Yaseen Awad-Igbaria

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, persistent complication of cancer treatment, yet the mechanisms sustaining pain remain unclear. Mitochondrial dysfunction has been implicated in chronic pain, but its role in spinal cord dysfunction after chemotherapy, and whether it can be reversed, is unknown. Here, we show that paclitaxel-induced persistent mechanical allodynia was associated with spinal cord (L1-L6) mitochondrial dysfunction 18 days after the last injection, including reduced oxygen consumption and membrane potential (Ψm) in the non-phosphorylated state, ATP-linked respiration, maximal respiration, and electron transfer capacity. Paclitaxel also increased susceptibility to mitochondrial permeability transition pore (mPTP)-induction, lowering calcium retention capacity at 3, 8, and 13 days after the last injection. Acute ex-vivo paclitaxel exposure had a similar effect, and cyclosporin A, an mPTP blocker, significantly reversed it. Consistent with a causal role for mitochondrial impairment, hyperbaric oxygen therapy (HBOT), initiated after allodynia developed, improved oxygen consumption and Ψm and progressively enhanced mechanical thresholds. Likewise, intrathecal delivery of healthy mitochondria to the spinal cord attenuated established allodynia in paclitaxel-treated rats and reduced mechanical and thermal hypersensitivity in other pain models, sciatic nerve crush and capsaicin. These findings identify persistent spinal mitochondrial dysfunction and increased mPTP susceptibility as features of CIPN and support mitochondrial protection as a therapeutic strategy for CIPN and other pain conditions.

Psychological distress and chronic stress were suggested to contribute to the pathophysiology of idiopathic pain conditions such as provoked vulvodynia (PV). The comorbidity of PV and mood disorder is quite common. Thus, vulvar pain can trigger anxiety, and mood disruption, whereas elevated anxiety and mood disruption play a critical role in pain maintenance. Yet, whether chronic stress can facilitate the development of chronic vulvar pain remains unclear. Here, we aimed to assess the effects of chronic stress on anxiety, depression-like behaviors, and the development of chronic vulvar pain after vulvar inflammation, which combines acute inflammation with chronic unpredictable stress (CUS) in female rats. Current result indicates that CUS leads to a reduction in vulvar mechanical thresholds and an increase in anxiety-like behavior, including reduced entries and time spent in the open arms of the EPM, reduced time in the center, increased distance moved in the OF, and reduced sucrose intake compared to the non-CUS group. Blood corticosterone levels and gene expression related to neuronal activation (cFOS) and GABA-synthesis (GAD67) were significantly increased in the amygdala and PAG in the CUS group compared to the non-CUS group. Following vulvar injection (saline/zymosan), there was a significant reduction in vulvar mechanical threshold in all groups: non-CUS/Saline, non-CUS/Zymosan, CUS/Saline, and CUS/Zymosan. However, mechanical thresholds returned to baseline in all groups except the CUS/Zymosan group, which exhibited prolonged vulvar hypersensitivity with no sign of recovery. Long-term behavioral assessments revealed reduced open-arm entries, altered locomotion, and decreased sucrose intake of the CUS groups compared to non-CUS groups. In conclusion, chronic stress enhances vulnerability to chronic vulvar pain following acute inflammation, alongside persistent anxiety and depression-like behaviors. These findings support a biopsychosocial model of PV, emphasizing the interplay between stress and inflammation in vulvar pain chronification.

Mitochondrial dysfunction was reported as a potential factor that contributes to the development of migraine and peripheral hypersensitivity. The recent ac

There is a growing interest in ToM performance among individuals with psychiatric disorders. However, the difference and the performance level between different diagnoses are unclear. Here, we compared the ToM abilities of schizophrenia (SZ), schizoaffective (SZaff), and borderline personality individuals (BPD) with healthy individuals. Individuals with SZ (n = 44), SZaff (n = 11), BPD (n = 11), and healthy individuals (n = 18) were recruited from Mazor Mental Health Center. All groups underwent the Reading Mind in the Eyes (RME) and the Faux Pas recognition test (FB) to assess TOM ability and completed empathy and autism questionnaires. The current results show that the three diagnostic groups performed worse in the RME and FB test compared to healthy individuals. However, women with BPD performed significantly better in ToM tasks than women with SZ and SZaff. Individuals with schizophrenia and BPD scored higher on the autism spectrum questionnaire, while all the diagnostic groups scored lower on the empathy quotient scale than healthy individuals. Finally, a positive correlation was found between ToM ability and empathy. Strikingly, our findings challenge the ability to use ToM as a differential clinical diagnostic tool, especially among men, and strengthen the correlation between decreased empathy and impaired ToM.

