Clinical Review of Neuromusculoskeletal Complementary and Alternative Approaches for the Treatment of Chronic Pelvic Pain Syndrome.

Chronic pelvic pain syndrome (CPPS) is a functional pain disorder characterized by ongoing pain in the apparent absence of clinically identifiable causes. The prevalence of functional pain disorders demonstrates the importance of adequate management of ongoing symptomatology, but due to the uncertain etiology and myriad patient presentation phenotypes, reliable treatment options are difficult to implement. New interventions involving non-pharmacological approaches to pain management have been investigated across a spectrum of clinical and pre-clinical studies. Given that conservative care such as exercise, counseling, and musculoskeletal therapy is widely recommended as first-line treatment for CPPS, an updated review of these and related methodologies are needed. Familiarizing physicians and the public with the newest evidence for complementary and alternative medicine (CAM) and other conservative care treatments will assist with the promotion of evidence-based practices in a safe and reliable manner. This review aimed to summarize the current evidence and proposed mechanisms for non-pharmacological treatment specific to CAM and management of chronic pelvic pain centered on neuromusculoskeletal focused intervention such as acupuncture, auriculotherapy, manipulation, manual therapy, myofascial release, and phototherapy. The discussion suggests that reported improvements in pelvic pain or related symptomatology may be attributed to changes in the peripheral inflammasome and somatic origins of peripheral sensitization. Robustness of the included clinical studies is discussed throughout the review, and attention is paid to delineating inclusion criteria of formally diagnosed CPPS compared to general pelvic or abdominal pain. Overall, this review consolidates the current state of evidence regarding the utilization of non-traditional interventions using CAM techniques for the management of chronic pelvic pain and recommends a future direction for the field.

Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice.

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.

Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice.

ABSTRACT: Patients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms, and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS. Here, we provide further evidence that voluntary wheel running can attenuate increased perigenital mechanical sensitivity, bladder output, and mast cell degranulation in the bladder and prostate in male mice that underwent neonatal maternal separation (NMS). Sedentary male NMS mice had reduced serum corticosterone, which was not impacted by voluntary wheel running, although stress-related regulatory gene expression in the hypothalamus and hippocampus was significantly increased after exercise. Neurogenesis in the dentate gyrus of the hippocampus was diminished in sedentary NMS mice and significantly increased in both exercised naïve and NMS mice. Sucrose consumption increased in exercised naïve but not NMS mice, and anxiety behaviors measured on an elevated plus maze were increased after exercise. Together these data suggest that voluntary wheel running is sufficient to normalize many of the UCPPS-related outcomes resulting from NMS. Exercise also increased hippocampal neurogenesis and stress-related gene expression within the hypothalamic-pituitary-adrenal axis, further supporting exercise as a nonpharmacological intervention for attenuating outcomes related to ELS exposure.

Voluntary wheel running attenuates urinary bladder hypersensitivity and dysfunction following neonatal maternal separation in female mice.

AIMS: Patients with interstitial cystitis/painful bladder syndrome (IC/PBS) commonly suffer from widespread pain and mood disorder, which has been attributed to improper functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Voluntary exercise has been shown to improve HPA axis function, therefore we are determining whether voluntary wheel running can attenuate urological pain and dysfunction following neonatal maternal separation (NMS) in female mice. METHODS: Mice underwent NMS for 3 h/day from postnatal Day 1-21, were caged with free access to running wheels at 4 weeks of age, and assessed 4 weeks later for bladder sensitivity, micturition, reward behavior, mast cell degranulation, and HPA axis-related in vitro analysis. RESULTS: Increased bladder sensitivity, void frequency, and mast cell degranulation was observed in adult sedentary (-Sed) NMS mice, compared to naïve-Sed controls. Sucrose preference was increased in NMS-Sed mice and corticotropin-releasing factor receptor 1 (CRF1 ) and glucocorticoid receptor mRNA levels were significantly reduced in the hippocampus. Exercise normalized bladder sensitivity, micturition output, and increased brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of NMS mice. Mast cell degranulation was also normalized in NMS bladders following exercise. CONCLUSIONS: Voluntary exercise normalized behavioral outcomes resulting from NMS in female mice, increased hippocampal BDNF mRNA levels, and decreased mast cell degranulation in the bladder. Together these results provide novel insight into the efficacy of voluntary exercise to attenuate comorbid outcomes resulting from exposure to early life stress.

