Accepted

Chronic pelvic pain (CPP) is a symptom that derives from a complex group of heterogeneous pathologies of the pelvic organs. The aim of this study was to review the available evidence on efficacy of neuromodulatory modalities including sacral neuromodulation, dorsal root ganglion stimulation, dorsal column neuromodulation, and pudendal nerve stimulation.

Diabetic neuropathic pain (DNP) is a diabetes complication experienced by many patients. Ventrolateral periaqueductal gray (vlPAG) neurons are essential mediators of the descending pain modulation system, yet the role of vlPAG astrocytes in DNP remains unclear. The present study applied a multidimensional approach to elucidate the role of these astrocytes in DNP. We verified the activation of astrocytes in different regions of the PAG in male DNP-model rats. We found that only astrocytes in the vlPAG exhibited increased growth. Furthermore, we described differences in vlPAG astrocyte activity at different time points during DNP progression. After the 14th day of modeling, vlPAG astrocytes exhibited obvious activation and morphological changes. Furthermore, activation of Gq-DREADDs in vlPAG astrocytes in naive male rats induced neuropathic pain-like symptoms and pain-related aversion, whereas activation of Gi-DREADDs in vlPAG astrocytes in male DNP-model rats alleviated sensations of pain and promoted pain-related preference behavior. Thus, bidirectional manipulation of vlPAG astrocytes revealed their potential to regulate pain. Surprisingly, activation of Gi-DREADDs in vlPAG astrocytes also mitigated anxiety-like behavior induced by DNP. Thus, our results provide direct support for the hypothesis that vlPAG astrocytes regulate diabetes-associated neuropathic pain and concomitant anxiety-like behavior.Many studies examined the association between the vlPAG and neuropathic pain. However, few studies have focused on the role of vlPAG astrocytes in DNP and DNP-related emotional changes. This work confirmed the role of vlPAG astrocytes in DNP by applying a more direct and robust approach. We utilized chemogenetics to bidirectionally manipulate the activity of vlPAG astrocytes and revealed that vlPAG astrocytes regulate DNP and pain-related behavior. In addition, we discovered that activation of Gi-DREADDs in vlPAG astrocytes alleviated anxiety-like behavior induced by DNP. Taken together, these findings provide new insights into DNP and concomitant anxiety-like behavior and supply new therapeutic targets for treating DNP.

Pain experience has a multidimensional nature. Assessment and treatment recommendations for pain conditions suggest clinicians use biopsychosocial approaches to treat pain and disability. The current pain research is overwhelmingly skewed towards the study of biological and psychological factors including interventions, whereas, cultural factors are often ignored.

We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals ( < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice ( < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia ( < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.

Painful HIV-associated neuropathy (HIV-SN) is a prevalent co-morbidity of HIV infection. Sensory phenotyping, using quantitative sensory testing (QST) could allow for improved stratification to guide personalized treatment. However, previous methods of QST interpretation have demonstrated limited association with self-reported pain measures. This study sought to identify differences in self-reported pain measures between composite QST-derived sensory phenotypes, and to examine any differences in participants reporting multi-site, multi-etiology chronic pain. In this cross-sectional observational study of participants with HIV (n=133), individuals were allocated to neuropathy and neuropathic pain groups through clinical assessment and nerve conduction testing. They completed symptom-based questionnaires and underwent standardized QST. Participants were assigned, by pre-determined algorithm, to a QST-derived sensory phenotype. Symptoms were compared between sensory phenotypes. Symptom characteristics and Neuropathic Pain Symptom Inventory scores differed between QST-derived sensory phenotypes: 'sensory loss' was associated with more paroxysmal and paraesthetic symptoms compared to 'thermal hyperalgesia' and 'healthy' phenotypes (p=0.023-0.001). Those with painful HIV-SN and additional chronic pain diagnoses were more frequently allocated to the 'mechanical hyperalgesia' phenotype compared to those with painful HIV-SN alone (p=0.006). This study describes heterogeneous sensory phenotypes in people living with HIV. Differences in self-reported pain outcomes between sensory phenotypes has the potential to guide future stratified trials and eventually more targeted therapy. PERSPECTIVE: This article presents quantitative sensory testing derived phenotypes, thought to reflect differing pathophysiological pain mechanisms and relates them to self-reported pain measures in people with HIV infection. This could help clinicians stratify patients to individualize analgesic interventions more effectively.

Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.

Substance use is the leading cause of preventable deaths in the U.S. Chronic pain is associated with risky substance use. Black individuals experience substantial disparities in pain and substance use outcomes and treatment. Maladaptive psychological reactions to chronic pain, such as pain catastrophizing and pain anxiety, can increase substance use among White individuals. However, no research to date has tested this among Black individuals. This study is the first to test the relationships between pain catastrophizing, pain anxiety, and substance use among Black individuals with chronic pain who use opioid medications.