mMCP7, a Mouse Ortholog of δ Tryptase, Mediates Pelvic Tactile Allodynia in a Model of Chronic Pelvic Pain

Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is a condition that affects a large number of men and has unknown etiology. We have previously demonstrated the presence of elevated levels of mast cell tryptase in expressed prostatic secretions (EPS) of CP/CPPS patients. In a murine model of CP/CPPS, we showed tryptase and its cognate receptor PAR2 as critical to the development of pelvic pain and lower urinary tract symptoms. Here, we extend these observations to demonstrate that an isoform of tryptase called delta (δ)-tryptase, is elevated in the EPS of patients with CP/CPPS and is correlated with pelvic pain symptoms. Using an Escherichia coli (CP1) -induced murine model of CP/CPPS, we demonstrated a differential response in C57BL/6J and NOD/ShiLtJ mice, with C57BL6/J mice being resistant to an increase in pelvic tactile allodynia, despite having equivalent levels of activated mast cells in the prostate. Activated tryptase+ve mast cells were observed to be in closer apposition to PGP9.5+ve nerve fibers in the prostate stroma of NOD/ShiLtJ in comparison to C57BL/6J mice. The mouse ortholog of δ-tryptase, mouse mast cell protease 7 (mMCP7) has been reported to be unexpressed in C57BL/6J mice. We confirmed the absence of mMCP7 in the prostates of C57BL/6J and its presence in NOD/ShiLtJ mice. To evaluate a role for mMCP7 in the differential allodynia responses, we performed direct intra-urethral instillations of mMCP7 and the beta (β)-tryptase isoform ortholog, mMCP6 in the CP1-infection model. mMCP7, but not mMCP6 was able to induce an acute pelvic allodynia response in C57BL/6J mice. In-vitro studies with mMCP7 on cultured mast cells as well as dissociated primary neurons demonstrated the ability to induce differential activation of pain and inflammation associated molecules compared to mMCP6. We conclude that mMCP7, and possibility its human ortholog δ-tryptase, may play an important role in mediating the development of pelvic tactile allodynia in the mouse model of pelvic pain and in patients with CP/CPPS.

Chronic Pelvic Pain and Sexual Dysfunction Among Females and Males Receiving Treatment for Opioid Use Disorder

Introduction: Chronic pain brings complexity to opioid use disorder (OUD). Psychosocial and neurobiological risks for Chronic Pelvic Pain (CPP) and OUD overlap. The primary objective of this exploratory study is to compare sex-specific prevalence of CPP and sexual dysfunction between individuals receiving buprenorphine for OUD and a comparison group receiving treatment for other chronic medical conditions (CMC).Methods: Participants from an OUD treatment (n = 154) and primary care clinic (n = 109) completed a survey between July 2019 and February 2020 assessing reproductive and sexual health. Sex-stratified CPP and pain interference measures were adapted from the Brief Pain Inventory for females, and for males, the Brief Male Sexual Function Inventory and NIH Chronic Prostatitis Symptom Index. The Male and Female Sexual Function Index assessed sexual dysfunction. Prevalence of CPP and sexual dysfunction between groups were compared using Pearson χ2 and Fisher's Exact tests.Results: Participants were 54.4% female and 75.0% Black with almost half having a psychiatric diagnosis. Among OUD females, the highest pain severity reported was for menstrual-related pain, and for OUD males, testicular pain. CPP most interfered with mood in OUD females vs. sleep and enjoyment of life in OUD males. There were no differences in prevalence for global sexual dysfunction with 91.6% of females and 84.2% of males screening positive across groups.Discussion/Implications: CPP and sexual dysfunction are important components of wellness and may play a role in OUD recovery trajectories. The value of addressing CPP and sexual dysfunction in tailored comprehensive, sex-informed OUD treatment approaches should be further investigated.

Factors Associated With Clinical Responses to Spinal Manipulation in Patients With Non-specific Thoracic Back Pain: A Prospective Cohort Study

