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Bearing in mind that pain and major depressive disorder (MDD) often share biological pathways, this condition is classified as depression-pain syndrome. Mounting evidence suggests that oxidative stress is implicated in the pathophysiology of this syndrome. The development of effective pharmacological interventions for the depression-pain syndrome is of particular importance as clinical treatments for this comorbidity have shown limited efficacy. Therefore, the present study aimed to evaluate whether the 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (SePy) was able to reverse the depression-pain syndrome induced by intracerebroventricular (i.c.v) streptozotocin (STZ) in mice and the possible modulation of oxidative and nitrergic pathways in its effect. The treatment with SePy (1 and 10 mg/kg) administered intragastrically (i.g.) reversed the increased immobility time in the tail suspension test, decreased grooming time in the splash test, latency time to nociceptive response in the hot plate test, and the response frequency of Von Frey hair (VFH) stimulation induced by STZ (0.2 mg/4 μl/per mouse). Additionally, SePy (10 mg/kg, i.g.) reversed STZ-induced alterations in the levels of reactive oxygen species, nitric oxide, and lipid peroxidation and the superoxide dismutase and catalase activities in the prefrontal cortices (PFC) and hippocampi (HC) of mice. Treatment with SePy (10 mg/kg, i.g.) also reversed the STZ-induced increased expression of inducible nitric oxide synthase (iNOS) and glycogen synthase kinase 3 beta (GSK3β) in the PFC and HC. An additional molecular docking investigation found that SePy binds to the active site of iNOS and GSK3β. Altogether, these results indicate that the antidepressant-like effect of SePy is accompanied by decreased hyperalgesia and mechanical allodynia, which were associated with its antioxidant effect.
Learn More >The treatment of noncancer pain in the United States and globally is met with significant challenges, resulting in profound physical, emotional, and societal costs. Based on this need, numerous modalities have been proposed to manage chronic pain, including opioid and nonopioid interventions as well as surgical approaches. Thus, the future of pain management continues to be mired in evolving concepts and constant debates. Consequently, it is crucial to understand the past as we move towards the future. The evolution of lessons for better pain management at present and for the future starting from the 1990s to the present date are reviewed and emphasized with a focus on learning from the past for the future. This review summarizes the evolution of multiple modalities of treatments, including multidisciplinary programs, multimodal therapy, interventional techniques, opioid therapy, other conservative modalities, and surgical interventions. This review emphasizes the individual, patient-centered development of an effective pain treatment plan after proper evaluation to establish a diagnosis. It includes measurable outcomes that focus on improvements in the quality of life and activities of daily living, as well as improvement in pain and function and, most importantly, return to productive citizenship. It is crucial that the knowledge of best practices be advanced, along with emphasis on lessons learned in the past to provide best practices for better pain management.
Learn More >Protocol for a pragmatic randomized controlled trial (the Exercise guideline Promotion and Implementation in Chronic SCI [EPIC-SCI] Trial).
Learn More >Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model.
Learn More >Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used to treat colorectal cancer, but it induces peripheral neuropathy as a serious dose-limiting side effect. Recently, thrombomodulin alfa, a recombinant human soluble thrombomodulin, was reported to prevent oxaliplatin-induced peripheral neuropathy in a clinical phase 2 study. Here we conducted preclinical pharmacology studies. Rats were given oxaliplatin (6 mg/kg) intravenously to induce mechanical hyperalgesia associated with peripheral neuropathy. Single intravenous administration of thrombomodulin alfa (0.1, 0.3, 1 mg/kg) dose dependently prevented the development of oxaliplatin-induced mechanical hyperalgesia, with no sex difference in the efficacy. The preventative effect of thrombomodulin alfa on mechanical hyperalgesia was attenuated by antithrombin or carboxypeptidase inhibitor. In addition, carboxypeptidase B, a homolog of activated thrombin-activatable fibrinolysis inhibitor (TAFI) and human-derived activated protein C, prevented mechanical hyperalgesia, whereas antithrombin or other anti-coagulants did not. These results suggest that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy through the activation of TAFI and protein C by modulating thrombin activity, but the effects are independent of an anticoagulant effect. On the other hand, thrombomodulin alfa did not affect the anti-cancer activity of oxaliplatin on human colon cancer cell lines or mice transplanted with HCT116 cells. These results indicate that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor activity of oxaliplatin. Therefore, thrombomodulin alfa is a promising drug to prevent the symptoms of oxaliplatin-induced peripheral neuropathy.