Differential Influence of Early Life and Adult Stress on Urogenital Sensitivity and Function in Male Mice.

Experiences of adverse childhood events have been associated with improper output of the hypothalamic-pituitary-adrenal (HPA) axis in adulthood, as well as development of comorbid functional pain disorders. Symptoms of chronic prostatitis/chronic pelvic pain syndrome frequently overlap with those of interstitial cystitis/painful bladder syndrome and symptom severity is often triggered by stress. The objective of this study was to investigate the influence early life stress and acute adult stress on (1) perigenital sensitivity, (2) micturition, (3) anhedonia, and (4) HPA axis regulation and output in male C56Bl/6 mice. Neonatal maternal separation (NMS) was performed for 3 h a day from postnatal day 1 to 21 and naïve pups remained unhandled during this time. As adults, male mice were tested for referred prostate sensitivity and micturition patterning prior to and 1 and 8 days after exposure to 1 h of water avoidance stress (WAS). Following testing, prostate and bladder tissues were used for mast cell and Western blot analysis and RT-PCR was performed on mRNA from hypothalamus, amygdala, and hippocampus. Serum corticosterone (CORT) was also measured by enzyme-linked immunosorbent assay (ELISA). A significant increase in perigenital sensitivity and micturition frequency was observed in NMS mice and these measures were exacerbated by WAS exposure. Exposure to NMS significantly increased mast cell degranulation in both the bladder and prostate. Mast cell degranulation was also increased in naïve prostate tissue following WAS exposure. Cytokine mRNA levels were influenced by both NMS and WAS exposure, though WAS had a larger impact on central gene expression. Protein levels of CRF1 were differentially regulated by NMS and WAS in the bladder and prostate and serum CORT levels were significantly diminished following stress exposure. Taken together, these data suggest that NMS results in neurogenic inflammation and hypersensitivity within the urogenital organs, coupled with diminished gene expression and output from the HPA axis. Future studies of NMS in male mice may provide a useful tool as a preclinical model of male chronic urological pain syndromes for investigating potential pharmacological and interventional therapies.

Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress.

Early adverse events have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. Despite high clinical relevance and reports of stress-related symptom exacerbation, animal models investigating the contribution of early life stress to female urological pain are lacking. We examined the impact of neonatal maternal separation (NMS) on bladder sensitivity and visceral neuroimmune status both prior-to, and following, water avoidance stress (WAS) in adult female mice. The visceromotor response to urinary bladder distension was increased at baseline and 8d post-WAS in NMS mice, while colorectal sensitivity was transiently increased 1d post-WAS only in naïve mice. Bladder micturition rate and output, but not fecal output, were also significantly increased following WAS in NMS mice. Changes in gene expression involved in regulating the stress response system were observed at baseline and following WAS in NMS mice, and WAS reduced serum corticosterone levels. Cytokine and growth factor mRNA levels in the bladder, and to a lesser extent in the colon, were significantly impacted by NMS and WAS. Peripheral mRNA levels of stress-responsive receptors were differentially influenced by early life and adult stress in bladder, but not colon, of naïve and NMS mice. Histological evidence of mast cell degranulation was increased in NMS bladder, while protein levels of protease activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) were increased by WAS. Together, this study provides new insight into mechanisms contributing to stress associated symptom onset or exacerbation in patients exposed to early life stress.

Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice.

Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD). VMR was also measured before and after treatment with intracolonic trinitrobenzene sulfonic acid (TNBS) or exposure to acute or chronic water avoidance stress (WAS). Myeloperoxidase (MPO) activity, proinflammatory gene and corticotropin-releasing factor (CRF) receptor expression were measured in distal colon. Baseline VMR was not affected by NMS, but undergoing CRD increased anxiety-like behaviors and mechanical hindpaw sensitivity of NMS mice. Treatment with TNBS dose-dependently decreased body weight and survival only in NMS mice. Following TNBS treatment, IL-6 and artemin mRNA levels were decreased in the distal colon of NMS mice, despite increased MPO activity. A single WAS exposure increased VMR during CRD in NMS mice and increased IL-6 mRNA and CRF2 protein levels in the distal colon of naïve mice, whereas CRF2 protein levels were heightened in NMS colon both at baseline and post-WAS exposure. Taken together, these results suggest that NMS in mice disrupts inflammatory- and stress-induced gene expression in the colon, potentially contributing towards an exaggerated response to specific stressors later in life.

Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a lifetime prevalence of 14% and is the most common urological diagnosis for men under the age of 50, yet it is the least understood and studied chronic pelvic pain disorder. A significant subset of patients with chronic pelvic pain report having experienced early life stress or abuse, which can markedly affect the functioning and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mast cell activation, which has been shown to be increased in both urine and expressed prostatic secretions of CP/CPPS patients, is partially regulated by downstream activation of the HPA axis. Neonatal maternal separation (NMS) has been used for over two decades to study the outcomes of early life stress in rodent models, including changes in the HPA axis and visceral sensitivity. Here we provide a detailed protocol for using NMS as a preclinical model of CP/CPPS in male C57BL/6 mice. We describe the methodology for performing NMS, assessing perigenital mechanical allodynia, and histological evidence of mast cell activation. We also provide evidence that early psychological stress can have long-lasting effects on the male urogenital system in mice.

Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice.

Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons. Serum corticosterone (CORT), mast cell degranulation, and corticotropin-releasing factor receptor 1 (CRF1) expression were measured as indicators of peripheral HPA axis activation. Colorectal and hind paw sensitivity were measured to determine cross-sensitization resulting from NVI. Adult NVI mice had significantly larger visceromotor response during VBD than naive mice. TRPA1 protein expression was significantly elevated in the vagina, and calcium transients evoked by mustard oil (TRPA1 ligand) or capsaicin (TRPV1 ligand) were significantly decreased in dorsal root ganglion from NVI mice, despite displaying increased depolarization-evoked calcium transients. Serum CORT, vaginal mast cell degranulation, and CRF1 protein expression were all significantly increased in NVI mice, as were colorectal and hind paw mechanical and thermal sensitivity. Neonatal treatment with a CRF1 antagonist, NBI 35965, immediately before zymosan administration largely attenuated many of the effects of NVI. These results suggest that NVI produces chronic hypersensitivity of the vagina, as well as of adjacent visceral and distant somatic structures, driven in part by increased HPA axis activation.

Stress and chronic pelvic pain.

Chronic pelvic pain is the number one reason that patients suffering from irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, vulvodynia, or chronic prostatitis/chronic pelvic pain syndrome seek medical attention. These syndromes generally have no associated pathology or identified underlying etiology, although dysfunction within the immune system, central nervous system, and peripheral nervous system has been identified. Due to the lack of pathology, chronic pelvic pain syndromes are often diagnosed by exclusion, and the high degree of comorbid symptomology among these and other functional pain disorders complicate identifying appropriate treatment strategies. Chronic stress exposure early in life has been shown to increase the likelihood of pelvic pain later in life, and acute stress exposure can induce or increase symptom severity. In this chapter, we describe the individual chronic pelvic pain syndromes and how stress influences the likelihood of diagnosis and the severity of symptoms experienced by patients.

Back pain and leg complaints that revealed non-small cell carcinoma: a case study.

OBJECTIVE: The purpose of this case study is to describe the clinical presentation of a patient with a chief complaint of low back and leg pain with no prior diagnosis of lung cancer. CLINICAL FEATURES: A 48-year-old man with a history of back pain presented to a chiropractic office with a complaint of low back and left leg pain. INTERVENTION AND OUTCOME: Abnormal examination and radiographic findings were discovered. The patient was immediately referred to the pulmonologist for co-management. Through the use of advanced imaging and biopsy, stage 4 lung cancer was diagnosed. CONCLUSION: Low back pain recurrence in an established patient should constitute a reevaluation of the problem. The cause cannot be assumed to be musculoskeletal in origin even though this may have been the case with the initial complaint. Metastatic disease should be considered with any type of recurrent low back pain.