Introduction: The management of musculoskeletal disorders is complex and requires a multidisciplinary approach. Manual therapies, such as spinal manipulative therapy (SMT), are often recommended as an adjunct treatment and appear to have demonstrable effects on pain and short-term disability in several spinal conditions. However, no definitive mechanism that can explain these effects has been identified. Identifying relevant prognostic factors is therefore recommended for people with back pain.Objective: The main purpose of this study was to identify short-term candidate prognostic factors for clinically significant responses in pain, disability and global perceived change (GPC) following a spinal manipulation treatment in patients with non-specific thoracic back pain.Methods: Patients seeking care for thoracic spine pain were invited to participate in the study. Pain levels were recorded at baseline, post-intervention, and 1 week after a single session of SMT. Disability levels were collected at baseline and at 1-week follow-up. GPC was collected post-intervention and at 1-week follow-up. Biomechanical parameters of SMT, expectations for improvement in pain and disability, kinesiophobia, anxiety levels as well as perceived comfort of spinal manipulative therapy were assessed.Analysis: Differences in baseline characteristics were compared between patients categorized as responders or non-responders based on their pain level, disability level, and GPC at each measurement time point. Binary logistic regression was calculated if the statistical significance level of group comparisons (responder vs. non-responders) was equal to, or <0.2 for candidate prognostic factors.Results: 107 patients (62 females and 45 males) were recruited. Mean peak force averaged 450.8 N with a mean thrust duration of 134.9 ms. Post-intervention, comfort was associated with pain responder status (p < 0.05) and GPC responder status (p < 0.05), while expectation of disability improvement was associated with GPC responder status (p < 0.05). At follow-up, comfort and expectation of pain improvement were associated with responder GPC status (p < 0.05). No association was found between responder pain, disability or GPC status and biomechanical parameters of SMT at any time point.Discussion: No specific dosage of SMT was associated with short-term clinical responses to treatment. However, expectations of improvement and patient comfort during SMT were associated with a positive response to treatment.

When Less Is More: Investigating Factors Influencing the Distraction Effect of Virtual Reality From Pain

Virtual reality (VR) is a powerful method of redirecting attention away from pain. Yet, little is known about which factors modulate the size of this distraction effect. The aim of this study was to investigate the role of cognitive load and inter-individual differences in the cognitive and affective domain on heat pain thresholds during a VR game. Ninety healthy participants (mean age ± SD: 23.46 ± 3.28; 50% identified as male and 50% as female) played a low and high load version of a VR game while heat pain thresholds and heart rate were recorded. The effects of cognitive load were assessed by computing the difference in pain thresholds between the high and low load condition for each participant. In addition, we computed the difference in heart rate variability (HRV) measures between both conditions to explore whether these would be correlated with the difference in heat pain thresholds. Prior to the VR session, participants completed questionnaires about their emotional distress, pain-related cognitions, and different executive functioning tasks. Contrary to our expectations, not all participants benefitted from a higher load in terms of distraction from pain. Logistic regression analysis revealed that participants who reported more emotional distress were more likely to exhibit higher pain thresholds in the low relative to the high load condition. Accordingly, these participants tended to show marginally higher HRV in the low compared to the high load condition. Our study demonstrates that the potential benefits of an increased cognitive load in VR on pain sensitivity depends on individual differences in affective state.

Small Fiber Polyneuropathy May Be a Nexus Between Autonomic Nervous System Dysregulation and Pain in Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly heterogeneous chronic and debilitating condition which effects millions of women and men in the United States. While primarily defined by urinary symptoms and pain perceived to be emanating from the bladder, IC/BPS patients frequently have co-occurring conditions and symptoms, many of which affect diverse body systems related to autonomic nervous system function. The impact on the autonomic system appears to stem from increased sympathetic innervation of the urinary tract, along with increased systemic sympathetic tone and decreased parasympathetic tone. Concurrent with these findings is evidence for destruction of peripheral sympathetic innervation to the sweat glands which may relate to small fiber polyneuropathy. It is unknown to what degree the wider alterations in autonomic function are also related to destruction/alterations in the small fibers carrying autonomic innervation. This potential nexus is an important point of investigation to better understand the unclarified pathophysiology of interstitial cystitis/bladder pain syndrome, the numerous co-occurring symptoms and syndromes, and for the identification of novel targeted therapeutic strategies.

Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome

Background and Aims: Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase (COMT) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining COMT effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs.Methods: Participants with IBS (N = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. COMT rs4680, gene-set, and genome-wide suggestive (p < 10−5) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined.Results: Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), −89.4 (42.3); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, −0.15; p = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation.Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction.Clinical Trial Registration:ClinicalTrials.gov, Identifier: NCT0280224.

