that biological compounds found in garlic (Allium sativum) may be effective for attenuating endometrial pain. Suggested mechanisms for efficacy include modulation of inflammation and potent antioxidant effects. Aged-garlic-extract (AGE) is a centuries old process describing ethanolic extracts of garlic bulbs for 12–20 months. The AGE formulation realised contains a complex array of stabilised biologics with significant immunomodulatory effects relevant to inflammatory conditions. This perspective article puts forward a hypothesis that AGE should be considered as a prophylactic to manage endometrial pain.

Aged garlic extract as a potential prophylactic to reduce the progression of endometriosis and associated pain burden

Women frequently report increased bloating, flatulence, and pain during the perimenstrual period. However, it is unknown whether women have more intraluminal gas during menses. To evaluate whether pain-free women or women with dysmenorrhea have different amounts of intraluminal bowel gas during the menses, we utilized magnetic resonance imaging (MRI) to determine colonic gas volumes throughout the menstrual cycle. To avoid dietary influence, the participants were instructed to avoid gas-producing foods before their scheduled MRI. We verified the measurement repeatability across the reviewers and obtained an intraclass correlation coefficient of 0.92. There were no significant differences in intraluminal gas volume between menses and non-menses scans (p = 0.679). Even among the women with dysmenorrhea, there was no significant difference in the intraluminal gas volume between menses and non-menses (p = 0.753). During menstruation, the participants with dysmenorrhea had less intraluminal gas than participants without dysmenorrhea (p = 0.044). However, the correlation between the bowel gas volume and the pain symptoms were not significant (p > 0.05). Although increased bowel symptoms and bloating are reported in the women with dysmenorrhea during menses, our results do not support the hypothesis that increased intraluminal gas is a contributing factor. Although dietary treatment has been shown in other studies to improve menstrual pain, the mechanism responsible for abdominal symptoms requires further investigation. Our findings demonstrate that the intraluminal bowel gas volume measurements are feasible and are unaffected by menses under a controlled diet. The method described might prove helpful in future mechanistic studies in clarifying the role of intraluminal bowel gas in other conditions.

Women frequently report increased bloating, flatulence, and pain during the perimenstrual period. However, it is unknown whether women have more intraluminal gas during menses. To evaluate whether pain-free women or women with dysmenorrhea have different amounts of intraluminal bowel gas during the menses, we utilized magnetic resonance imaging (MRI) to determine colonic gas volumes throughout the menstrual cycle. To avoid dietary influence, the participants were instructed to avoid gas-producing foods before their scheduled MRI. We verified the measurement repeatability across the reviewers and obtained an intraclass correlation coefficient of 0.92. There were no significant differences in intraluminal gas volume between menses and non-menses scans (p = 0.679). Even among the women with dysmenorrhea, there was no significant difference in the intraluminal gas volume between menses and non-menses (p = 0.753). During menstruation, the participants with dysmenorrhea had less intraluminal gas than participants without dysmenorrhea (p = 0.044). However, the correlation between the bowel gas volume and the pain symptoms were not significant (p &gt; 0.05). Although increased bowel symptoms and bloating are reported in the women with dysmenorrhea during menses, our results do not support the hypothesis that increased intraluminal gas is a contributing factor. Although dietary treatment has been shown in other studies to improve menstrual pain, the mechanism responsible for abdominal symptoms requires further investigation. Our findings demonstrate that the intraluminal bowel gas volume measurements are feasible and are unaffected by menses under a controlled diet. The method described might prove helpful in future mechanistic studies in clarifying the role of intraluminal bowel gas in other conditions.