Provoked vulvodynia (PV) is the leading cause of vulvar pain and dyspareunia. The etiology of PV is multifactorial and remains poorly understood. PV is associated with a history of repeated vulvar inflammation and is often accompanied by sensory neuromodulation as a result of activation of the metabotropic glutamate receptor 5 (mGluR5) in the sensory nerve terminals. Therefore, this study aims to examine the role of glutamate-mGluR5 signaling during the initial inflammatory phase in chronic vulvar pain development in an animal model of PV.Thermal and mechanical vulvar sensitivity was assessed for three weeks following zymosan vulvar challenges. Anxiety-like behavior and locomotor activity were assessed at the end of the experiment. To investigate the role of glutamate mGluR5, the MTEP (mGluR5 antagonist) was injected into the vulva during vulvar inflammation. On the other hand, glutamate or CHPG (mGluR5 agonist) were injected in order to examine the effects of mGluR5 activation. RT-PCR was performed to assess changes in the transcription of genes related to neuroinflammation, neuromodulation, and neuroplasticity in the spinal cord (L6-S3). Zymosan-induced inflammation resulted in a significant thermal and mechanical vulvar hypersensitivity that persisted for over a month after the zymosan injection. However, local treatment with MTEP enhanced the vulvar mechanical and thermal hypersensitivity. On the other hand, activation of the mGluR5 via injection of glutamate or CHPG into the vulva leads to long-lasting vulvar mechanical and thermal hypersensitivity. The activation of the glutamate pathway was found to be accompanied by an increase in the transcription level of genes related to neuroinflammation and neuroplasticity in the sacral spine region. The present findings indicate that vulvar hypersensitivity is mediated by mGluR5 activation during inflammation. Hence, modulation of the mGluR5 pathway during the critical period of inflammation contributes to preventing chronic vulvar pain development. Conversely, activation of the mGluR5 pathway leads to long-lasting mechanical and thermal hypersensitivity.

Provoked vulvodynia (PV) is characterized by localized chronic vulvar pain. It is associated with a history of recurrent inflammation, mast cell (MC) accumulation and neuronal sprouting in the vulva. However, the mechanism of how vulvar-inflammation promotes neuronal sprouting and gene-expression adaptation in the spinal cord, leading to hypersensitivity and painful sensations, is unknown. Here, we found that vulvar tissue from women with PV (n = 8) is characterized by MC accumulation and neuronal sprouting compared to women without PV (n = 4). In addition, we observed these changes in an animal study of PV. Thus, we found that repeated vulvar zymosan-inflammation challenges lead to long-lasting mechanical and thermal vulvar hypersensitivity, which is mediated by MC accumulation, neuronal sprouting, overexpression of the pain channels (TRPV1 and TRPA1) in vulvar neurons, as well as a long-term increase of gene expression related to neuroplasticity, neuroinflammation and nerve growth factor (NGF) in the spinal cord/dorsal root ganglia (DRG) (L6–S3). However, regulation of the NGF pathway by stabilization of MC activity with ketotifen fumarate (KF) during vulvar inflammation attenuates the local increase of NGF and histamine, as well as the elevated transcription of pro-inflammatory cytokines and NGF pathway in the spinal cord. Additionally, KF treatment during inflammation modulates MC accumulation, neuronal hyperinnervation and overexpression of the TRPV1 and TRPA1 channels in the vulvar neurons, consequently preventing the development of vulvar pain. A thorough examination of the NGF pathway during inflammation revealed that blocking NGF activity by using an NGF-non-peptide-inhibitor (Ro08-2750) regulates the upregulation of genes related to neuroplasticity and the NGF pathway in the spinal cord, as well as modulating neuronal sprouting and overexpression of the pain channels, resulting in a reduced level of vulvar hypersensitivity. On the other hand, stimulation of the NGF pathway in the vulvar promotes neuronal sprouting, overexpression of pain channels and increase of gene expression related to neuroplasticity, neuroinflammation and NGF in the spinal cord, resulting in long-lasting vulvar hypersensitivity. In conclusion, our findings suggest that vulvar allodynia induced by inflammation is mediated by MC accumulation, neuronal sprouting and neuromodulation in the vulvar. Additionally, chronic vulvar pain may involve a long-term adaptation in gene expression in the spinal cord, which probably plays a critical role in central sensitization and pain maintenance. Strikingly, regulating the NGF pathway during the critical period of inflammation prevents vulvar pain development via modulating the neuronal changes in the vestibule and spinal cord, suggesting a fundamental role for the NGF pathway in PV development.

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia’s pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as “vulvodynia”, “chronic vulvar pain”, “vulvodynia induction”, and “animal models of vulvodynia” to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults, characterized by primary and secondary injury. Primary injury is the immediate mechanical damage, while secondary injury results from delayed neuronal death, often linked to mitochondrial damage accumulation. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment for modulating secondary post-traumatic neuronal death. However, the specific molecular mechanism by which HBOT modulates secondary brain damage through mitochondrial protection remains unclear. Spatial learning, reference memory, and motor performance were measured in rats before and after Controlled Cortical Impact (CCI) injury. The HBOT (2.5 ATA) was performed 4 h following the CCI and twice daily (12 h intervals) for four consecutive days. Mitochondrial functions were assessed via high-resolution respirometry on day 5 following CCI. Moreover, IHC was performed at the end of the experiment to evaluate cortical apoptosis, neuronal survival, and glial activation. The current result indicates that HBOT exhibits a multi-level neuroprotective effect. Thus, we found that HBOT prevents cortical neuronal loss, reduces the apoptosis marker (cleaved-Caspase3), and modulates glial cell proliferation. Furthermore, HBO treatment prevents the reduction in mitochondrial respiration, including non-phosphorylation state, oxidative phosphorylation, and electron transfer capacity. Additionally, a superior motor and spatial learning performance level was observed in the CCI group treated with HBO compared to the CCI group. In conclusion, our findings demonstrate that HBOT during the critical period following the TBI improves cognitive and motor damage via regulating glial proliferation apoptosis and protecting mitochondrial function, consequently preventing cortex neuronal loss.