The Potential Clinical Utility of Pressure-Based vs. Heat-Based Paradigms to Measure Conditioned Pain Modulation in Healthy Individuals and Those With Chronic Pain

Conditioned pain modulation (CPM) is a physiological measure thought to reflect an individual's endogenous pain modulation system. CPM varies across individuals and provides insight into chronic pain pathophysiology. There is growing evidence that CPM may help predict individual pain treatment outcome. However, paradigm variabilities and practical issues have impeded widespread clinical adoption of CPM assessment. This study aimed to compare two CPM paradigms in people with chronic pain and healthy individuals. A total of 30 individuals (12 chronic pain, 18 healthy) underwent two CPM paradigms. The heat CPM paradigm acquired pain intensity ratings evoked by a test stimulus (TS) applied before and during the conditioning stimulus (CS). The pressure CPM paradigm acquired continuous pain intensity ratings of a gradually increasing TS, before and during CS. Pain intensity was rated from 0 (no pain) to 100 (worst pain imaginable); Pain50 is the stimulus level for a response rated 50. Heat and pressure CPM were calculated as a change in TS pain intensity ratings at Pain50, where negative CPM scores indicate pain inhibition. We also determined CPM in the pressure paradigm as change in pressure pain detection threshold (PDT). We found that in healthy individuals the CPM effect was significantly more inhibitory using the pressure paradigm than the heat paradigm. The pressure CPM effect was also significantly more inhibitory when based on changes at Pain50 than at PDT. However, in individuals with chronic pain there was no significant difference in pressure CPM compared to heat or PDT CPM. There was no significant correlation between clinical pain measures (painDETECT and Brief Pain Inventory) and paradigm type (heat vs. pressure), although heat-based CPM and painDETECT scores showed a trend. Importantly, the pressure paradigm could be administered in less time than the heat paradigm. Thus, our study indicates that in healthy individuals, interpretation of CPM findings should consider potential modality-dependent effects. However, in individuals with chronic pain, either heat or pressure paradigms can similarly be used to assess CPM. Given the practical advantages of the pressure paradigm (e.g., short test time, ease of use), we propose this approach to be well-suited for clinical adoption.

Tactile Detection in Fibromyalgia: A Systematic Review and a Meta-Analysis

Fibromyalgia is a chronic pain syndrome characterized by sensorimotor deficits and distortions of body representation, that could both be caused by alterations in sensory processing. Several studies suggest a hypersensitivity to various sensory stimulations in fibromyalgia but results on detection of both noxious and non-noxious tactile stimulation, which are particularly relevant for body representation and motor control, remain conflicting. Therefore, the aim of this study is to systematically review and quantify the detection thresholds to noxious and non-noxious tactile stimuli in individuals with fibromyalgia compared to pain-free controls. A systematic review and a meta-analysis were performed in the MEDLINE, EMBASE, CINAHL, Cochrane, PsycInfo and Web of Science databases using keywords related to fibromyalgia, tactile pain detection threshold, tactile detection threshold and quantitative sensory testing. Nineteen studies were included in the review, with 12 in the meta-analysis. Despite the heterogeneity of the results, the data from both the review and from the meta-analysis suggest a trend toward hyperalgesia and no difference of sensitivity to non-noxious tactile stimuli in participants with fibromyalgia compared to healthy controls. This contradicts the hypothesis of a general increase in responsiveness of the central nervous system to noxious and non-noxious stimulations in fibromyalgia. This study shows no alteration of the sensitivity to non-noxious tactile stimulation in fibromyalgia, suggesting that an altered unimodal processing is not sufficient to explain symptoms such as sensorimotor impairments and body representation distortions. Future research should investigate whether alterations in multisensory integration could contribute to these symptoms.

The Influence of Examiner Gender on Responses to Tonic Heat Pain Assessments: A Preliminary Investigation

Background: The influence of examiner gender on pain reporting has been previously explored in both research and clinical settings. However, previous investigations have been limited, with the majority of studies employing single, static assessments of pain (e.g., cold pressor test, verbal pain ratings). The impact of examiner gender on both static and dynamic heat-based pain assessments is currently unknown.Methods: Thirty eight participants (20 females aged 24.1 ± 4.44, and 18 males, aged 24.8 ± 4.54) completed two identical testing sessions, randomized to a male and female examiner in a cross-over design. Pain sensitivity was examined using heat pain thresholds, verbal pain ratings to tonic heat, computerized visual analog scale (CoVAS) rating to tonic heat, and participant-controlled temperature (PCT) heat pain assessments.Results: Female participants reported higher verbal pain to tonic heat with a female examiner compared to male participants, with similar trends for CoVAS responses to tonic heat. Conversely heat pain thresholds and PCT were not significantly influenced by experimenter gender.Conclusions: Overall, verbal ratings were the most impacted by examiner gender, with temperature-based methods such as PCT and pain thresholds showing little to no examiner gender effects. While the gender of the examiner may be an important consideration in the measurement of sex and gender differences in pain research, the choice of pain assessment method may be of similar consequence.