Learn More >The Medial Prefrontal Cortex as a Central Hub for Mental Comorbidities Associated with Chronic Pain.
Chronic pain patients frequently develop and suffer from mental comorbidities such as depressive mood, impaired cognition, and other significant constraints of daily life, which can only insufficiently be overcome by medication. The emotional and cognitive components of pain are processed by the medial prefrontal cortex, which comprises the anterior cingulate cortex, the prelimbic, and the infralimbic cortex. All three subregions are significantly affected by chronic pain: magnetic resonance imaging has revealed gray matter loss in all these areas in chronic pain conditions. While the anterior cingulate cortex appears hyperactive, prelimbic, and infralimbic regions show reduced activity. The medial prefrontal cortex receives ascending, nociceptive input, but also exerts important top-down control of pain sensation: its projections are the main cortical input of the periaqueductal gray, which is part of the descending inhibitory pain control system at the spinal level. A multitude of neurotransmitter systems contributes to the fine-tuning of the local circuitry, of which cholinergic and GABAergic signaling are particularly emerging as relevant components of affective pain processing within the prefrontal cortex. Accordingly, factors such as distraction, positive mood, and anticipation of pain relief such as placebo can ameliorate pain by affecting mPFC function, making this cortical area a promising target region for medical as well as psychosocial interventions for pain therapy.
Learn More >Acceptance and commitment therapy (ACT) has accrued a growing evidence-base for a wide variety of psychological difficulties. Given that ACT promotes broad and flexible repertoires of behaviour as well as neutralizing the ubiquitous psychological processes theorized to be responsible for much human suffering, such an approach may hold promise. The use of ACT-informed parenting interventions offers another alternative to solely behavioural approaches but it remains relatively understudied and in need of further exploration.
Learn More >Tonic spinal cord stimulation (SCS) has been used as a treatment for chronic neuropathic pain ever since its discovery late 1960's. Despite its clinical successes in a subset of chronic neuropathic pain syndromes, several limitations such as insufficient pain relief and uncomfortable paresthesias, have led to the development of new targets, the dorsal root ganglion, and new stimulation waveforms, such as burst and high frequency. The aim of this review is to provide a brief overview of the main mechanisms behind the mode of action of the different SCS paradigms. Tonic SCS mainly acts via a segmental spinal mechanism where it induces GABA-release from inhibitory interneurons in the spinal dorsal horn. Tonic SCS concurrently initiates neuropathic pain modulation through a supraspinal-spinal feedback loop and serotonergic descending fibers. Mechanisms of stimulation of the DRG as well as those related to new SCS paradigms are now under investigation, where it seems that burst SCS not only stimulates sensory, discriminative aspects of pain (like Tonic-SCS) but also emotional, affective and motivational aspects of pain. Initial long-term study results on closed-loop SCS systems hold promise for improvement of future SCS treatment.
Learn More >Approximately 35%-50% of people with haemophilia (PWH) report living with chronic musculoskeletal pain. Although exercise based rehabilitation is effective for pain in other arthritises, there are no published guidelines for management of chronic pain in PWH. This review aims to evaluate and appraise the current evidence of effectiveness of physiotherapy interventions on (a) pain intensity, (b) quality of life (QoL) and (c) function in PWH.
Learn More >Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the pre-existing pathological pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain is controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of trigeminal neuropathic pain. Capsaicin has long been used as an analgesic to treat chronic pain conditions. Topical capsaicin is a FDA-approved treatment for neuropathic pain. However, the mechanisms underlying capsaicin-induced analgesia have been enigmatic for centuries. Despite evidence for clinical analgesia, data supporting the analgesic effects of capsaicin on neuropathic pain in preclinical model is rare. We found that a single focal injection of capsaicin to facial skin robustly attenuated trigeminal neuropathic pain in mice for longer than two weeks, which is mediated by localized ablation of TRPV1+ terminals in the skin. These results suggest that TRPV1+ afferents contribute to the maintenance of TNP and that capsaicin injection could be a safe and effective treatment for TNP.
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